Hope lies in dreams

Chapter 1: an ugly place

Brady Huggett: Chapter 1: an ugly place

Stan Crooke told me something once that I've never forgotten. This was back in 2015, when I was interviewing him in a Hilton hotel, in San Francisco near Union Square. Stan was 69 years old then, gray hair, maybe a little less than 6 feet tall. His voice, then and now, has a pinched tone to it at times, which he attributes to allergies and “an Indiana nasal twang.” He has a damaged ring finger on his right hand, the middle joint dislocated so many times playing basketball in his youth that the top half juts at an angle. He is forthright, sometimes sharp in tone, but he also laughs easily, and he can be very funny. He was in San Francisco to attend a biotech conference, as CEO of a company he founded in 1989.

Stan grew up destitute, in downtown Indianapolis in the ’40s and ’50s. An “ugly place,” as he called it, and as we talked I asked him how he managed to overcome that neighborhood and his hard upbringing and get himself to college, and then beyond.

Stan Crooke: So, mostly desperation, and anger. And just the whole idea of having no hope, no aspirations. I mean, poverty is not the loss of money — though of course that’s sad. It’s the loss of dreams, it’s the absence of hope. That’s poverty.

Brady Huggett: The absence of a real future.

Stan Crooke: Beyond that. At least from my perspective, it’s the inability to even dream, you know?

Brady Huggett: His comment stuck with me because I immediately knew it was a truth. Poverty is ruinous not because it prevents buying new clothes, or having enough to eat. Those things are damaging in their own way, but poverty is ruinous because it stifles the ability to dream, as he said. It limits one’s vision of the future, and keeps it small.

And so it is remarkable to me that Stan Crooke, who came from a background unique among scientific researchers, certainly unique in the biotechnology industry, was able to not only dream of a better life for himself, but to actually achieve it. And it is even more remarkable that in doing so, he became a champion for a brand new drug modality, keeping the technology afloat through decades of laboratory and marketplace failures. Until, finally, his company won approval for a drug that would provide hope and dreams for thousands of terminally ill kids.

This is the story of Stan Crooke’s life. It’s the story of the biotech company he founded, and it’s the story of a powerful drug discovery technology called antisense. Together, they cracked the degenerative disease known as spinal muscular atrophy, which had been stealing the lives of children, and traumatizing families since it was first discovered more than a century ago.

From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

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Brady Huggett: Stan Crooke was born in Indianapolis in 1945. He’d always been told his birthday was March 28, but when he went in search of a birth certificate as an adult, the one he found in the Marion County records had been filed years after he was born, and it listed March 26. So he’s not entirely sure of the day, or possibly even the year, but either way, he thinks his life began near the end of March in 1945.

His family history is similarly cloudy, but he heard that his mother’s lineage — the Carley name — runs mostly through Indianapolis, except for a period of time when the family moved to Kansas only to be turned back by the Dust Bowl. What he does know is that his mother grew up during the Great Depression in a struggling family. And he knows that she gave birth to him when she was around 15 years old, though to this day he does not know who his father is or where, exactly, he was born.

After his birth, his mother promptly left him with his grandmother and great grandmother, and he spent the first year of his life with them, squatting in a tar paper shack on the edge of the grounds of the Republic Creosoting Company in Indianapolis, alongside a railway line on the Southwest side of the city. Then they moved about 4 miles east, to 363 Terrace Avenue, into a tiny shotgun house, just over 500 square feet. Their blue collar neighborhood was less than two miles south of the heart of downtown, where tourists would come to take pictures of Indy’s iconic Soldiers and Sailors monument, but it must have felt much farther. The homes were valued at as little as $1,000 and could be rented for $20 or $30 a month. The men here were truck drivers, machinists, dock hands, bartenders, and the women mostly did not work outside the home. I asked Nelson Price, an Indianapolis historian, about the area at that time.

Nelson Price: That would have been the South Side. And it would have been a very hardscrabble area. A lot of Appalachian white families, not ethnically diverse, there would have been very few African Americans living there. There would have been no ethnic presence — the city at that point as a whole didn’t have an immigrant population. We weren’t a sea port, we were primarily a German heritage city. Those immigrants had come many generations before, so the city was pretty much either white or Black. And that would have been a very tough neighborhood to grow up in. Hardscrabble, working-class neighborhood. With the expectation that those kids are probably not going to grow up and go to college.

Brady Huggett: Their new place had a living room that was maybe 8 feet by 12 feet. The house had a toilet but no tub, and the family washed up in the sink. Two of Stan’s cousins, a boy and a girl, lived with him there, and together the kids slept on the floor. It was a difficult, tenuous existence, not a book to be found in the little house, and not much happiness either, his grandmother and great grandmother seemingly always tired, emotionless.

Stan Crooke: It just, I mean you just didn’t say nice things. Uh, there were no nice things to say, really. I mean we were scrabbling around, trying to have enough money to eat, and they’d been doing that for a lifetime.

Brady Huggett: Yeah.

Stan Crooke: And they were just beaten down. And, so — but they weren’t bad people. They were not mean. And they both liked one thing, and that was baseball.

Brady Huggett: Both your grandmother and great grandmother?

Stan Crooke: Oh, they loved it. We didn’t have a TV, but they had a radio, and they’d listen to the Indianapolis Indians baseball team — it was the Triple A baseball team. And so, you know, very quickly I learned to love baseball. And that was the one joy they had. At night they’d sit — the living room was big enough for two rockers and this one little couch, and then the heater. And they’d sit in their rockers and listen to the radio broadcast of the Indianapolis Indians. As did I.

Brady Huggett: When Stan was around 5, his mother came to claim him. She’d married a man, changing her last name from Carley to Crooke, and Stan began spending time with them, first in one place and then another, the second home a duplex of sorts located near the women’s prison, in the near East Side of Indianapolis. This neighborhood was maybe a little bit better, and there was a higher percentage of African Americans than his old neighborhood, but regardless, the differences were slight — it was still working class, still a tough place, the Blacks and the whites living separately. Stan moved in with his mother and began adjusting to his new life.

Stan Crooke: As I told you, my stepfather was a really good guy. I mean, a really nice man. You know, just a hard-working mechanic, who was great at his craft and who worked two jobs to try and make things go. And my mom had lots of needs, of course, and stuff.

Brady Huggett: The “lots of needs” Stan is referring to is partially about prescription drugs. His mother was an addict, using amphetamines and barbiturates, he said, and later she also had rheumatoid arthritis, and took a lot of cortisone. That meant she was a kind of “test case” he said, for all the toxicities related to steroids. On top of all that, she wasn’t happy with her life either, and she showed it.

Stan Crooke: And she was a hater. She hated people who had Cadillacs because they were rich. She hated people who had Lincolns because they were pretending to be rich. She hated people in the neighborhood because they were poor. Uh, she hated people from Kentucky and Tennessee because they were coming up and taking our jobs from ‘good Hoosiers.’ Hate came quite naturally. She was one of the great haters of our time.

Brady Huggett: That included across racial lines. Though being racist didn’t make her unique for the neighborhood, the state or the times.

Stan Crooke: Oh yeah, everybody was. I mean, it was just a, it was just a fact of life. I think I mentioned Crispus Attucks, the school.

Brady Huggett: Yeah.

Stan Crooke: I don’t have many memories, but I have a stark memory of one of the rare gatherings or more than — maybe three or four people, I can’t remember — sitting around watching the basketball. And everybody hating Crispus Attucks because they were Black.

Brady Huggett: Crispus Attucks, the all-Black high school named after the Black patriot killed in the Boston Massacre of 1770. In 1955, led by the great Oscar Robertson, Crispus Attucks won the state championship — the first time an all-Black school had done this in Indiana, or any other state in the nation. Stan was 10 years old at the time, and while he wouldn’t go so far as to say he had a “moral epiphany” while watching the game, he admits he was enthralled by the team, and the shocking talent of Oscar Robertson, and he remembers thinking he didn’t see “any reason to hate them.”

The Crispus Attucks victory won over a lot of people in Indianapolis — but drew out the hate in many, many others. And this was true in Stan’s neighborhood, which had plenty of hostility.

Stan Crooke: You know, where I grew up, the next poorest always hate the poorest, and we had a lot of Tennesseans and Kentuckians, and then ‘Hoosiers,’ and the whole environment was hate filled. I mean, it just was.

Brady Huggett: Yeah, there’s that sort of scrabble at the bottom.

Stan Crooke: Uh-hm. Everybody fighting for scraps. And hating each other for having a scrap.

Brady Huggett: And Stan’s mother, in particular, seemed filled with an anger that constantly leaked out.

Stan Crooke: The earliest memory I have, at home, with her, was the first bath she gave me. She had these long red fingernails, and she was cleaning my hair, ostensibly. And my scalp started bleeding and I watched blood in the water. I mean, that’s a bad memory.

Brady Huggett: Stan would spend weekends with his cousins and his grandmother and great grandmother in that shotgun house until he was 9 or so, but the rest of the time he was with his mother. He never went to kindergarten, but he taught himself to read, from the scraps of comic books he’d pick up on the streets, so he was fairly prepared when his mother got him into grade school early. She needed a babysitter for him, because she had started a family with Stan’s stepfather, giving birth to his half sister and brother.

He got a morning paper route when he was somewhere between 8 and 10 — he can’t quite remember the year now. Waking up, and leaving the house in the dark, collecting his papers, distributing them to homes around the neighborhood. When he was finished, the sky still black, he’d buy a doughnut at a nearby bakery just as it opened — a kind of reward for himself. Then returning to his own house, and his bed, sometimes able to fall back asleep before school, sometimes not.

The paper route was seven days a week, and the money went to his mother, to help pay for her rheumatoid arthritis medication. “I just was tired all the time,” he told me, but this pattern helped form in Stan a work ethic he’d carry the rest of his life.

Somewhere, amidst all this, he was moved up a grade because he was overachieving. Then in the 4th grade he was put in with the advanced kids, classmates he called “brainiacs” at the time. But he was such a “punk” he says, he was thrown out of it — a great chance ruined. Stan knew he was smart, but was too angry and too arrogant, too mouthy and too sure that these people couldn’t teach him anything, to get much out of school. He was constantly self sabotaging in this way. Just in general, he seemed to be careening through a childhood devoid of affection and without support.

But that’s the thing about Stan, and it’s one of his defining characteristics. He will not be a victim. He’s willing to hint at the stories of his past, especially now that he’s older, and admit he has some bad memories of that time. But he will not be pitied, and he’s always aware, always conscious that there are many others who have been through more than he has.

Stan Crooke: You know, there was a lot of, there was abuse that was not constant, not, not — my mother was easily annoyed and volatile. She was just physical. Whatever she had near you, she’d hit you with. Well, that tends to make you a little anxious. You know, because you don’t know when you’re gonna, when it’s going to go. But it’s not like somebody deliberately set out to destroy me, like other abusers. And there was nobody in my family — my family wasn’t — there are many families poorer. There were no hardened drug users, with, you know, the one exception.

Brady Huggett: Your mother.

Stan Crooke: Yeah. And there were no, um, criminals. No repeat offenders. And I was surrounded by people who had it much worse. But, there was no joy. There was no aspiration. For reasons that make no sense, all those little moments that you celebrate, I didn’t experience. You know, really, I don’t remember a single time I was told, We love you. I don’t remember anyone putting their arm around me. I don’t remember getting a gift, Christmas or birthday or anything like that.

Brady: But I don’t think everyone is as forgiving as Stan is. I spoke with Evan Crooke, Stan’s son, about his father’s upbringing, and that side of Evan’s family. Evan has a smile a lot like his dad’s, and sounds a little like him, too. He works in the independent film industry, running a distribution company. This is what he had to say about Stan’s family.

Evan Crooke: His mom particularly was, from what I know, really, really bad. I mean really bad. And, I remember watching, uh, the movie Mommy Dearest, which is based on a true story, you know, about an actress who basically got abused by her mom, and who was abusive and so on. My dad’s a very strong guy, emotionally, so I don’t remember too many times where he actually, um, visibly broke down and was upset. And watching the movie, I remember him having to get up and walk out. I mean, he was upset, clearly. Later I learned that his mom did some pretty terrible things. Awful people, really not good.

Brady Huggett: The grandmother and great grandmother too?

Evan Crooke: No, from what I know the grandmother was decent, and if she wasn’t it would have been a lot worse. But he started a newspaper route that he was trying to earn a buck, if you will, at 8 years old, and all that money went to the family. So I think that’s where that came in, that he had a responsibility to take care of his brothers and family and his mom, financially at 8 years old. It’s insanity.

Brady Huggett: He said his stepfather was a pretty decent fellow, in the end.

Evan Crooke: Yeah, I never met — you know what? I never met any of them. Uh, I wanted to, before I learned more in depth about them. And I remember him telling me that, uh, I don’t think you would like them. [laughs]

Brady Huggett: To clarify Evan’s comments, Stan had only one half brother, and his half sister. Anyway, some of this environment was caused by poverty. The stress and anxiety of it, the precarious nature of not having enough money. One summer, Stan spent the entire school break indoors, babysitting his half-siblings. The blinds pulled low, out of worry that social services might realize two young children were being left in the care of another child. These are the things that have to happen when there’s no money for child care, as Stan well knows. But it didn’t make it any easier at the time, for a boy who longed to be outside, playing ball.

The bottom line is that Stan did not have a great mother, and if she loved him at all, she was not good about showing it. And it’s safe to say he struggled to love her in return.

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[ad]

Brady Huggett: When Stan was 11 or maybe 12, he got a job in a corner drugstore — another formative moment for him. It was called The Tech Corner, located across from Arsenal Tech, a trade high school on the near eastside of Indianapolis. Stan enjoyed the work. He liked the routine of it, he liked the praise he received for doing a task well, and he liked the money, too — though, like with his paper route, that money went to help the family.

He started high school around age 12, at Arsenal Tech — young, but his mother had put him in grade school early, and he’d also skipped a grade. Tech is a big, looming place with thousands of kids, and I asked Nelson Price, the historian, about what it might be like for a 12 year old to be on that campus.

Nelson Price: Tech would be an intimidating place for someone at 12. And even beyond that, it wasn’t the largest high school in the country, but it was still an extremely large high school, at that point, with separate buildings, and in his case, older kids who probably had their own turf. I think you would have encountered a lot of challenges with acceptance there.

Brady Huggett: Stan remembers it a lot like Nelson describes it. The school was maybe 75% white kids, and 25% Black when he was there, with the Black population rising, Nelson Price told me. Either way, almost all the kids were from working-class families, and it was a tough, mean place.

Stan Crooke: And then, I went to Tech, which was a big, very violent place. It looked just like the women’s prison. And it was violent, and I was little. And aggressive.

Brady Huggett: So you’re young, younger than everyone else.

Stan Crooke: Young, little.

Brady Huggett: Young, little and aggressive.

Stan Crooke: And too stupid to keep my mouth shut, so naturally I got beat up a lot. I’ll give you an example of the things that went on. I know this stuff sounds unbelievable, but one of the games that was played on the campus was, You’d put a quarter in front of you and stand there. And that became an invitation for someone to come up and take the quarter, and then there’d be a fight.

Brady Huggett: Yeah.

Stan Crooke: And one day, this giant, big guy laid a dollar on the ground, which was a lot. I didn’t — I was just coming from class and I noticed the dollar on the ground. I thought, Holy Cow, it’s a dollar! I picked it up, took it, walked away. And I was just heading into the next building, getting ready to go up the stairs, and this giant hand clamped around my neck, lifted me up on the wall. [laughs] I won’t say the words he called me. And he said, You took my dollar. And I said, Oooh, oh, I didn’t know it was your dollar. I gave it back to him. If I hadn’t given it back to him I think I’d of been a dead guy about then.

Brady Huggett: Yeah.

Stan Crooke: I mean, that stuff, that’s what went on. It was the sort of stuff that happens, at least in those days, in inner-city schools.

Brady Huggett: He’s spending time in that school, and also working at The Tech Corner, which was filled with the same kind of crowd, students coming in between classes and after school let out.

Stan Crooke: I mean, The Tech Corner, there was a gang that could, you know, the folklore was that they could take the motor out of a car in 30 minutes in the dark. They made their living doing that. And there were lots of — it’s not like it is today. Drugs were not a big business. There were no guns. So it was so much easier. You know, if the business of drugs were available for me in those days, I’d have probably done it because it was entrepreneurial and it was a way to make money. And for sure, if I’d had access to a gun there was somebody I would have killed, because you get tired of getting beaten up.

Brady Huggett: Yep.

Stan Crooke: But it’s nothing like as bad as life today is, in those environments. And so, sure, you can get beaten up, but you can survive getting beaten up. You can’t survive getting shot. And of course it was violent in the sort of capricious way violence is. You know, it just comes out of the blue.

Brady Huggett: And by now, all that violence he just mentioned, and the constant threat of it, and the crime and the people he was hanging around with, had influenced him, too.

Stan Crooke: And, I got arrested, because my buddies and I were stealing stuff out of cars because we were too small to steal them.

Brady Huggett: So you would just break the window and take whatever was in there.

Stan Crooke: Yeah, yeah.

Brady Huggett: How old were you then?

Stan Crooke: 12?

Brady Huggett: So they put you in, like a —

Stan Crooke: Juvie.

Brady Huggett: Juvie, yeah.

Stan Crooke: Just one night. But that was enough. First of all, I had to sit in the house of the people who caught me. For about an hour, waiting on the cops. It was so humiliating, I felt so terrible.

Brady Huggett: I bet.

Stan Crooke: These were just poor people, and I was stealing from them? I felt awful. So that humiliation was really good for me. And then I was scared. [laughs] I was in this cell with guys who were hardened.

Brady Huggett: [laughs] Like 35 years old.

Stan Crooke: They were 17, but my god they were big, and they were mean. And a big-time terror fixed me of my hoodlum ways. I said no thanks.

Brady Huggett: All right, so that was kind of the end of that?

Stan Crooke: The humiliation really mattered.

Brady Huggett: Yeah.

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Brady Huggett: Eventually he left The Tech Corner, and took a job at Rodenbeck Pharmacy, on East Michigan Street, about 7 blocks from the high school. He liked this place better. Working-class folks came in after the job, bought their booze, drank it on the sidewalk or street, talking to each other in the growing dusk, and then going home. It was less chaotic, more community, but still, the arrest and night in juvenile detention had solidified what Stan already knew about himself — that he wanted to get out of that neighborhood, that he wanted a different life than the one he’d been shown. That meant going to college. If he didn’t, he’d end up like everyone else he knew, meeting the same violent end that they were meeting. Like what happened to Rex Curtis.

Stan Crooke: You know, Rex Curtis, who got a full scholarship to Columbia when he was 17, he had acquired a new stepfather. And um, um. And he wanted the car, and his stepfather said no. And they lived next to A&P grocery store, so they parked their car over there in the far end of the lot on 10th Street in Indianapolis. I think it was 10th Street. And, um, so Rex was going to go take the car and his stepfather knew he was, and he was drunk and he waited for him in the backseat. And when Rex opened the door, he blew his head — blew his brains out with a shotgun.

Brady Huggett: He shot his — it was his stepson?

Stan Crooke: Yeah. And I happened to be going by there, it was about 10 at night, and actually saw Rex dead on the porch of this house, where he’d run to to try to find help. All kinds of things like that happened.

Brady Huggett: So he got shot, stumbled off and died?

Stan Crooke: Yeah. Uh-huh. And I had another friend, a car fell on him when they were working on it. And another who got shot. I mean, that’s what happens if you, if you’re just unlucky or if you continue in those kinds of activities.

Brady Huggett: All of this — the people he hung around, the people who had more than he did, the rich people who had it easier, the people who were bigger and meaner than he was that pushed him around, the mother who hit him, who didn’t show him any affection — he took all this in, and it began to form something hard inside of him.

Stan Crooke: But mostly what got me was the feeling of powerlessness. And how unfair the whole damn thing seemed to me. And it made me furious.

Brady Huggett: And that fury becomes its own kind of fuel for Stan. Anger can be a powerful motivator if it’s pointed in the right direction, and Stan was starting to figure out which direction he needed to point his. That anger would help him, would give him drive. And then, almost to his surprise, given his terrible relationship with his mother, he got another kind of help — from a female.

Stan Crooke: I don’t. I mean, I honestly don’t know what would have happened to me if I hadn’t met Nancy.

Brady Huggett: Kids came into Rodenbeck’s pharmacy on their way home from school, to get a soda or some candy. And in that group was a blonde, green eyed, pretty teenager named Nancy Alder, who lived in the neighborhood. Her own home life was bad — her father was a mean drunk, who hit her mother. Nancy was a couple of years younger than Stan, but eventually he realized she was coming into the pharmacy to talk to him, and they began to form a bond. She was nice to him, supported him, showed him what love was. These two had an almost singular focus, which was to pull themselves out of the chaos of their families and get out of the lives they were leading. They were both smart, and driven, and believed in each other. And eventually, with Nancy helping him with the application, Stan took aim at college.

Stan Crooke: I filled out one application for college, which was for Purdue. And I went into aeronautical engineering because it was a four-year course, and I liked airplanes, I thought, and because I thought smart people were engineers. I’d never met an engineer, I didn’t know what an engineer was.

Brady Huggett: But when you say that statement — that you thought that was what smart people did — it tells me that you wanted to be a smart person. In fact, that you knew that you were, you just wanted access to that life.

Stan Crooke: Yeah. Uh, it was very obvious to me that I was smart. I mean, I got told it, you know, when I got put in the special classes. But, I mean, older people would come into the drugstore all the time and ask me questions about history and literature and stuff. I just knew stuff.

Brady Huggett: Yeah.

Stan Crooke: And taking tests. I never met a test I couldn’t ace.

Brady Huggett: "I never met a test I couldn’t ace." It must have been true for the SAT, because his grades weren’t going to get him into college, and somehow he got accepted into Purdue, into the aeronautical engineering program. Stan graduated from Tech in 1960 at age 16 — the first person in his family to earn a high school degree.

We are products of our environment, for sure. Though also, in some ways, our core is formed at birth. Stan likes to refer to himself as a “recombinational event” — the mix of his genes and his upbringing. He told me this little anecdote once, almost as an aside, and it was such a great image I felt I could immediately see what he’d been like as a boy, see his true essence.

Stan Crooke: Um, I was born happy. You know, when I was young, I’d have these what I’d call ‘light days.’ When I’d just wake up feeling so good. It took me some time to learn that I drove people crazy. Just, I was so happy.

Brady Huggett: Light days. That was Stan Crooke as a boy, waking up to another day, feeling like he was filled with light, an exuberance spilling out of him, annoying his mother, his grandmother. But the world does change us, Stan’s right. And he changed as he grew. He became this mix, this recombinational event. He built an angry shell around himself, but underneath he was still that hopeful kid waking up to a “light day.” Stan has a compassionate, empathetic soul — it’s the reason he couldn’t make it as a thief. It’s true he was also scared by his night in juvenile detention, but looking at the family he had just stolen from humanized them, he could see the real-life repercussions of his actions, could see that they were as poor as he was, and he didn’t have the stomach for that.

What he wanted was to leave town and never look back. He wanted an amnesia for all that happened to him in his life. He wanted to take Nancy’s hand, climb up to where the smart people were, and never think about his past again. Here’s Rick Hellman, who has been friends with Stan for nearly 50 years. Rick grew up in Chicago, and met Stan in medical school.

Rick Hellman: He didn’t, um, exhibit what I’d call angry-world phenomenon. But he’d talk about those things sometimes. But he didn’t like to talk about them. It’s sort of like, I guess it’s analogous to Holocaust survivors. When I grew up, I grew up in a neighborhood, people spoke German and Yiddish, and when you went to the foodstore, you saw a lot of people who had numbers, tattoos on the arms. Nobody talked about the Holocaust in the ’50s. Period. Or, I have an uncle, who it turned out was a war hero. And he was involved in World War II, and won the Silver Star and what have you. He never talked about the war, until the end of his life. Because it was so horrible. Um, I think that happens to some people. They did it. But now they are in another place.

Brady Huggett: Another place. That was exactly what Stan wanted. And now he had a chance, because he’d been accepted to Purdue. He was going to make something of himself after all. He was about to begin what would be a twisting road through higher education.

[theme music]

Thank you, now and always, to Stan Crooke. Thank you to Nelson Price, Indianapolis historian and author, for sharing his great knowledge of his city. Thanks to Rick Hellman, for his time and his insight. And thanks to Evan Crooke, for talking about his father.

Sound mix and original theme by Brian Flood. All art by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this chapter. Chapter two will be out in a week. Until then.

Chapter 2: a winding path

Brady Huggett: Chapter 2: a winding path

In 1960, Stan Crooke was accepted into Purdue University, for the aeronautical engineering program. Smart people, he thought, became engineers and they built airplanes and rockets. He was going to prove that he was as smart as those people. Or smarter, actually.

The first year of the program could be done at Purdue University extension, a satellite campus, of sorts, located north of downtown Indianapolis. Which meant that Stan would stay at home, be near his girlfriend Nancy, and still be able to work at Rodenbeck’s pharmacy, where he’d been trying to save money. When the semester started, he still couldn’t fully cover the tuition, but Frank Rodenbeck loaned him $300, and gave him a pair of used dress shoes to wear, and Stan’s higher education started. He bused to class every day, and when classes were over he took a mix of buses back to the Near East Side, and he’d work from 5 to 10 at Rodenbeck’s.

Stan treated college like he’d treated all the rest of his schooling — he put little effort into classwork, and just used his brain to pass the tests. There wasn’t much time for studying around his work schedule, and anyway, he hadn’t been able to afford all the textbooks.

This worked for a year. And then it became clear to Stan, and probably to the school, as well, that he was going to fail. From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: In Stan’s second year at Purdue, he needed to be living on campus in West Lafayette, about 60 miles northwest of Indianapolis. This was in order to access the hangar where the aeronautical engineering students had their hands-on learning. It was the first time he had meaningfully traveled beyond the borders of Indianapolis in his life. In typical Stan fashion, he did not attend the campus orientation for his second year, because he was still working to secure the tuition money. So when he arrived among those red brick buildings he was sort of lost, and just in general feeling insecure. Plus, the classes were more difficult the second year — math, physics, aeronautics — or difficult if you’re not studying, as Stan mostly wasn’t, spending his free time working almost 40 hours a week at a pharmacy near the campus.

Adding to all this, Nancy got sick. She’d had debilitating migraines since she was 14, sometimes bad enough to make her vomit. This was different, though, serious enough to put her in the hospital. There was no official diagnosis, and Nancy’s parents never told Stan much anyway, about anything, but regardless, he began hitchhiking back to Indianapolis once a week to see her.

This was on top of the hours at the pharmacy, and all the classes, and that advanced math, and the physics calculations. He was soon earning the worst grades of his life, “which is saying something,” he told me. His weight had fallen, and the worry over Nancy’s health had brought on a depression. It all suddenly seemed impossible. He took a long look around, saw the writing on the wall, and gave up on Purdue in his second year. Stan headed home to Indianapolis.

Maybe it was better to stick with what he already knew. He transferred into Butler University’s school of pharmacy, the only trade school in Indianapolis. It was a 5-year program, the math much simpler — “I can add” Stan said — and that meant he could get by the same way he always had. Spend his free time working, not study much, and then pass the tests. That’s what he did.

Stan and Nancy got married in 1964, when she turned 17. Stan was just 19 himself. They moved in together and lived in East Indianapolis, but not long after their union, a cyst ruptured on Nancy’s ovary and she had emergency surgery to excise it. She wasn’t watched closely in the hospital after the surgery, she bled internally, and nearly died. Another moment of terror for Stan, and Nancy too, and another incident in Nancy’s long battle with her body.

Amidst this trauma, Frank Rodenbeck sold the pharmacy to Jim Smith, who in turn sold it to someone else and then Jim opened a new place in a better neighborhood. In Stan’s third year of pharmacy school, Jim asked Stan to come work there. And to entice him, he made Stan a “tiny owner” of the new place.

For the last two years of pharmacy school, Stan basically ran Jim Smith’s business, he told me, helping triple the revenue with a higher profit margin. Now Stan was making good money, too. He and Nancy had a new car, and were thinking about buying a house. Stan figured this would be his life. Why not? It was already a big step up from where he had come.

But somewhere deep inside, Stan kept a small flame alive for a bigger dream. He must have, because he took the LSAT, the test required for law school admission. It was another half measure on his part — he had the scores sent to the law school at Indiana University, at Indianapolis, “not the good one in Bloomington,” he said, but he never actually applied anywhere.

Stan Crooke: And, one day I was home, and the secretary called and said, The Dean of the law school wants to speak to me. Well OK. And he said, You know, we have your test scores, but, strangely, we don’t have your application. And I said, Oh golly, I forgot to do that. And he said, Well here, let my secretary fill out that application for you. And, the secretary filled out my application. And that’s how I got into law school.

Brady Huggett: Things like this seemed to happen to Stan all the time. This is why he says — to this day — that he’s the luckiest person anyone will ever meet. It happened again while he was still in pharmacy school. Stan had developed a tradition where he skipped the first week of every semester. Initially this was to keep earning tuition money, but by his fifth year it had become habit. In his absence that first week of his final year, he was elected a class officer. It was meant as a “middle finger to the school,” he said, because Stan often made dismissive comments during lectures or was sarcastic with professors. His classmates thought it a worthy joke to elect him as voice of the student body.

Being a class officer opened another door for him, again by chance.

Stan Crooke: Which meant for the first time in my life I had to be in the office of a dean. I didn’t know what a dean was. And the dean, to whom I’d been grossly unpleasant — I’m in the office, doing some dumb thing, and he says, What are you doing after you graduate? And I said, Oh, I don’t know, run a drug store. And he said, Have you ever considered graduate school? I said, No. What’s graduate school? And he says, Well, you know, we have a master’s program. Why don’t you go to graduate school here? I said, Well, OK. And so they filled out the application for me, or Nancy helped me, and I got into graduate school. And that’s how I ended up running a drug store, being in law school and going to graduate school all at the same time.

Brady Huggett: Law school didn’t last. Being in the law buildings felt like “an old man’s hotel,” Stan said, and he dropped out after a week. So being an engineer was out, and now so was being a lawyer, but he did the graduate work at Butler and earned a master’s degree in pharmacy, and then fell back to his plan of running some drug stores.

Yet still that flame flickered in his chest. Could there be more? He thought maybe. And it stemmed from his time at Purdue, when he’d known a chemical engineering student named Gary Keener; a big, tough kid, whose dad worked in the steel mills. Gary was another son of the Midwest like Stan.

Stan Crooke: And we became good friends. And, I played a lot of chess in those days. Played tournament chess.

Brady Huggett: Oh, you did?

Stan Crooke: Oh yeah. And I beat poor old Gary 500 straight games.

Brady Huggett: [laughs]

Stan Crooke: He was a very competitive guy. But Gary was, an intellectual. It was the first time I’d run into anybody who thought as a way of living. I always thought, I always read, I liked history. I liked literature. That’s what I really liked. But then Gary dropped out and went to medical school.

Brady Huggett: Stan had rarely gone to a doctor as a child. Or a dentist, as far as he could remember. He didn’t know much about medicine, beyond what pharmacy school had taught him, or what he had learned through Nancy’s hospital visits. Real medicine was a foreign world. But he stayed in touch with Gary after both had left Purdue, and watching Gary, and his wife, go through medical school made it a tangible thing, something Stan might actually achieve himself.

And medical school also spoke directly to Stan’s desire to keep climbing.

Stan Crooke: I wanted the letters after my name. And I wanted that kind of control. That kind of prestige. And I was interested in cancer.

Brady Huggett: When Stan had taken a class on cancer in pharmacy school — from yet another professor to whom he would not give his respect — he had what he felt was an original thought. Maybe what happens, he mused, is that when cells lyse, as they do in their normal life cycle, the DNA in the nucleus breaks down, and fragments enter the bloodstream, where they are taken up by other cells. This, he thought, must be the cause of cancer. In fact he was sure of it.

He was completely wrong, of course, but the exhilaration he’d felt at his “discovery” stuck with him, and in that moment he began to view science not as something you memorize and apply in certain situations, but as an exploration. And it stirred something in him.

With Nancy’s help filling out applications, he applied to a handful of mostly mediocre schools, including as far abroad as the University of Jamaica. He didn’t have much hope, since his grades in pharmacy school had “sucked,” he said, maybe a 2.5.

To little surprise, he got rejected by all of them, except Emory and Baylor University. The “two good schools” Stan marveled. And the acceptance letter for Baylor came from the chairman of the pharmacology department himself, Harris Busch, who suggested Stan come get both a PhD and an MD, and he invited Stan down to see the campus. On Baylor’s dime. Stan, who had grown up listening to all that baseball with his grandmother and great grandmother, and who loved the sport himself, thought it sounded like a good chance to see the Houston Astrodome, which was new at the time, so he accepted the offer, and he and Nancy flew down.

The medical school at Baylor was run by a super tandem of Harris Busch and Michael DeBakey. Busch as chairman of the pharmacology department, and DeBakey as chairman of the surgical department, and he was also president of the college after 1969. The trip changed Stan and Nancy’s lives. Or more precisely, meeting Harris Busch at his lab altered the trajectory of Stan’s life.

Stan Crooke: Nancy and I went in. I left her down in the lobby, said I’ll be back in an hour. Harris gave me a lab book, a white coat — I didn’t know anything about science — and said, Here’s your project. You’re going to sequence U1A RNA. Oh, OK. What’s an RNA? I mean, I didn’t know what RNA was. [laughs] Because I was trained in, you know, sort of, the most primitive pharmacology. It was pharmacy school pharmacology, of those days. And, along around 7 or 8 at night, I realized it was 7 or 8 at night. In those days I really didn’t eat anything, because I was just used to not eating. And I thought, Oh shit, and ran down. Nancy was still sitting there waiting for me. And that’s the first time I encountered scholarship. Uh, medicine.

Brady Huggett: He was hooked on true science, and the voyage inherent in the world of research. Harris agreed to accept Stan as a PhD student, and Stan won a fellowship to Baylor. Suddenly “school made sense” Stan said, because he was getting paid to be there, instead of the other way around. And because he was earning money it made the lab feel like a job. And Stan had always excelled at work, ever since his first newspaper route.

Thus began one of the most important relationships in Stan’s life. Harris Busch became “the closest thing to a father that I’ve had,” Stan said. Harris, and his wife, Rose — also a researcher — introduced Stan to “power science,” to rigor, and high intellect. Just about anything good in life, actually, except love, which Nancy had already shown him.

In a way it was surprising that Harris took to Stan, considering Stan was so green. Harris was notoriously hard on his PhD students and he didn’t suffer fools. When Stan showed up to begin the program at Baylor, he could still see the remains of Harris’s past battles strewn about, like warnings.

Stan Crooke: Harris was a really tough cookie. I mean, when I arrived, Harris took one graduate student at a time, one PhD student, and the previous PhD student was just finishing. And the story goes, I wasn’t there, but the story goes that Harris got so mad at him, told him he was worthless and didn’t deserve an office and bodily drug his desk out into the hall. When I arrived, he was still sitting in the hall at his desk.

Brady Huggett: [laughs]

Stan Crooke: So I wouldn’t want you to think of Harris as warm and fuzzy. [laughs]

Brady Huggett: But Busch had come from a modest place himself. He’d served in the US Army, had worked for the US Public Health Service after World War II, and had climbed hard and long to his current position. He saw something of himself in Stan.

Stan Crooke: People were terrified of him. You know, I was born looking for a fight, so Harris and I just hit it off, you know. Years later I asked Harris why in the world he took me. And he said, I thought you were really smart and I’d never seen anyone as angry as you. [laughs]

Brady Huggett: [laughs]

Brady Huggett: Harris also introduced Stan to RNA — ribonucleic acid — the single strand of the four base pairs (adenine, cytosine, guanine and uracil) found inside cells that play a part in protein production. This, too, was a big deal. It would help shape Stan’s research interests for the rest of his life.

After that initial visit to meet Harris, Stan and Nancy moved to Houston. In this new environment, with his intellect fully challenged and engaged, Stan began to thrive, finishing his PhD in less than three years, and finding people at Baylor who felt and thought the way he did.

He met John Rose in an elevator on the Baylor campus. John was in his first year of medical school there, another “flyover person,” as John said, who had grown up in St. Louis, though he’d gone to Princeton for his undergraduate degree. The two men bonded over being outsiders, of sorts, both geographically and culturally, in the middle of Texas.

John Rose: We were the 10-percenters. Ninety percent was good ol’ Texans. And then there were 10 percent of us from the rest of the world. I was coming out of the Ivy League. Which was ground zero for, again, the cultural revolution in the late ’60s. So we had a similar, like I say, cultural and political viewpoint, which was not shared by a lot of Texans at that time.

Brady Huggett: Can you tell me a little bit more about this Cultural Revolution idea? I mean I understand the ’60s was, you know, you had the Vietnam War, you had Martin Luther King, Civil Rights era. You’re talking about all that?

John Rose: We had women’s liberation, we had the beginning of the gay liberation movement. That all was happening, basically between Boston and Washington, DC. And in California, of course. From basically the whole ’60s. And, again, I’m not sure what was happening in Indiana, but Stan was certainly very much for the new order.

Brady Huggett: Nancy gave birth to Evan in Houston in the fall of 1969. A very difficult labor, Nancy hemorrhaged, and Evan was born with a low Apgar score. The test determines if a newborn needs immediate attention, particularly resuscitation, and scores range from 0 to 10. Evan had a score of 5 — worrisome enough, but not critical.

Still, the whole event had been scary, and Evan was the only child they would have — Stan wanted more, but doctors told them another pregnancy would be too risky for mother or child.

Evan would be difficult to raise — he was smart, but had dyslexia and a speech impediment that kept him from enunciating clearly until he was 7 or 8. The only one who could understand him in those years was Stan, Evan told me. When Evan entered high school he was trailing his classmates by 4 or 5 grade levels, but overcame the dyslexia almost through anger and sheer will, he said, and graduated with honors and made the Dean’s list. In this way, from the outside his life would look a lot like his father’s — a late bloomer who then flourishes.

Evan’s early troubles added another layer to Stan’s now very full life in Houston. He was a husband with a partner who was sometimes quite sick, and the father to a child who needed special attention. All the while in the midst of a grueling Phd-MD program. But Stan has never shied away from work. The problem wasn’t exhaustion, but rather that there weren’t enough hours in the day to handle it all.

Stan won the award for the most outstanding student in pharmacology, and started medical school in 1971, his PhD complete. He met Rick Hellman in orientation — Stan was now mature enough to actually attend orientations — and they, too, quickly became friends. Both were already married, both from the Midwest (Rick from Chicago) and both from working-class roots. Rick’s wife Pat got along well with Nancy and they were a tight foursome. Stan and Rick spent free time playing basketball while Nancy and Pat talked, Evan right here with them, and then the group would eat a picnic meal, because there wasn’t money for going out.

By 1975, Stan was nearing the end of medical school and his residency. John Rose had signed up for the National Service Corps, to begin a career as a country doctor, someplace where the need was great. This appealed to Stan’s caregiver mentality, his sense of a higher purpose, and he and John discussed possible rural places they could set up a practice together.

John Rose actually went on to have that career. He and a partner built a general practice in Brownsville, California, a town about 75 miles north of Sacramento, and still only around 1,200 people today. It’s the foothills of the Sierras, beautiful, and remote. During the next 45 years, John would see more than 250,000 patients, and his partner even more. It is satisfying medicine, the kind that requires creativity, and fast thinking.

John Rose: I got a call for a guy that had a heart attack when he was putting a roof on a building. And we make house calls and things, so I actually made a roof call. I had to grab my little bag and climb up on a ladder on this roof where this guy was having a heart attack and stabilize him while the ambulance was coming. Uh, delivered a baby in a driving rainstorm at the office. We didn’t have time to get to the hospital. And while I was getting her ready, the lights went out. And the volunteer fire department showed up and they had these big searchlights, and so that’s how we delivered the baby. In the office. Uh, there are hundreds of little stories like this.

Brady Huggett: Including once trying to shock a man back to life by using a car battery, because the office didn’t have a defibrillator. When I asked John about his career, he told me he could “look in the mirror with a clear conscience.” He’s done the kind of doctoring that really matters, providing care to people who have no other options. This was nearly Stan’s career, too. He would have been great at it, with his tireless work ethic, his understanding that the world is unfair and that many who need help don’t get it.

But that’s not what happened. Harris Busch wanted Stan to become head of the oncology division at Baylor, but that didn’t happen either.

The main reason is that Nancy was getting sicker. She had what doctors could only describe as a vasculitis. It was becoming a constant part of her life, and thus Stan’s, too. Fever, headaches, vomiting, weight loss, and bouts in the hospital. Whatever it was, it remained mostly undiagnosed and untreatable with any real efficacy. Finishing up medical school, Stan knew he was going to need money, not only for Nancy but Evan, too, who would require private schools for his learning disability. So Stan couldn’t be a country doctor, and he couldn’t become a full-time professor and an academic researcher, scrambling around for government grants.

Here’s Rick Hellman.

Rick Hellman: Senior year, our last year, when everything should be roses, is when Nancy was becoming ill. And this was very, very difficult. They had these ideas about what we’re going to do, and he had to make some really, really tough decisions in the face of basically working your buns off. I mean you were — medicine there, although the acuity in medicine is difficult, the patients, you really worked hard. And he had to make this really tough decision about stepping into the world of pharmacology. I don’t think Harris Busch was happy about it, but he had to do it. He knew what he had to do.

Brady Huggett: What he had to do, was go where the money was. In his residency Stan had been seeing cancer patients, in particular testicular cancer patients, sometimes being the one to reveal a terminal diagnosis. These conversations required such compassion and intimacy that Stan called it “an honor” to be the one trusted enough to have them. In his experience seeing these patients, he’d come across a cancer drug called bleomycin sulfate. It had a crazy chemical structure, he said, and it sometimes produced odd side effects in patients. The exact mechanism of action for the drug wasn’t known, but it was thought to inhibit both DNA and RNA synthesis, and stop protein production. In some tests it has been shown to arrest the cell cycle, and thus was used to treat cancers. Bleomycin fascinated Stan, and he wanted to work with the analogs, so he called up the company that had them, Bristol Laboratories, and asked for a job.

They hired him. “People like me,” Stan said, didn’t go to industry back then. And by that he meant people who were accomplished researchers, because Stan had already reached double digits in scientific publications from his work at Baylor. But he also had a master’s in pharmacy and an MD. Even the year at Purdue didn’t hurt. Those sidesteps on his way toward his true calling were now meshing into something unique in the drug making world. Stan once told me he was “born knowing how to make a drug.” If that wasn’t exactly true, it seemed like he was ready now.

Stan and Nancy packed up Evan and moved the family to Syracuse, New York, in 1975. He became assistant director of medical research at Bristol Laboratories.

When he got there, Stan realized there was no molecular biology department at Bristol, and not one at the Upstate Medical Center where he did rounds with cancer patients. To develop drugs, Stan would need that kind of team, so he went to his boss at Bristol and asked if he could set up a lab at Baylor. His boss gave him $40,000. Stan turned to his old mentor Harris Busch, who offered attic space at Baylor and some aged lab equipment — centrifuge, a battered refrigerator. Stan got the lab running and applied for some National Cancer Institute grant money, which he won.

It was enough to get him started. He began flying to Houston every two weeks, and over the next 5 years, he trained 5 PhDs, including a researcher named Chris Mirabelli, and 2 master’s students, and the lab published around 100 papers. He also lectured at Baylor, condensing his classes around his trips. He’s funny and self-effacing in front of a crowd, and students liked him. He was voted favorite Baylor faculty member in the college of medicine more than once.

By any account, he flourished at Bristol Labs, too. Under his watch, the company got new indications approved for Bleomycin and Mitomycin C, as well as Cisplatinum, among other cancer drugs. The cancer program he built, with the help of the research lab at Baylor, was thriving. He’d been promoted several times, and by 1980 was a vice president. He had quickly made a name for himself in the industry, and people began calling.

Including Smith Kline & French Laboratories, in Philadelphia. The pharmaceutical company was on the upswing and flush with money from Tagamet, a histamine H2 receptor agonist, approved for ulcers and other gastric disorders. It was the first drug of its kind. Stan saw a bright future for himself there, and a ladder to even greater heights.

Stan Crooke: My appetite was to win everything. To be in control of everything. I wanted to be an MD-PhD, I wanted to be a great scientist, I wanted to be the CEO of a big company, because that was the highest rung. Nothing more. Just that kind of naked, blind, uninformed ambition.

Brady Huggett: Huh.

Stan Crooke: That’s the honest — that’s about as truthful as I can say it.

Brady Huggett: SmithKline knew it had a weakness — it didn’t discover or develop drugs well. And they knew the money coming in from Tagamet would eventually be eroded by competition. They brought Stan on in 1980 as a Vice President, overseeing Research & Development. Stan Crooke knows how to make drugs, they thought, and that was exactly what they needed. The company allowed him to build a gleaming new research facility on 300 acres in Upper Merion, the northwest part of Philadelphia, and he brought in academic researchers from the University of Pennsylvania to consult and collaborate. He knew, even then, that academic research could be more fertile ground for drug discovery than the staid halls of big pharmaceutical companies. All he needed to do was gather the talent and then guide it.

Stan also gave himself plenty to do on the side. The University of Pennsylvania was rebuilding its pharmacology department, and asked Stan to join the faculty, which he did, overseeing a collection of talented PhD students, including Brett Monia and Rosanne Snyder. He had given up the lab at Baylor, but was still a full professor there and regularly flew down to teach. He had his own lab in the research facility he’d built in Philadelphia, and also had an office in the executive building downtown, where he’d go once or twice a week. Every couple of weeks he flew to London to check in on a research facility there, spending two days before flying home, where he’d crash in his own bed before going into the office the next morning. Maybe once a quarter he flew to Belgium to visit the R&D team, where he supervised the discovery of the first recombinant DNA hepatitis B vaccine.

He was also scheduled to go to Bangalore every year in December. But he never made it, not once in all his years at SmithKline. The reason was Nancy.

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Brady Huggett: Stan loves literature. William Faulkner and Mark Twain, Emily Dickinson. A little Sylvia Plath. He likes art, too, likes the history of it. But he has no talent for it. That was Nancy’s skillset. She was a great pianist, for example, and followed contemporary music. For years her younger sister had lived with them in Philadelphia, and one Christmas the sister gave Nancy a collection of new albums. Nancy sat looking at the intricate art on the covers, and thought they were original enough that she could curate a show around them. She spent two years flying to LA and putting together a collection of album cover art, and Stan and her wrote an accompanying picture book. Both were a success, and led her to consider the other forms of art that musicians did, which she also turned into a show. Through this work, they got to know Cat Stevens. David Crosby. John Rose remembers coming to visit the Crookes in Philadelphia and Richie Havens was singing in their living room. Nancy once got to be on stage during a David Bowie concert.

So what can be said about the life of Nancy Alder? Or Nancy Crooke, for that matter? She emitted a kind of vibrant joy when healthy. John Rose adored her. Rick Hellman and Pat loved her, too. Nancy had met Stan when his general opinion of women was low, given all the abuse and disdain his mother dumped on him. Nancy had changed that, shown him how caring, supportive and gentle a woman could be.

But something was wrong with her immune system, and there was no fixing it. It was bad genes, or maybe emotional remnants from her unhappy childhood, that toxic environment she’d grown up in. Maybe just bad luck. Or maybe a mix of all that, as Evan thinks. She had been in and out of hospitals over the years, had seen specialists, and no one seemed to know how to heal her. In Philadelphia it all got worse. She was in the hospital every few weeks. Her weight dropped to less than 100 pounds. In her last couple of years she was often in bed, struggling with migraines, weak from the vomiting they caused.

Here’s Rick Hellman.

Rick Hellman: She had this terrible vasculitis syndrome, basically, that was just refractory to therapy. And I don’t know the particulars, but I know she kept on having problems with clots and vasculitis, weight loss and fever, pain — I mean, it was not good. And there are these vasculitis syndromes, and I didn’t pry about the specifics, but that’s what — and it was chronic and unremitting.

Here’s John Rose.

John Rose: It was an unusual vasculitis, that uh, uh, it was tragic. And the whole Nancy situation is tragic. Just tore us all apart. She was a wonderful, wonderful woman. Brilliant, creative, artistic. Extremely lovable. It was just tragic to get this illness that they couldn’t do anything with. And uh. Yeah. It still hurts me to think about it.

Brady Huggett: The last 10 years of the family's life had been difficult, the final five almost unbearable. Obviously for Nancy, but Stan and Evan, too. Never a big eater, in the last year of Nancy’s life Stan himself had shrunk down to 130 pounds. He was also driving himself hard at work, partly because hard work defines him, but also partly because it was a respite from the awful scenes at home, the sight of Nancy so frail, and the depression her long illness was pulling him into. He’d hired all the help he could — housekeepers, nurses. That had been the reason for his career in pharma: to get the money to care for his wife, and his son. He’d done that. But her illness just kept getting worse, and Stan could do nothing but to stand around helplessly and watch.

Stan Crooke: I guess maybe five or six years before she died, I came to the conclusion that I was never going to be happy again. Being not happy — people who have been that know it feels like you moved to a planet with gravity that is 10 times more. It’s just this weight that you feel. And Nancy had become, um — she was never who I thought she was, I created that. But she became less and less. I mean her life just wasted her.

Brady Huggett: Yeah.

Stan Crooke: I just saw myself taking care of her for the rest of her life, and Evan. And finding whatever moments of happiness I could get, however I did it. And, um, I saw no way out. I mean, looking back, I’m really quite certain I could never survive that again.

Brady Huggett: Until, finally, it was over. She died in 1984, at 37 years of age. Here’s Evan.

Evan Crooke: So, I, uh, I went to school one morning and came back home and the housekeeper was in the kitchen, hysterical. There was nobody else in the house. I was about 14. And she didn’t want me going upstairs, and I knew instantly, I had a feeling that something terrible had happened to my mom. So I ran upstairs and then searched in the master bedroom. She wasn’t there. We were living in a pretty big house at that time. I went down to the other guest rooms and so on, and then I went into one room. It was a guest room. And I went in there and saw the bed, and she was not on the bed. I looked to the one side of the bed, she wasn’t there. I looked to the left side and she was there on the floor. Her feet were blue.

Brady Huggett: Oh no.

Evan Crooke: And so, I didn’t touch her. I was sort of in shock, I didn’t, um. It registered in my head that obviously seeing blue feet was not a good sign.

Brady Huggett: Stan got the news at work, while in a meeting.

Stan Crooke: My assistant came in — I mean it was a big meeting, I was chairing it — and said that there was a problem at home, um, and I needed to leave. And it seemed very clear to me that something bad happened. And she drove me, she drove me home. But I didn’t know for sure that Nancy was dead until I walked into the house.

Brady Huggett: By then Evan was at the neighbor’s, and Stan collected him there. A terrible day. It would reverberate throughout Evan’s life. It was something they all knew was coming, but the suddenness of it still was traumatic. And, as is often the case, the ones left behind struggled with guilt.

Evan Crooke: I remember that the night before I had, uh — I was in puberty, I was very irritated with my mom the night before. Because we were sitting down to dinner and she, uh, she was, I don’t know. She was just sick. She was sick and having a hard time, or she was just chewing with her mouth open, or something. It was something that under normal circumstances I should have tolerated but I didn’t. I think, I can make all the excuses in the world, but I think I was angry at her illness. Quite honestly, and for being ill. And being weak. I think I was angry at her for being weak. So I wasn’t very pleasant the night before, and we sort of got into a little bit of a verbal argument. And I was not, um, as kind as I should have been. Or would want to be. So, the next day, when I found her dead, the second person to find her dead. Um, that was, that weight was quite heavy.

Brady Huggett: For Stan, it was something bigger. Given how much Nancy had supported him in his youth, how he’d clung to her, and what she had taught him about love when he had no idea what it was, it is not unreasonable to say she had saved his life. So, beyond the pain of her passing, what hurt Stan was that in the end, even with his advanced degrees and his research, and his access to leading scientific minds, he could not save hers.

They had been married for 20 years, and known each other even longer. She was the most important person in his life for decades. Stan knows that, will never forget it. But in his darker, most reflective moments, Stan will admit it was also a relief when she passed. Because at times during those final years, life did not feel worth living, and the two of them seemed locked in a “death spiral,” he said, that would never end.

Now it had. Nancy’s illness had kept her from fully participating in their life, but now Stan was truly on his own with his son. They had only each other, and in the wake of Nancy’s passing Stan and a teenage Evan formed an even tighter bond, forever loyal to one another. Maybe that helped.

Maybe work also helped. There was always joy in the job for Stan, as there had been his entire life.

But SmithKline would come to an end, too.

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Brady Huggett: Tagamet had been discovered and developed by SmithKline & French. The drug was a major breakthrough. The man responsible for it — James Black — would win the Nobel prize for Physiology or Medicine in 1988, for his work with beta blockers and H2-receptor blocking drugs. Tagamet was approved in the UK in 1976 and the United States the next year. It immediately began wracking up sales, and by the time Stan joined the company, Tagamet was sold in 100 countries. SmithKline bought Beckman Instruments in 1981 as a growth strategy and became SmithKline Beckman, but it could not stave off the inevitable. By 1983, the pharmaceutical company Glaxo had introduced a competitor called Zantac, another H2-receptor blocker, and the company mounted a heavy marketing campaign to support it. Tagamet still hit sales of ~$1 billion in 1986, making it the world’s first blockbuster drug, and then peaked in 1987 with $1.1 billion in sales — a massive amount of money at the time. But sales began to slip from there as Zantac took market share. SmithKline also had the diuretic Dyazide, which brought in hundreds of millions of dollars in 1986, but was hit by the first generic competitor in 1987. SmithKline had no blockbuster drug coming up behind Tagamet or Dyazide to replace all that lost revenue, and as share prices fell, the company took heavy pressure from stockholders. A merger seemed likely.

Drug development. Research. That was Stan’s area. By 1988 he was worldwide president of Research & Development, overseeing 3,000 researchers and a budget of more than $400 million. It was his job to generate new drugs, and he’d been given free reign to do just that, building the research facilities in Upper Merion to accomplish that goal.

And yet, the drugs Stan had “resurrected” did not sell, he told me. That included Auranofin, an oral organic gold compound for rheumatoid arthritis. It had high marketing predictions, but it fizzled when approved, and eventually the space would come to be dominated by the tumor necrosis factor drugs.

Stan thought the best thing to do was continue to invest in research. He was dead set against a merger, and he was “very aggressive” about making his thoughts known, he said. But his arguments were falling on deaf ears, especially because sometimes it seemed Zantac had simply marketed its way to the top. This was opening up a tension between Stan and upper management, and pretty soon it was clear that he “wasn’t willing to stay,” and that “they didn’t want me,” he said.

But there was something else, too. Everyone knew Stan was smart, and his work ethic was above reproach. He also had a reputation for being fair — he would never ask you to do something he himself would not. If he told you to be in the lab on Saturday, you were assured he would also be there. But he drove his employees hard, and he was demanding, as always. Some chafed at that. Here’s Fred Frank, one of the first original big-time bankers in the biotech industry, talking about what happened at SmithKline in those years.

Fred Frank: Well I knew Stanley from his prior places. And I knew him quite well at SmithKline. And actually, people don’t really realize, he was fired at SmithKline. And uh —

Brady Huggett: Why?

Fred Frank: He’s, you know, he’s very demanding of his people. And um, little bit too much of a control freak. Brilliant guy. I mean his record of new product development is second to none. [laughs] He’s an amazing guy. But he doesn’t tolerate anything but the best. And a lot of people can’t live up to his standards.

Brady Huggett: The firing stung. So much so that when Stan talks about leaving SmithKline to this day, he will stress that he was fed up with the glacial pace of big companies, and he’ll point out that he’d learned that pharmaceutical giants like SmithKline can be nearly incapable of innovating. Both statements are true enough. But that does not override the fact that they cut him loose in August of 1988, and replaced him with George Poste, Stan’s second in command.

Stan once told me his three biggest faults are that he is “intemperate, intolerant and impatient.” That can be seen in the angry arrogance of his high school years, and in pharmacy school too, where he didn’t bother showing up for classes and disrespected the instructors. That impatience can be hard on those who work beneath him. It’s possible he’d also adopted the confrontational culture he’d seen at Bristol, where the scientists briskly challenged any and all science in order to pressure test it. Or perhaps Stan had modeled his management style on Harris Busch, who had once dragged a PhD student’s desk out into the hallway and left it there, publicly belittling the man because his science wasn’t good enough.

Whatever the case, Stan struggled to be a good manager at SmithKline. After his departure, The New York Times wrote an article on SmithKline’s inability to generate new drugs, and dropped the blame squarely at Stan’s feet.

The article described Stan’s integration of academic researchers into SmithKline’s culture as “an unusual strategy” and called it “notably unsuccessful.” The article paraphrased an academic consultant from the University of Pennsylvania as saying he doubted academics had “the correct orientation to find major drugs,” as if Stan had been foolish for thinking they did.

On top of that, SmithKline, having seen what Glaxo did with its Zantac marketing, decided it would have the strategic marketing people work more closely with research — a move that would take power away from the science team and give it to the salespeople.

For a person who had built a research group where there had been none, and who had worked tirelessly even as his wife’s health slowly declined, this was particularly wounding.

Stan Crooke: And that affected me for years. And, um, you know, I had all kinds of other, horrible life events going on at the same time. So it was one of the hardest things I’ve experienced, and it did me a lot of harm. It took me years to recover — that article. Because it wasn’t true and it wasn’t fair. I thought I was an enormous success at a very young age, and there were people who agreed and there were people who didn’t. And that really infuriated me, because I knew I had done great things.

Brady Huggett: Firing Stan wasn’t going to fix SmithKline — in 1989 it merged with the Beecham group, forming the second largest pharmaceutical company in the world. But that was little consolation. Stan’s public rebuke hurt because he’d felt like an outsider for most of his life, staring up. And when he’d finally joined these powerful people, they pushed him back down.

Here’s Jeremy Levin, the CEO of Ovid Therapeutics and former chairman of the Biotechnology Innovation Organization. He has deep experience in the biotech and pharmaceutical worlds.

Jeremy Levin: If I were that person, I wouldn’t have a chip on the shoulder, I’d be pretty damn mad.

Brady Huggett: Yeah.

Jeremy Levin: Because to fight your way out of those circumstances and then to go into these very stately, very mechanistic, very process-oriented organizations. And then to be successful and then to be rejected? You know, that’s a hard pill to swallow.

Brady Huggett: If Stan had let any of his anger go during his success at Bristol, if he’d felt it dissipate with the control he was given at SmithKline to build a research group in his model, now it was back. He had worked like a dog for a company and they had cast him out. SmithKline had told him his way of thinking was wrong, when he knew it was not. The anger felt like he was young again, like he was a poor kid in the near East Side of Indianapolis staring at the rich people, who were not as smart as he was, and who did not impress him, and they were the ones running the world.

So this is Stan at 43. His childhood sweetheart and mother of his child is gone. He’s trained in pharmacy. He has a PhD in pharmacology, has worked extensively with RNA. He’s an MD with years of experience seeing patients, and fully understands their needs, and their fears. He had seen firsthand the shortcomings in the ways big pharmaceutical companies make drugs.

But also, he’d been publicly blamed by SmithKline, and had his name dragged through the mud by the world’s leading newspaper.

He was furious. The end of his time at SmithKline confirmed only one thing — he needed to be in a position where he answered to nobody but himself, and he’d do innovative science the way he knew it should be done, and never deviate.

It turns out that is exactly the kind of person, the kind of temperament, needed to develop a brand new drug modality. And for months before his firing, he had been working on an exit plan from SmithKline.

[theme music]

Thank you, now and always, to Stan Crooke. Thanks to Rick Hellman, for his time and his thoughts. Thank you to John Rose, for the insight into his old friend. Thanks to Fred Frank for his long view, and to Jeremy Levin, thoughtful as always. And thanks to Evan Crooke, for telling me about his mother.

Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous chapter. Chapter three will be out in a week. Until then.

Chapter 3: San Diego restart

Brady Huggett: Chapter 3: San Diego restart

In 1978 a Harvard researcher named Paul Zamecnik and colleague Mary Stephenson published a paper in the Proceedings of the National Academy of Sciences titled “Inhibition of a Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide.” It showed that by using a short, single-stranded piece of deoxyribonucleic acid (or, DNA) it was possible to slow a virus’s ability to replicate.

Zamecnik and Stephenson published a second paper on their work at the same time, but in truth the concept had larger implications than just that. When DNA is unzipped in the nucleus, a sequence of precursor ribonucleic acid, or RNA, is formed from one strand. That precursor RNA is then transformed into messenger RNA and released into the cell cytoplasm, where it is translated into a protein.

DNA and RNA are made of nucleotides, and the pattern of nucleotides in messenger RNA that codes for a protein is called a ‘sense’ sequence. The sequence of nucleotides that is exactly complementary to that sense sequence is called the ‘antisense’ sequence.

What this work pointed to was that if oligonucleotides, which are just short strands of nucleotides, could be created to bond to the ‘sense’ strand in the cell cytoplasm, it would be possible to manipulate protein production. And that would have tremendous applications in the fight against disease, well beyond stopping viral replication.

The most-used descriptor for this “antisense” technology among scientists is the word “elegant.” Beautiful might be another term. Partially this is because the technology is so simple — an attempt to harness something already present in nature. But also because it is extremely specific. It uses the Watson and Crick discovery that DNA is a double-stranded molecule held together by hydrogen bonds between complementary nucleotide bases. That “Watson and Crick” hybridization means that antisense drugs, if crafted correctly, could bind only to the desired target RNA, and nowhere else. This specificity has long been sought after in drug development. It is a holy grail of sorts.

The term antisense would become synonymous with Stan Crooke, and antisense oligonucleotides would define the rest of his professional life. From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: Rosanne Snyder had grown up knowing she wanted to be a scientist, and by the fourth grade she’d narrowed that focus down, specifically, to making drugs. She followed that path all the way to grad school, and the University of Pennsylvania pharmacology program. Before making her choice to enroll, she met Stan to see if she’d fit into his lab. Because she “loved pharmacology,” she wanted the close tie to industry that Stan’s lab promised. When she met him she immediately picked up on his intelligence and felt his lab would be a great place to learn, but beneath that she could also sense that he was hard-driving and demanding. She went home and told her husband that if she could “survive” Stan’s lab, she “could survive anything in the world,” and she asked to join his group.

Once she was there, she began to see the other side of Stan, the warm, affable side that earned him those teaching awards at Baylor, the soft side that comes out when he’s focused on patients. She was “stunned,” she said, to find how nice he could be, how caring he was to his PhD students, encouraging them to come to him with questions, night or day.

She was aware of Nancy’s illness and, like everyone else, saw the physical toll it took on Stan, who grew so thin in Nancy’s last year. And while in his lab, she began to have issues with her own personal life. Her marriage was “dissolving,” she said, and she carried the stress of that with her to the bench. Stan, who knew something about using work as a lifeline, told her to focus on her research, “something you can control,” he said.

That helped. It also helped to get out of the house, and to exercise. She began playing tennis with some other grad students on Saturdays, and Stan, still just in his late 30s at that point, joined when he could. A true friendship formed. When Rosanne’s marriage was over, and after Nancy had died, their friendship changed into something stronger. In their own way they’d each lost someone, each watched a future they’d once envisioned disappear. They helped each other through the process, talked about it. And when it was in their respective pasts they were able to look at each other in a new way.

“I don’t know,” Stan told me. “We just came together.”

He and Rosanne were married by the end of 1986, about two years after Nancy’s death, and a year after Rosanne finished her PhD. They are still together today.

That was the first step toward Stan rebuilding his life. The second thing he needed to do was get out of SmithKline, because the company was in dire financial trouble. It had publicly predicted annual growth of 10% and that was not going to happen, with Tagamet under fire from Zantac. Stan himself knew the end was near when he got a call from SmithKline CEO Henry Wendt.

Stan Crooke: I get a call one night from Henry saying that he’s got bad news. And, instead of being 10% growth in profits, we were going to decline profits by 30%. And that we had to announce it. Uh, when I got that call, I decided that there was no way that SmithKline was going to survive and certainly I wasn’t going to be running R&D. Because remember I had to retool all of R&D. And it was still, you know, much work left to do. And there had been nothing in the pipeline.

Brady Huggett: That phone call was the beginning of the end. Stan wanted more time to finish what he’d started with his research division, but he knew that when SmithKline announced that massive drop in earnings it would open the company up for a merger, and would severely curtail research spending — neither of which was he willing to support. He also knew, in the back of his head, that if there was a merger — as it looked like there would be — his dream of someday being CEO of SmithKline was probably over.

In typical Stan fashion, through a series of meetings with the top echelon of SmithKline, he openly expressed his distaste for their plans. That didn't help matters. He made it clear that he would not stay if the company was going to consider a merger or cut research, and it also became clear that SmithKline “didn’t want me,” Stan said.

So it was only a matter of time. Well before SmithKline let him go in 1988, and laid the blame for their empty drug pipeline at his feet in The New York Times article, Stan was thinking of what might be next. And he had an idea.

It came from a symposium series he and George Poste, Stan’s second in command, had put together at SmithKline. Sometime in 1987, Stan thinks, they brought in Paul Ts’O, a biologist from Johns Hopkins University working on oligonucleotides as antiviral and anticancer agents. As Ts’O presented his work, in the audience Stan sat up a little straighter. The idea itself was “seductive,” he said. It was rational and used nature’s own solution to specificity. And it appeared to be a simpler way to make drugs than building proteins themselves.

Stan dug up the original Zamecnik papers describing antisense. It had been nearly 10 years since they had been published and for many of those years the idea had languished. Partially this was because no one could quite reproduce what Zamecnik had done, and that made it easy to dismiss, but also because making DNA segments at the time was expensive and labor-intensive, which meant the raw material needed to do experiments was basically out of reach. Since those seminal papers on antisense, the field had progressed hardly at all.

Though Stan had gotten approval for a handful of new cancer drugs while at Bristol, and the franchise he built there had helped advance cancer treatment, he knew those drugs were shotgun blasts to the body. For all the damage they did to the cancer they were aimed at, they hit a lot of other stuff, too, and he hated that. There had to be a better way, and antisense seemed like the answer. Stan took the Zamecnik papers and went looking for Dave Ecker.

Dave Ecker’s family is originally from Mount Carmel, Pennsylvania. That's coal country. His grandparents on both sides worked in the mines, and his father did, too, until the mines closed in the ’50s and the family moved to New Jersey for factory work. Dave became a first-to-college kid, attending the College of New Jersey, and then he earned his PhD in biochemistry at Utah State University, before doing a postdoc at the University of California at Berkeley.

He has a good sense of humor and a sharp mind for details and history. This is him.

Dave Ecker: He came down to my office, I mean, he was up here as the head of worldwide R&D, but he had his own research group, of which I was one. And he came down with a publication from Paul Zamecnik and he plunked it on my desk. And he said, Look at this concept. Think about this. If you could use oligonucleotides as therapeutics, they have this Watson-Crick specificity. And there is no better specificity in biology than the Watson-Crick interaction. That’s how nature stores information, that’s how nature transmits information. And he says, Wouldn’t it be awesome if we could make a category of drugs based upon that kind of specificity? And so that was, um, that was ground zero.

Brady Huggett: Stan acknowledged antisense was “light years away” from being a therapeutic. But he still wanted Dave to try to run some experiments. SmithKline’s merger with Beckman Instruments in 1981 had given the company access to a DNA synthesizer — a short-lived model not as good as the ones being made by Applied BioSystems, but it allowed Dave to “make DNA” and that meant he could actually begin to explore oligonucleotides.

It was slow going. Any oligo you put into plasma degraded “within minutes” Dave told me, and for a while they didn’t make “anything that mattered.” Dave spent his off time thinking about what chemical modifications were possible to entice the oligonucleotides to last longer in the body, and then one day Stan floated a proposition.

Dave Ecker: It was 1988, I remember it was the summer time. And uh, because he was busy, he was head of worldwide R&D for a major pharma organization, we had to steal time whenever we could to go over our research. So I would go on the weekend, like I would go on Saturday out to his house and we’d shoot some hoops of basketball and I’d bring my data from the week. And we’d sit and talk science and so forth. When we were done one day, he said, I’m thinking about starting a company to do antisense, and we would leave SmithKline. And I said, OK. [laughs] Would you like me to come along? And he said, Absolutely, I’d like you to help me get it going.

Brady Huggett: SmithKline had yet to fire Stan, but in his mind, he was already gone. And he’d formulated an exit plan.

What Stan wanted was an organization that would focus on science, and science alone. It would be built around R&D — his strengths — and it would have nothing to do with the marketers, or the sales people who were currently getting more attention at SmithKline. If that top rung he’d been reaching for — big pharma CEO — was gone, he’d need to find some other way to lead the kind of company he thought drug development needed. He just wasn’t sure what form that might take.

Back when he’d been at Bristol, he’d been friendly with one of the company’s finance people, Mark Skaletsky. Mark understood the ways in which drug research could be funded, and Stan went to him for his thoughts. Mark sent Stan to a venture capitalist he knew, named Chris Gabrieli.

Chris had once been a medical school student at Columbia, but his father — a physician and researcher himself — had gotten the family into financial trouble with a few “pipe dream” ideas, and Chris had to drop out. For lack of any other way to make money, Chris began shopping one of his father’s ideas to those same VCs who were “never willing” to back his father, he said. But with Chris behind the idea, it was better received. He founded a healthcare software company, named it GMIS, and eventually sold it for $250 million. That earned him in 1986 a position at Bessemer Venture Partners, a venerable name in the VC world.

Chris Gabrieli knew nothing about drug companies, but Genentech — a young flagship biotech on the west coast at the time — had recently gone public, and Bessemer thought this burgeoning industry might be worth investing in. It wanted Chris to launch the firm’s healthcare practice, and this meant that Chris was actively looking for biotech investments when Mark Skaletsky told him about Stan. Chris thought Stan at least would be a good person to meet.

This is Chris.

Chris Gabrieli: So, when I first met him, he was in an awesome office inside a new research and development building that he took a lot of pride in having helped build. He was a commanding presence, he had a huge office, he’s a commanding individual, as you know. Um, the next time I met him, in person, he had been relegated to this type of site where SmithKline, I think, sent people who were definitely leaving. He was at SmithKline Chemicals. He was in this chemicals factory, in sort of a crappy little office that, you know — he had been demoted-slash-moved out-slash something. I mean, I was very respectful of him, he was an MD-PhD, I was 27 or 28 years old, he was, 40s —

Brady Huggett: 40-something, yeah.

Chris Gabrieli: So I certainly, I certainly didn’t say, like, Well you seem to be downwardly mobile here! [laughs]

Brady Huggett: [laughs]

Brady Huggett: It was clear that something was going on with Stan and SmithKline — the former head of worldwide R&D was now stuck in an off-site office, with chemical trucks groaning by on the highway outside the building. In their meetings, Stan asked Chris what he was looking at for investments. Chris had been researching a young company called Vertex, which was built around a protein crystallography technology that the founders hoped would open the door to new drugs. Vertex would, of course, go on to be a massively successful company, today valued at more than $50 billion, but the science back then was not revolutionary enough for Stan.

Chris Gabrieli: He told me, Well, protein crystallography, we all have protein crystallography. Why is that a small company? What’s the edge? So, I thought that was a pretty good argument. And I said, OK, well what’s a better idea? And he said, Well, there’s this thing called antisense oligonucleotides, which I’ve always thought would be interesting but I can’t even get my own people to research it, it’s too risky.

I wrote down, frenetically, antisense oligonucleotides. I didn’t, you know, I didn’t know what that word really meant, but Stan didn’t seem like the kind of guy you’d admit your ignorance to.

Brady Huggett: [laughs]

Chris Gabrieli: So, uh, I wrote it down, pretended like I knew what it was. He explained it pretty well and I read some more about it. And so that’s how — when I said to him, OK, well what’s your better idea? He told me what his better idea was.

Brady Huggett: Soon enough Chris would see the article in The New York Times, blaming Stan for the empty pipeline. That did give Chris pause. But in truth, in those meetings, he was taken with Stan’s intelligence, his experience, and his conviction behind his “best idea.” While out looking for investments, Chris had already sensed that the academic scientists and mid-level pharma executives who were populating the nascent biotech industry at the time, “knew nothing” about making drugs, he said. But here was Stan, a man who had lived a big pharma life and had already ushered several drugs to the market, and who was also a top-level scientist. This combination seemed worth betting on.

It helped that Chris himself had been an entrepreneur, and knew what it took. Entrepreneurs, he thought, perform best when cornered, when they are in a desperate place, as he had been when he’d been forced to drop out of medical school. Failure was not an option for him at that point, and he got a whiff of something similar from Stan.

Chris Gabrieli: I believe entrepreneurs succeed because they have no other choice. And so here was a guy who had succeeded, and then, you know, had this black mark. And I thought, He is going to do — this is his best idea, and he is going to, you know, kill himself or others trying. That’s all you can ever do. The idea seemed big, and the guy seemed driven.

Brady Huggett: And besides all that, it is difficult to hear about the machinations behind antisense and not marvel at its simplistic beauty. The problem was that even Stan didn’t know exactly what to do next. He thought they could finance a leveraged buyout some place, get a chunk of money on loan against the assets of a small pharma company, install Stan as the CEO and run it solely as a research unit. That would give Stan total control over operations, and they’d focus on antisense.

But Chris was a venture capitalist, not a banker. “What’s that old saying?” he said to me. “When you’re a hammer, everything looks like a nail?” Chris knew startups, and so everything to him looked like a startup. And he was convinced that was the correct vessel for Stan’s antisense dream. Stan agreed. Now all they needed was to construct the bones of the thing and convince Bessemer to write a check.

Chris Gabrieli: So I said to him, I’m interested. But you’d have to have, like, a business plan. Three or four days later, a full business plan — no perfect, but pretty damn good — shows up. He’s that kind of guy, right? And I look at this thing and I go, I love this guy. I want to work with this guy. Because normally people would take a month! Or six months! Or they’d say, I need you to hire me a consultant who writes business plans. And it was a pretty good business plan. And we dove right in.

Brady Huggett: Chris went to his partners at Bessemer and asked for seed money. He came back with $50,000 and handed it over. This was the beginning of the company, in July 1988. Stan would be officially let go from SmithKline in a matter of weeks, and with that money they would begin to build an antisense company.

Stan and Rosanne’s house in Bryn Mar became an incubator of sorts. Chris Gabrieli is listed early on as a co-founder of the new company for his role in its financing, but the three scientific founders were Stan Crooke, Dave Ecker and Chris Mirabelli. Chris Mirabelli had gone to pharmacology school at Baylor for his PhD — mainly because they offered him a “free ride” he said — and Stan was his thesis advisor there, back when Stan was still at Bristol. When Stan moved to SmithKline and needed to start a molecular pharmacology department, he asked Chris Mirabelli to come aboard upon completion of his thesis.

Mirabelli has been at SmithKline about 8 years and risen to director of the molecular pharmacology department. He’d been investigating oligonucleotides with Stan, though they hadn’t been able to get SmithKline executives to “embrace it,” Mirabelli told me. He was an obvious fit for the new company, and Stan asked him to join.

Stan Crooke, who had lost Nancy and left behind his boyhood family, was creating a new one. He had Evan and Rosanne, and now his old students and co-workers were rambling around the house, too. Rosanne remembers that time as exciting, a handful of people always seemingly gathered in the kitchen or the living room, yellow legal pads in hand, talking about oligonucleotides, with her right there in the middle of it. What were the hurdles to using them in the body? What might their toxicology profiles look like? How could they be manufactured? How could they be delivered to the patient? And how would the Food and Drug Administration regulate all this? There was a lot to consider, but it did not seem insurmountable.

[music]
[ad]

Brady Huggett: First, the new company would need an intellectual property lawyer, and to raise an official, sizable amount of funding. They also needed a name. Stan figured he’d call it Crooke Pharmaceuticals, but it was quickly pointed out that his last name was a branding problem. For a while they thought they would call the company Mercury, after the fleet-footed messenger god in Greek mythology, playing off the concept of messenger RNA as a drug modality. But the branding was off there, too — no one was going to buy drugs from Mercury Pharmaceuticals. Dave Ecker came up with Isis, the Egyptian god of healing, and that name stuck.

The other big question was where to place it. The biotech scene was growing in two main areas of the US then. The Bay area in San Francisco had Genentech. Cambridge in Boston had Biogen and Genzyme as flagships. The Isis team considered both locations, but Stan leaned toward California. Mainly, he said, because the weather was better. Real estate in San Francisco was already too expensive, but Stan had frequently flown to Carlsbad during his time at SmithKline to visit a Beckman Instruments division there, touching down into tiny Palomar airport. He remembered the area around the airport as being mostly undeveloped. Carlsbad is some 35 miles up Interstate 5 from San Diego, and he sent Chris Mirabelli out to scout the area, with the difficult job of trying to explain to potential landlords what Isis as a company was, and what they would need.

Chris Mirabelli: So I went, and I end up getting introduced to the landlord of what was called the Santa Fe, I think it was the Santa Fe Railroad Research complex, or whatever it was. There was no biotech going on.

Brady Huggett: Yeah.

Chris Mirabelli: And so I remember going and meeting this guy, and I start to tell him what our business plan was. This guy is looking at me like — [laughs]

Brady Huggett: [laughs] What are you talking about?

Chris Mirabelli: What are you talking about? [laughs]

Brady Huggett: Dave Ecker made trips, too.

Dave Ecker: So I drove up here and scouted around and found this street called Faraday Avenue. It was dedicated to being, like, a future science park. Except there was no science on it at the time. There was golf companies and all kinds of other things. But somebody had envisioned science somewhere along the line because the streets are all named after scientists.

Brady Huggett: [laughs]

Dave Ecker: So we found a nice spot and we leased half of a building. And, now again, 1988, 1989, the notion of building out a lab was foreign to any architect or building firm in the area. So I had to go sit with my chemist — we hired somebody to do the chemistry. And the chemist and I, we went down to an architect and we sat down and the architect says, Well, you’re gonna build a lab. So what’s in a lab?

Well there’s benches.

Well how high are they?

I don’t know, they’re about to here. There’s plumbing in them.

What kind of plumbing?

We had to basically sit and recapitulate in our minds what a lab looked like. And they

had to draw it up and go get plans approved by the city. It was like a nine-month process.

Brady Huggett: Nine months was too long to sit around waiting, and anyway, that has never been Stan’s style. So they secured a temporary space in a town called Sorrento Valley, about 25 miles south of Carlsbad, allowing them to begin running experiments while they tried to nail down a first round of venture capital funding. Here’s Dave Ecker again, talking about Sorrento Valley.

Dave Ecker: There was, like, huge storage garages and stuff like that. So we found one, and occupied it, and uh, set up a lab. We built tissue culture hoods out of 2x4s and plastic. The chemistry area, we had these huge warehouse roll-up garage doors with the big pane where you raise this thing up. We put the chemistry in there. We managed to find how we could buy some fume hoods and the like. And, uh, we got started.

Brady Huggett: When Brett Monia finished his thesis back in Philadelphia, where Chris Mirabelli had been his advisor, he joined the team in Sorrento Valley. By now they were into 1989. A roughshod group filled with enthusiasm and free from the constraints of SmithKline, but short on money and material. They learned that if all four hoods were turned on at once in their converted space, it sucked the air from the room and the chemists would pass out. This was “bad for morale” Stan wryly told me, and it isn’t exactly conducive to good science, either. But it didn’t seem to matter. Isis was consumed with the mission, high on what they were doing, and proper ventilation was something they’d fix, along with everything else, when they moved into their space up Interstate-5 in Carlsbad.

They soon added Frank Bennett, who had been at Baylor and then did his post-doc under Stan at SmithKline. He came on as a senior scientist at Isis. Why not? he thought. He already knew the team, and loved the idea of focusing on oligonucleotides full time. He figured they’d know within three years if the technology would succeed or fail, and if it failed he would find a job somewhere else in San Diego. There was always work for a smart bench scientist like him.

As Stan and Chris Gabriele went out making pitches for investment, they realized they were not the only antisense startup around. They came across Hybridon, which had been started by Zamecnik himself, with a sharp young researcher named Sudhir Agrawal. Genta had already been launched, around methylphosphonate technology, from Paul Miller and Paul Ts’O, which tweaked conventional DNA by replacing a non-bonding phosphoryl oxygen with a methyl group, to help stabilize the molecule. And Gilead, which had been formed in 1987 as Oligogen but changed its name, had inherited technology from scientific co-founder Peter Dervan (DERV-an), and was being run by founder Mike Riordan, an MD and venture capitalist. In those days, if an investor was going to put money into a certain technology, it would often stop at one company. There was no need to fill a portfolio with the same type of risk, and anyway, it might seem like a conflict of interest.

So already money was getting competitive. Here’s Stan.

Stan Crooke: We had no inherited technology. My challenge was to prove to venture capitalists that I was free and clear. That I didn’t have encumbrances coming from SKB. And so all of those companies had significant inherited technology, and we had none.

[music]

Brady Huggett: Without inherited technology, the company needed another kind of validation. And the way to get that, Stan thought, was through pharmaceutical partners. A collaboration would prove that others thought his technology was valuable, and it would also bring in money.

The company hired the law firm Cooley Godward, which already represented known biotechs like Amgen and Genentech. Their assigned lawyer from Cooley Godward was a woman in her mid-30s named Lynne Parshall, a “hired gun” she said, used by Isis for issues around intellectual property in the early days of the company.

As Stan knew well, big pharmaceutical companies were struggling to innovate, and their productivity was on the decline. In response, many were starting to look outside their walls for new ways to make drugs. Three pharma firms came to visit Isis in Sorrento Valley: Ciba-Geigy, headquartered in Basel, Switzerland; Rhone-Poulenc, a French company, and Eisai, located in Japan. All were there based on Stan’s reputation — regardless of his exit from SmithKline, he had overseen large research groups that had gotten new drugs approved in his career. Still, they could not have been excited by what they found, upon arriving at the converted warehouse.

Dave Ecker: It was a garage and next door to it was a junk shop of some sort, that bought and sold junk. They used to have this big clown, blown-up clown out front. And I schemed with one of the chemists, who stole it and hid it somewhere, because we were embarrassed that our pharma partners were going to come up to a building and see a big blow-up clown. You know?

Brady Huggett: I mean, but what about your plastic and wooden hoods inside? That wasn’t a problem?

Dave Ecker: We couldn’t do anything about that. [laughs]

Brady Huggett: [laughs]

Brady Huggett: Ciba-Geigy was the first to show serious interest. The pharma was skilled in nucleic acid chemistry, and Stan already knew that Isis would need to make chemical modifications to their oligonucleotides if they were to be stable and effective in the body. Ciba’s interest helped Chris Gabrieli sell Isis to other investors. Bessemer committed to lead the venture round, hoped to be $6 million, and Gabrieli beat the bushes for a syndicate. In his pitch he highlighted the potential of antisense, and the impressive scientific advisory board Isis has accumulated, which included Stan’s old mentor Harris Busch, from Baylor. Chris mentioned the interest shown by Ciba-Geigy. And he of course emphasized Stan. In his notes to potential investors, he described Stan as “one of the five most qualified people in the world” concerning antisense, though he admitted that Stan’s time at SmithKline was “clouded” by recent events — The New York Times article.

As Gabrieli worked to secure a syndicate, he realized venture capitalists were already choosing sides. In particular, he lost an investing partner he’d previously worked with, Venrock, which showed initial interest in Isis but decided instead to back Gilead. Suddenly the technology Gabrieli had heard about just months ago had heat to it.

Isis raised $5.2 million in its series A round of private funding, in March 1989. That is the company’s official founding date, when the greater world first heard about a small company on Faraday Avenue in Carlsbad, focused on antisense. Bessemer led the round, and included investors Accel, Rothschild, and Sutter Hill Ventures.

It was no surprise to anyone that Isis promptly began running through the money. It now had 15,000 square feet of lab space, and it took aim at what the team considered the low-hanging fruit: herpes and genital warts. Given how little was known about antisense oligonucleotides, and the general inability to make them work inside the body, these programs targeted a virus’s replication, as Paul Zamecnik had thought he’d shown in his seminal paper. It also helped that drugs for these indications could be applied locally, by injection or topically. Here’s Stan.

Stan Crooke: We said we were going to focus on local applications first. Learn how these drugs were going to behave — remember, you couldn’t make them in those days, either, so we were going to have small quantities. Then when we cut our teeth on that, we’d move to systemic administration for cancer and severe diseases. And then, only after experience there, would we move into the broader disease categories where safety and tolerability were much more important.

Brady Huggett: By the end of 1989, the company had burned through $2.7 million, the only thing in the plus-side of the ledger was about $280,000 in interest income. Isis already needed more cash.

Bessemer scared up a $1.5 million bridge loan in May 1990, with current investors participating. But Isis soon had money coming in through pharma partnerships. Ciba and Eisai and Rhone-Poulenc all decided to take deals with Isis, though Isis had no data to show them, and it wasn’t exactly clear how the partnerships would work. The Ciba deal was first, and because it was first, it was particularly difficult to negotiate. Here’s Lynne Parshall, the lawyer from Cooley Godward, talking about the first time she met Stan, and the two of them working out the details of the Ciba contract.

Lynne Parshall: I met him in a hotel lobby in Basel. And he had with him a napkin, literally. He had a napkin that he and the business person at Ciba-Geigy had gotten together, you know, presumably at a bar, I think, and written down what this deal was going to look like. And he had called me and said, Come to Switzerland. We’re gonna do this deal — it was the two of us — and plan to stay for however long it takes to get it done.

And that was — you know, Isis was tiny then. And hadn’t done deals before. And antisense technology was basically a research lab phenomenon. And trying to think about how we were going to craft something that was both focused on drugs but was going to share science in a way that, um, at a very early stage was — you know, if we work together, who is going to own this? Who’s going to own that? In an area that was entirely unknown, with a research plan that was at the very beginnings of being able to be fleshed out, was fascinating. And really formed the basis for an awful lot of stuff.

Brady Huggett: It was exhilarating work. Lynne loved it. She was not only taken with the technology, but she was impressed with Stan’s business acumen. He’s an “MD-Phd” she realized, “and he’s thought hard about how this can be structured.” And Stan, as always, was an exhaustive worker. Lynne spent her days in Basel working out the details of the contract, and whenever she returned to the hotel, however late, Stan would be waiting. “Let’s strategize for tomorrow,” he’d say.

The deal called for Ciba to buy $8.5 million in Isis stock, and supply research money for Isis to investigate compounds against four disease targets. Ciba had some 25 to 30 employees that could work on the chemistries for antisense, and it also would help fund the work and develop “large scale” manufacturing processes for Isis. If an approved drug came out of the deal, Isis would get royalties on sales.

In other words, it was a near perfect deal for a small, new company — Isis collected money through the stock sale, and it would also receive funds to develop its own chemical knowledge that would improve the antisense technology. Also, Ciba would help build out Isis’ manufacturing capabilities. The deal would become a model for Isis’s future negotiations: the 3-year, single-target deal with Rhone-Poulenc and the five-year, single-target deal with Eisai both looked similar in structure, if not as rich.

In 1990, the company spent $4.7 million in research and development money, and posted a net loss of $4.5 million. It was clear this sort of spending was going to continue and Chris Gabrieli began to talk about Isis having an initial public offering.

Chris Gabrieli: I had pushed very aggressively for us to get public, because I thought we could. And the reason I pushed for that was, it was good for Bessemer, because we got liquidity in our shares. It wasn’t that I was being a charitable person. But I also understood that Stan needed the open-ended spigot of public money. He was going to run through private money too fast, for private money happiness. And we got lucky that the window was open.

Brady Huggett: For the public markets, Isis needed an IPO prospectus. That meant Lynne’s talents and experience. She came in and translated the Isis story into a legal document, and Isis went out and tried to build a book — the process of securing underwriters and participants for their initial public offering. In that process Stan met a man named Stelios Papadopoulos, a Greek-American who had been one of the first equity analysts covering the biotechnology space, but who had moved to investment banking for Paine Weber. Papadopoulos was a rarity in banking in that he was also a trained scientist. He had a PhD, and had been a faculty member at New York University’s Department of Cell Biology. He was already interested in antisense, and saw the potential in it but he had not yet chosen a horse to bet on.

Stelios Papadopoulos: So I went and I visited every antisense company that was out there, trying to understand what they were doing, what the issues would be. To me, it was abundantly obvious, after several months of visiting the big ones and many smaller ones. And the only company that convinced me that it had the wherewithal to stay in the game and, at the end, outlast everybody and succeed was Isis. There was just no doubt about it.

Brady Huggett: It wasn’t just Isis’s science and the beginnings of its oligonucleotide chemistry. Stelios also came away impressed by Stan’s intellect, the force of his will, and his tenacity. Those attributes cannot be taught, and they were exactly what Stelios thought would be needed to shepherd this technology through the long path ahead. He wanted Isis’s business, and set out to try and win it.

Stelios Papadopoulos: So I began talking to them, working with them — there’s a funny story here, which is, when I concluded what I should be doing it was 1990.

Brady Huggett: Uh-huh.

Stelios Papadopoulos: The company was barely a year old. And I was trying to convince them that we should do an IPO, and I should be the lead banker for the IPO. In fact we went so far as to begin working, and in the fall of 1990, I was in a meeting in San Diego and I stayed an extra weekend in my hotel room. And I literally took the old documents of the business plan for the private placement, and truly cutting and pasting, in the way it used to be done. With scissors and scotch tape. And by longhand, I wrote what I thought was the business section —

Brady Huggett: For the prospectus?

Stelios Papadopoulos: For the prospectus. And I faxed it to Stan at the time, and we kept on talking.

Brady Huggett: But Paine Webber was a middle-tier bank in the biotech world, and Stan, forever competitive, wanted the best. When Isis got wind that they might be able to do better, they cut Paine Weber loose and upgraded their IPO underwriters to Morgan Stanley and Leehman Brothers, the pre-eminent biotech bankers of the time.

Stelios was “hugely disappointed,” he told me. But like with almost all things in Isis’s history, the IPO was not without its drama.

The first thing is that Morgan Stanely wasn’t particularly upfront with Isis. The bank agreed to take Isis public, but did not tell Stan that it was also underwriting the IPO for the biotech MedImmune, which was set to go at around the same time. That could possibly hurt Isis’s ability to draw interest. Business is business, and banks tend to follow the money. Fair enough. But Stan Crooke prizes honesty and loyalty maybe above all else, and to Stan's eye, it didn’t look like Morgan Stanely had been either of those things. It was the last time Isis would use Morgan Stanley for their banking. Later Stan would approach Stelios and admit he’d made a mistake, and Stelios would become the regular banker for Isis and eventually join its board.

Here is the story that Isis took to investors for the IPO. That it was a leader in the small, young field of antisense. It had filed 22 patents with the United States Patent Office. It was building a 3,000-square foot manufacturing facility, and had synthesized more than 350 novel classes of oligonucleotides. The company had grown to 66 full-time employees, nearly half of which had a PhD or an MD. It had scored some federal research grants, had three pharma partnerships, and a pipeline of 11 RNA-targeted programs against a range of diseases, including their two lead programs: Isis 1082, directed at herpes, and Isis 2105, for treating genital warts from human papillomavirus. Isis planned to start human clinical trials with those two programs within a year.

Investors saw potential in that 11-program pipeline. But some of the indications Isis wanted to attack had no usable animal models, and antisense drugs had never been put into humans. The scale of the problem before the company was enormous. Even a staunch believer like Stan suspected that the current theories around antisense were probably wrong, and to fully understand the technology it was going to take many years and lots of money. The company had already accumulated a deficit of more than $8 million, and so far any money that the company earned went straight into research and development. Pitching the Isis story took “an astonishing amount of hubris,” Stan said.

On top of all that, the public market for biotechs had quickly turned cold. A young biotech company called Regeneron went public in April 1991 at $22 a share — a high price that drew criticism for the lead underwriter, Merrill Lynch. The stock immediately dropped on the open market, and a month later it was trading at less than half the IPO price. Furious shareholders filed a class-action lawsuit against the company, and the nickname for the company’s IPO among bankers was “Regurgitron.”

Regeneron today is alive and well, with a market cap of more than $50 billion and a reputation for brilliant science, but their stock performance just as Isis was trying to go public hurt the market. It didn’t help that the data Isis were generating in their experiments only raised more questions.

Stan Crooke: It was really difficult. The market had closed. There was a lot of skepticism. And, um, we were just beginning to learn that a lot of what we were observing wasn’t really antisense. That, with the first-generation ASOs, we had a lot of pro-inflammatory effects.

Brady Huggett: Isis originally sought to sell 3 million shares priced between $13 and $15 a share. They couldn’t find the interest at that price, or at that volume. “We had to take a haircut,” Stan said, and in May of 1991 they sold 2.5 million shares at $10 apiece, for gross proceeds of $25 million.

Less than what it wanted, and, as was almost always the case with Isis, less than what it needed. But it was public now, and that gave it broader venues for financing than it had as a private company. Isis staged a little celebration for going public, and Stan asked Lynne Parshall to fly to San Diego and join them for it.

Lynne Parshall: I flew down to Carlsbad, and Stan took me out to lunch. Now that I know Stan, I realize he never, like, leaves the building for lunch, you’ve probably gotten that.

Brady Huggett: [laughs] Yeah.

Lynne Parshall: He never takes anyone out to lunch. But we met at a restaurant and he took me to lunch. We spent a lot of time talking about his organization and, you know, what it needed to do to go to the next step of maturity. And we sort of outlined who, you know, who was going to fill this, sort of, strategic finance gap that he had in the management team. And we sort of outlined this sort of young, aggressive investment banking type of person who was going to come onto the team. And work on BD and strategic finance and a variety of things. It got time to have coffee, and Stan of course doesn’t drink coffee, either. As you know, he’s rarely without a Tab can in his hand.

Brady Huggett: Yeah.

Lynne Parshall: But he sat there while I drank coffee. And at the end of it, he said, So, do you want the job?

Brady Huggett: She did want the job. Lynne flew home, talked it over with her husband, and agreed to move the family to Carlsbad and become the in-house counsel for Isis. “You can’t imagine how rewarding it is,” she told me, to not only be conceiving the contracts, “but then living with them” as an actual employee of the company.

Meanwhile, in the lab, no one was sure if what they were seeing in their experiments was true antisense, or a rogue effect. But at least now they had an entire team to aim at the problem. They had built a true startup around the technology, and gotten Isis public. With access to the markets, Isis would now have an honest shot at decoding this technology that had first captivated Stan Crooke back in 1987. Here’s Chris Gabrieli

Chris Gabrieli: One thing I’ve come to believe is, you know, entrepreneurs are an important part of the ecosystem of creation. And they come with their own foibles, but man, are they valuable to have. And I do think — it’s funny, I haven’t thought about this in a while, Brady — but I do think that one of the things I’m proudest of is: Stan is a natural-born entrepreneur. He has the belief in his vision, the ability to get other people on, the ability to see, you know, years ahead, where things are going to have to go. The ability to go after that. The intensity, right? Who was, at that point, surprisingly, trapped in the body of a corporate guy. Right? And I do feel that it was a happy luck that the only thing I knew how to do — he was asking me about these private equity things. I didn’t know anything about that. I didn’t think it fit him, and now I understand how much it didn’t, but at that time of my life I would have had a hard time explaining why it wouldn’t have made any sense. He vaguely knew what these startups were, but he didn’t know almost anything about it.

Brady Huggett: Yeah

Chris Gabrieli: And I’m kinda glad that I unleashed this force of nature in the right venue. Right? If Michael Jordan had stuck with baseball, basketball would have been impoverished for it. If Stan Crooke had stayed a corporate guy, somehow — that wasn’t the right venue for him. He’s a builder. He needs his own thing. He is such a natural entrepreneur, right? And I think at that point in his life, though, he did not realize that. I think the validation that came with the big titles he held at Bristol Myers meant a lot to him personally. Because part of being an entrepreneur is, the beginning, you work for some crappy little company you started. How can you tell the difference between that and the used-car salesman, or the Fuller brush salesman? But I do feel good about getting the right guy in the right vehicle.

Brady Huggett: Stan Crooke grew up scrambling to make money for his family. Money that helped put food on their table, helped his mother, with her rheumatoid arthritis, stay out of the wheelchair. The newspaper route. The thousands of hours working at The Tech Corner drug store, while still in high school. That is a life of hustle. That is the life of an entrepreneur. Startups are gritty, they need to make due with less, and they persevere — in other words, they mirror Stan’s background perfectly.

But his youth had taught himself something else, too. As a boy he’d felt he was on the receiving end of the world. At the mercy of bullies, guidance counselors, and, perhaps most importantly, his mother. He swore that when he was grown, he’d build a life that he was in control of. He thought he’d had that at SmithKline, with 3,000 researchers under his direction. But he’d been shown that someone else pulled the strings there. A startup might not have carried the prestige of a big pharmaceutical company, but he now had Isis, and he was fully in control of it.

[theme music]

Thank you to Stan Crooke, now and always. To Rosanne Crooke, for sharing her memories. To Stelios Papadopoulos, for his incredible archival work on this industry, and his deep knowledge. To Chris Mirabelli, Dave Ecker, Brett Monia, and Frank Bennett for their stories about the beginnings of Isis. To Chris Gabrieli for his uncanny memory of biotech banking decades ago. To Lynne Parshall, for her insight into Isis’s dealmaking. Rest in peace to Mark Skaletsky, who passed away in January of 2020.

Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the two previous chapters. Chapter 4 will be out in a week. Until then.

Chapter 4: three kinds of failure

Brady Huggett: Chapter 4: three kinds of failure

Art Krieg was born in Cleveland, Ohio. His dad was a researcher and moved the family around: first Alaska; then Massachusetts; then Syracuse, NY; until finally they settled in Hershey, Pennsylvania. When Art began his higher education, he moved around, too. He went to Haverford College in Philadelphia for his undergraduate degree, and then attended medical school at Washington University in St. Louis, then did a residency in internal medicine at the University of Minnesota. That was where he realized he wanted to go into research. His reason, as he himself admits, was a common one. As a doctor you help patients one at a time. But if you develop a drug, you might be able to help hundreds of thousands of people. So Art in 1986 went to train in rheumatology at the National Institutes of Health, a place he still calls “a national treasure.”

In the early 1980s, a biochemist named Marv Caruthers and his team at the University of Colorado at Boulder had developed phosphoramidate chemistry that allowed the building of an automated DNA synthesizer.

Suddenly anyone with one of these machines could type into the keyboard the sequence of DNA they wanted, hit the start button, and then “go and have a cup of coffee,” Art told me, while the desired DNA was produced into vials.

This opened the door to all kinds of experiments, and interest began to flow back toward antisense. Art caught wind of the technology while at NIH, and he went to the first antisense conference ever in 1989, where he learned about the new companies being formed. He was naive about the difficulties ahead, but the concept behind antisense intrigued him.

He went on to have a career focused on the mechanics of antisense. Art co-founded the first academic journal for the technology, called Nucleic Acid Therapeutics, and co-founded the Oligonucleotide Therapeutic Society. Over the past decades, he has co-founded or worked at several oligonucleotide companies, including Checkmate Pharmaceuticals, which is focused on immunotherapy and where he’s currently chief scientific officer. He has more than 50 patents covering oligonucleotides to his name, and he has spent decades investigating antisense. This is him talking about the original Paul Zamecnik paper.

Art Krieg: And Paul Zamecnik deserved a lot of credit for thinking of this in 1978, when it took six months to make enough synthetic DNA to do a single experiment. And yet we now know that the experiment he performed could not possibly have worked through an antisense mechanism of action. Because he was using unmodified DNA, and whatever they saw had to be an artifact.

Brady Huggett: In other words, the entire antisense industry of the late 1980s, this collection of companies that included Stan Crooke and Isis, had been formed on a misleading finding. From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: In March of 1992 Isis began clinical trials with its compound against human papillomavirus (or HPV), called ISIS 2105. The trial called for the drug to be injected into the skin after genital warts had been surgically removed, and the study was meant to measure a reduction, delay or elimination of wart recurrence. In December that year, they moved the compound to phase 2. In culture dishes, the drug had been shown to inhibit the production of a protein required for strains of HPV to replicate, and the company eventually tested it in more than 300 people, at considerable cost.

To this day, Stan still thinks the genital warts trial “should have worked.”

But it didn’t. The drug wasn’t showing an antisense mechanism, and it wasn’t spurring a pro-inflammatory immune response to knock down the virus either, and it certainly wasn’t doing those two things in tandem, as Stan had once hoped it would. By 1995 Isis had stopped development.

The herpes drug program was stopped before ever being tested in people. “It just wasn’t the right drug,” Stan said.

But partner Eisai wanted Isis to look at cytomegalovirus. CMV, as it is called, often presents no symptoms, but when the immune system is compromised, the virus sometimes causes CMV retinitis, an inflammation of the retina that can lead to blindness. Isis called the compound ISIS 2922, or ‘fomivirsen,’ and it was a synthetic 21-nucleotide phosphorothioate oligodeoxynucleotide. That meant it had a sulphur atom in place of a non-binding oxygen in its phosphate backbone. It was aimed at CMV messenger RNAs that code for a protein needed for replication. With Eisai paying half the costs, Isis moved it into phase 3 in 1995 — the final trials needed for approval.

Isis had always prided itself on being open about the work it was doing. It scheduled a day of events that year to share their progress with the greater world: first an internal board meeting, then a shareholder’s meeting with the press invited, and finally a session focused only on their science, with presentations and posters set up under tents outside the company’s headquarters.

Yet early in the day, it went off the rails. Here’s Stan.

Stan Crooke: During the board meeting, which preceded the annual meeting, Dan Kisner, who was here then, got a call, left the meeting. Came back, ashen. And said, Oh, well this and that.

Brady Huggett: And said, Hey we have a problem? We may have blindness?

Stan Crooke: Yeah, oh yeah. And so, on the spot, we had to decide if we were going to keep the trial going, or suspend it, or stop it altogether.

Brady Huggett: Dan Kisner had worked with Stan at SmithKline, had admired his energy and his intellect, and he joined Isis right after the 1991 IPO. He was chief operating officer when he got the call from a clinical director in the fomivirsen trial. One of the patients had ophthalmitis in one eye, with acute vision loss. There had been nothing “traumatic” about the injection, the physician said, but it was terrible for the patient and Dan knew it could very well sink both the trial and the drug.

In Kisner’s mind, there was only one thing to do, which was stop enrollment in the trial. That meant halting patient accrual, and those already in the trial would get no more drug either. He also decided that all patients should go see an eye doctor as a precautionary step. Those decisions were made immediately.

But that still left dealing with the long day ahead of them, and the many visitors. Dan and Lynne Parshall and Stan and the rest of the management team huddled in Stan’s office to think through their responsibilities. First they agreed to report the adverse event to the FDA, as required, and to not reopen the study until they’d conducted a full evaluation. But Dan also argued, “with no debate,” he said, to inform everyone scheduled to be at their company that day. Dan had about half an hour to overhaul his slides for their annual meeting, and when he’d made the changes he stood before the assembled shareholders, analysts and biotech trade press and said they were halting the trial of their lead product. When that was done, the company relayed the same message to those attending the scientific presentations that afternoon. For hours, to everyone, they passed out the bad news about fomivirsen

“It was not my best day,” Dan Kisner told me.

Ethically this was the only path forward, but it turned out to be the right thing for the share price, too. Isis had expected the stock to get hammered — their only clinical product had just reported a serious adverse event — but the next day shares inched upward. Analysts “patted us on the back,” Dan told me. They appreciated the transparency and were willing to wait on the results of the investigation.

The ophthalmitis turned out to be a complication of the injection itself, and had nothing to do with the drug. No other problems had been discovered, and nothing grew in the culture they performed from the affected patient. The trial continued. But it was a lesson for Isis: always be honest, always tell the truth.

But the problem becomes when your version of the truth doesn’t match up with what everyone else thinks. Because then your truth begins to look like a lie that you won’t stop spreading.

[music]

By the end of 1997 fomivirsen had completed four phase 3 trials, one of which was in combination with other drugs. All measured time to disease progression. The package Isis sent to the FDA had data on more than 300 subjects, and the agency approved it to treat CMV retinitis in AIDS patients in 1998, just five months after the application was submitted. The drug was branded Vitravene, and approval in Europe and Brazil followed.

Stan, as quoted in The New York Times, called the approval “one more piece in the mosaic of evidence” that suggests antisense can work.

Though Isis had high hopes, publicly saying Vitravene might reach $100 million in annual US sales, the drug would earn Isis only $674,000 in royalty revenue over the course of its short life. Isis had argued to the FDA that an increasing number of AIDS patients were failing the HAART antiretroviral therapy regimen used at the time, and that would cause the incidence of CMV retinitis to rise, but in truth that didn’t happen. Isis itself had trouble completing enrollment in its trials — in 1997 it had added “nearly zero” new patients, it said, and that trend of decreasing disease incidence continued after approval. The drug was withdrawn by the FDA in 2001, with partner Novartis withdrawing it from Europe in 2002, due to low demand.

Vitravene was the result of 9 years of research into antisense. It was applauded as the first antisense drug in the world, but when it never sold, the narrative changed.

Stan Crooke: It was a big deal to us, and others, that we got the first antisense drug approved, but it then became, really, just another failure that Isis had. You know, How come you fail all the time?

Brady Huggett: It had been more than 10 years since Stan Crooke first considered forming an antisense company. Over that period he had included his wife, close friends and colleagues, and his mentor Harris Busch into his dream. Much of that core remained. Frank Bennett was still there, well past his self-appointed 3-year deadline for knowing if antisense would work. So was co-founder Dave Ecker. Chris Gabrieli was still on the board. Brett Monia remained. There had really been only one notable departure from that initial core: Chris Mirabelli in 1993. He and his wife had had a baby, and they moved back to the East Coast to be closer to family. He had been working with Stan for a decade at that point, and “with Stan around, it’s hard to see yourself ever failing,” he said. It felt like it was time to go off on his own.

Here he is talking about leaving Isis.

Chris Mirabelli: Um, it was, it was difficult. It was difficult. I think for both of us it was difficult.

Brady Huggett: Because of this long history that you had?

Chris Mirabelli: Yeah, yeah. And, you know, like you said, it was one where — I don’t know whether loyalty or whatever was — as I said, I think it was just a hard thing for me to communicate to him. And Stan is somebody who expects you to, expects, sort of, longevity, if you’ve been working together. It had only been five years and I was one of the founders.

Brady Huggett: They’d started a company to transform the concept of antisense into a viable drug development platform, and that work was far from complete. To Stan, departing after only five years felt a little like quitting. But on a personal level, Chris Mirabelli moving to Boston was also like someone leaving the family, and that would always be hard for Stan to stomach.

Otherwise, however, the company was undergoing consistent growth. By mid-1998, Isis was up to ~340 employees. It had been awarded more than 90 US patents, and another 70 in foreign countries. It continued to attract interest from pharmaceutical partners, including in 1995 a significant deal with Boehringer Ingelheim, in which Boehringer bought $28.5 million of Isis stock, gave Isis a $40 million line of credit, and soon paid another $10 million for a milestone achieved in their partnered program around ISIS 2302. That compound was being widely tested by the companies, including a phase 3 in Crohn’s disease, then also psoriasis, ulcerative colitis, renal transplant rejection and asthma. Lower in the pipeline Isis had programs in cancer.

So what did it matter, in the long run, if Vitravene didn’t sell? There was plenty else coming.

To fund all this research, Isis had brought in money in just about every way imaginable. Here’s Stan.

Stan Crooke: It turns out I had hired a guy named Yasunori Kaneko, who was a Japanese national, who had gone to the right preschool, gone to the right, University of Tokyo and KO medical school, and was very highly connected in Japan. And it was really he who helped me do the secondary in Japan. And the market was still closed in the US, and so Yasunori and I were talking, and he said, I think we can, we could take advantage of the relationships I have in Japan and raise money there. There really wasn’t much other choice. So off we went to Japan.

Brady Huggett: Kaneko was chief financial officer at Isis then. He took Stan around to the big investors — Mitsubishi, Zaibatsu — and Stan gave them his perhaps overly hopeful, but still frank pitch: antisense had big potential, but it would require a lot of money and time to get there. Isis eventually raised ~$19 million from Japanese investors in 1991, then $13.7 million later that year in the US. It raised ~$37 million across two public offerings in 1993, and more from the public in 1994 and 1995.

Basically, Isis raised money when and wherever it could, and it borrowed money to fill in the gaps. But mostly it was fueled through its research partnerships with pharmaceutical firms — in 1998 alone it earned almost $39 million from collaborations, and signed deals with Abbott Laboratories and Zeneca Pharmaceuticals, to go along with their partnerships with Boehringer Ingelheim and Novartis.

But there was trouble there, too. In March of that year, Isis got a call from Novartis. For months Isis had been trying to reproduce the data they were getting from their partner, related to their cancer program. Isis couldn’t do it, and that raised a lot of questions. Here’s Brett Monia, who was in charge of oncology drug discovery at the time.

Brett Monia: We were also getting, at that time, now questions from collaborators, and even competitors. Who were trying to do, you know, reproduce what we were sharing with everybody.

Brady Huggett: Because they’d seen your publications?

Brett Monia: They saw our presentations at conferences, presentations usually precede publications, and then some publications, as well. So, you can see how this would build. Our efforts intensified, we were putting more and more pressure on Novartis. Not questioning whether or not there was something going wrong, really questioning our own capabilities. What were we doing wrong? We were really intensifying the effort.

It was around this time that I received a call from the global head of oncology at Novartis. Who informed me that a single individual at Novartis, who was responsible for analyzing all the data — he was really responsible for all the animal data in cancer at Novartis — that that single individual admitted to falsifying all the data. But also their internal drugs. It was all phony. This obviously was a shock to us. But more than that, it was very concerning because we had clinical trials in progress that were based, in large part, on that data.

Brady Huggett: In retrospect, maybe they should have suspected. The data Isis was getting from Novartis in these animal studies were “stunningly positive,” Brett Monia told me. Isis began to sift through the wreckage, trying to establish exactly what data had been falsified, and by how much. The companies were investigating three cancer compounds together, including ISIS 3521, meant to inhibit the expression of protein kinase C (alpha), and ISIS 5132, designed to inhibit C-raf kinase. When they knew where the lies had been laid, they set out to fix the public record. Isis published a correctionin Nature Medicine for its paper “Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase.” Isis also informed the biotech trade press of the fraud and disclosed the entire thing to the American Association for Cancer Research, and the American Society for Clinical Oncology.

The false data centered around dosing — the researcher had faked results showing tumor suppression from tantalizingly small levels of drug. But when Isis redid many of the studies, they still detected an anti-tumor effect, albeit at a higher dose, and decided to continue the program.

Though this had been no fault of their own, issuing journal corrections and alerting the American Society for Clinical Oncology about inaccuracies that directly related to clinical work was not a good look for Isis. Or antisense. And if that wasn’t enough, in 1998 Gilead left the antisense field completely.

In many ways, the company had functioned as a colleague to Isis, a compatriot in antisense located up the California coast. But in other ways, Gilead seemed like an older brother, with all the sibling rivalry that entails. Formed first, and with a medical doctor/venture capitalist at the helm, the company had an easier time with investors, bringing in more than $40 million from venture capitalists and then raking in ~$86 million in its sought-after initial public offering in January 1992. And it had gotten to the CMV retinitis market first with its antiviral, nucleotide analogue drug named Vistide, which, in its first three years on the market, brought Gilead more than $25 million, before its sales also shrank away with the declining incidence of CMV retinitis.

In other words, Gilead cast a long shadow with the public, and Isis at times seemed caught in it.

Steve Tighe was one of the first analysts to cover the antisense field, and wrote in 1992 what was considered the first analyst’s note on public antisense companies. Here he is, talking about the field at that time.

Steve Tighe: As I stated in the report, money raising was a big deal. At the particular time that I wrote that report, Gilead was much more successful, or at least had more money in the bank at the time. I think they had double what the other — at least double what the other players had. And Mike Riordan, who at the time was the founder and CEO of Gilead, had a real gift for, um, just changing his story, you know, a couple times a year. Same underlying story, but he was able to market it in a different manner and to different sets of people. I think he proved to be very adept at getting money in the door. So yeah, it was, it was a real serious competition, and at that particular time, um, you know, I think Mike Riordan at Gilead was winning that war.

Brady Huggett: When Stan Crooke started Isis, he thought he knew how to speak to investors — he’d been in front of them many times through his role at SmithKline. But he learned that doing it as CEO of a startup was riskier, somehow more naked. He had to sell them on the great potential in this unproven technology, but still be honest about all the things they had to overcome. If he focused too much on the potential, it might seem like hype. If he was too blunt about the technological hurdles, it would scare everyone away.

In fact he was accused, in his career, of overhyping antisense. It was a walk on a tightrope for him, and Stan struggled to find the balance.

Stan Crooke: I don’t feel like I ever knowingly hyped anything, but certainly that was said about me.

Brady Huggett: So you said you’d understand why they might say that. What’s your understanding of why they might say that?

Stan Crooke: Because I was selling, and I was still learning how to do investor relations, and I don’t think I ever got very good at it. You know, I never, I couldn’t quite figure out what language to use. Just, the way investors wanted people to talk at that time.

Brady Huggett: Mike Riordan, at Gilead, on the other hand, was great at it. He was charismatic, had experience as a venture capitalist, and an MBA. Selling Gilead’s story to bankers must have felt like second nature to him. Stan, competitive as ever, had to watch money flow toward Gilead, when he was sure he had the better antisense company.

Stan Crooke: I would just say it was very frustrating to me.

Brady Huggett: In truth, though, Gilead’s antisense efforts were not progressing well. It had signed a big deal with Glaxo Wellcome in 1990 to develop genetic code-blockers — Gilead’s name for their antisense technology. The deal had been extended over the years, but Glaxo pulled out in 1998 without the companies ever producing a drug. Gilead began looking for a new partner, but when nothing materialized, it simply left antisense behind.

It was a moment of opportunity for Isis. Stan had long wanted to hold the dominant IP position in antisense. “If we didn’t invent it, the plan was to buy it,” he told me. By the end of the year Isis had paid $6 million for all patents and patent applications Gilead held around antisense chemistry and drug delivery.

Gilead quit antisense because it had better prospects to pursue. In the early ’90s Gilead had formed a partnership with a researcher named Antonín Holý, who was at the Institute for Organic Chemistry and Biochemistry in Prague, Czech Republic. And also with his collaborator Erik DeClercq, at the Rega Institute for Medical Research, at Katholic University in Leuven, Belgium. The collaboration broadly covered biologically active nucleotide analogues, which are synthetic, chemically modified to be incorporated into DNA or RNA and inhibit both cellular division and viral replication. The collaboration included three specific compounds — cidofovir, tenofovir and adefovir. These would become Vistide, the CMV retinitis drug that beat Vitravene to market, and Viread, which was soon a blockbuster and a major asset in the fight against AIDS. Adefovir became Hepsera, for chronic hepatitis B. Gilead had fought hard for the pool of money available for antisense, and won a lot of it, but the company simply didn’t need antisense any longer. Here’s Steve Tighe.

Steve Tighe: Look, every time I covered a group of companies, you know, neuroscience companies, antisense companies, they all, um, they all, as I recall they all talked a lot of trash about one another. I’m not saying it was necessarily open, but also I think there was a likelihood that investors would interpret the movement away from antisense as negative. When in fact what was probably said was, Well, we found a better opportunity in this space. And so we’re allocating our capital in that direction. It was probably a very rational decision.

Brady Huggett: Yeah.

Steve Tighe: I don’t know that it necessarily meant antisense was bad. I just think that the other chemistries or projects were better. And I think in the case of Gilead, they found some AIDS drugs in, I think, the Czech Republic at Rega or one of the institutes over there that proved out to be really compelling. And as we all know, it became an AIDS company.

Brady Huggett: It had been a practical, straight business decision. But the problem, for Stan, Isis and anyone left in the field, was that Gilead justified its departure by telling anyone who asked that antisense didn’t work. Or anyway, that’s how Isis remembers it. Here’s Dave Ecker.

Dave Ecker: Gilead went on to do something else, and uh, they actually scorched the earth leaving antisense. They were sort of a high visibility, Wall Street company. And um, they actually said, We’re getting out of antisense because it doesn’t work. Right? And uh, we’ve got Gilead scorching the earth and people saying antisense doesn’t work, and the world was not believing that antisense could be a therapeutic.

Brady Huggett: This is not the way Gilead recalls this period of its history, however. Michael Riordan did not want to be interviewed or recorded, but he did agree to provide his thoughts. Riordan left Gilead in 1997, so the sale of the antisense intellectual property came “after my tenure,” he told me. He agreed that attempts to use antisense oligos as therapeutics were generating “poor results” at that time, and “it would be understandable,” he said, “if this caused a dampening effect on the field.” But he doubts anyone at Gilead “would have bothered to attempt” to criticize antisense, he said, as the company left the room.

The CEO at the time of the IP sale, John Martin, who helmed Gilead through two decades of tremendous success, passed away in March of this year. But current Gilead management told me that they do not “recall any wholesale comment that the technology would never work.” Rather, they said, Gilead knew “it would be difficult” to find success with antisense, and as a smaller company at the time, it prioritized work in other areas.

Regardless, prioritizing another area was not a decision Stan Crooke would have made. He had committed to antisense for life. Walking away for a better opportunity was a kind of cheat, taking the easy way out, he thought. Gilead’s departure, and then its subsequent success in the HIV field, was another source of tension between the companies — or at least in Stan’s mind. He has told me, dismissively and more than once, that he thought he could in-license a nucleotide analog and get it approved “in his sleep.” He was out to do something bigger, no matter all the massive success, financially and for patients, that Gilead has achieved through in-licensing since.

At that time, Isis had already begun to accrue a valuable patent estate, enough to out-license in 1998 patents covering immune stimulation by phosphorothioate oligonucleotides to a smaller company, called CpG ImmunoPharmaceuticals. Isis’s IP position was further strengthened in December 1999 when it was awarded U.S Patent 6,001,653, covering Human RNase H1, a cellular enzyme that degrades RNA when antisense drugs bind to it. This was a key component to most antisense compounds, and also when the technology was used as a screening tool. It helped push the company toward the patent domination Stan long wanted.

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Brady Huggett: Even before Gilead’s departure, there had been a murmuring of disbelief about antisense in academic circles. Art Krieg in 1995 had published a paper in Nature titled CpG motifs in bacterial DNA trigger direct B-cell activation. What the paper said, roughly, was that a cytosine-guanine dinucleotide sequence in the backbone of an antisense drug could generate an immune response in the patient, and that immune response would sometimes appear to be an antisense effect. This “CpG motif” was in nearly all the antisense drugs being developed at the time, including Vitravene. Krieg’s paper directly called the current generation of antisense drugs into question.

Art Krieg: The first approved antisense drug, for the eye, and I’m putting air quotes around ‘antisense,’ that’s fomivirsen. This drug that was developed for CMV retinitis. That oligonucleotide does not work through an antisense mechanism of action. Or, it did not work — it’s no longer marketed. And so even though at the time it was considered to be a proof of concept that antisense therapy works, when you go through the data on the drug, it’s actually clear that it could not have been working through an antisense mechanism of action.

Brady Huggett: That’s clear now, or that was clear then?

Art Krieg: Well, so I went to Isis in, I think it was 1995. And I gave a seminar there, where I talked about the immune-stimulatory effects of oligonucleotides. And I used their own published data with this oligo fomivirsen to show them that their drug could not have been working through an antisense mechanism. Because they had made, they had published that if you change bases on the ends of the oligo, where there is a sequence G-C-G, on each end of the oligo. And they had published that if you change those bases, you lose all of the activity of the drug. But if you change the sequence of the bases in the middle of the oligo, that ought to be the most important for binding to your target, it didn’t affect the activity of the drug. And the discovery that I had made, at that time, was that C-Gs,C-P-Gs, are immune stimulatory.

And so, what I told them was that, Your drug is not working through an antisense mechanism. It’s working through some kind of an immune mechanism that’s due to these C-Gs on the ends. And one of the scientists came up to me afterwards and said, You caused a minor riot in the back room there. Of Isis. Because I think a lot of people realized, Yeah, that’s gotta be true.

Brady Huggett: Isis wasn’t blind about it. Dan Kisner remembers that presentation. Isis was sure its drug inhibited the expression of proteins required for virus replication, but Dan also said that Art’s paper and discovery on the CpG dinucleotide “was real science.” It could not be dismissed or ignored. Vitravene, also called fomivirsen, worked — the clinical trial proved that — but exactly how Vitravene worked, Dan to this day “can’t say.”

Others were questioning antisense. Cy Stein, a former researcher at the National Cancer Institute and current professor and researcher at City of Hope, had written a paper even earlier, in 1993 in Science, titled Antisense Oligonucleotides as Therapeutic Agents — Is the Bullet Really Magical?In the paper he laid out the six things that would be required for antisense to work in patients, including resolving issues around manufacturing and uptake by the target cells. Only if those six rather sizable hurdles could be cleared, he wrote, could antisense live up to its potential.

Art Levin, senior vice president of drug development at Isis during this period, told me that while he was on an early phone call with FDA reviewers to discuss Vitravene, a reviewer wondered aloud why they were having the call, given that “antisense doesn’t work.” It was yet another “eye-roll moment,” Levin said, the kind of thing the company heard daily from those outside its walls.

Through all this, Isis pushed ahead. With Vitravene doomed on the market, the next hope was the compound ISIS 2303, or alicaforsen, as it was called, partnered with Boehringer Ingelheim. It was designed to inhibit the expression of the I-CAM-1 gene, and Isis had it in phase 2 trials for a handful of indications, the most advanced being Crohn’s disease. An interim analysis of 150 patients in late 1998 showed the drug caused a steroid-free complete remission in 29% of patients. The placebo arm had a remission rate of just 14%. Isis expected the full trial to bear similar results, but when it ended in late 1999, only 12% of drug-treated patients in the second half of the study had a steroid-free remission. The placebo group was much higher.

The trial, Stan told me, “was a zero.” The difference between the interim and the final analysis was hard to quantify. It’s possible that clinicians were putting their most needy patients into tumor-necrosis factor antibody trials, which were new then for Crohn’s patients. So maybe enrollees in the second half of the trial had something more nebulous, like irritable bowel syndrome, and the drug didn't work. But either way, alicaforsen was another clear failure.

Seeing those final results was a “desperately bad moment,” Stan said.

Stan Crooke: I went to look at the unblinding, just assuming it was going to be positive because we already had statistical significance at the halfway mark. Couldn’t believe. Couldn’t believe and couldn’t explain, and couldn’t understand how this drug could have failed.

We were out of money, I had to lay off about half the people. And there was no hope.

Brady Huggett: Nasdaq, expecting a bloodbath, halted trading of Isis's stock the day the company went public with its news, until it could hold a conference call. But when that was over and trading resumed, the stock fell through the floor, ending the day down 64%, at $5.59.

Even Stan had to wonder if the dream was over.

Stan Crooke: So the first step was to convince ourselves that we had the right to ask for money, and the right to stay the course. Once we got to that, then it was just a question of how. But the big, the big issue for me was, Do I have any justification in continuing to pursue this technology, when everyone was saying, when everyone smart gave up?

There was never a moment when I saw that the concept, that the technology had gotten to a place where we couldn’t succeed. No, the science taught me what I needed to know there. There was certainly a moment when I thought — and this was the worst feeling of all — was that I felt we were on the cusp of doing this, and that it was unlikely that we’d be able to get the money. And that bothered me a lot because it meant that the truth of this opportunity was going to be lost, and it would probably be lost for a long time.

Brady Huggett: The truth. It was getting difficult to understand just what that was. In science, answers tend to come slowly, almost emerging out of a fog. A hypothesis only leads to more questions. There were some people who already thought they knew the truth about antisense, which was that it didn’t work. Others, including Stan and everyone at Isis, thought they knew the truth, too, they just needed to get the proof.

The first thing Isis had to do was reduce its size. Stan treated Isis like a family, and now he was going to have to let people go, people that depended on him for their livelihood, who needed the job to support their real families at home.

Stan Crooke: I had to lay off people who were friends that had invested, you know, their careers and their lives in trying to do this. That day I had an all employee meeting and laid it all out. Said, I’m not sure we can make it, but I am very confident that we should. That we have solutions to these problems. And I said, If I can raise the money, here’s the plan.

I mean, you just need to tell the people the truth and show them you’ve got a path, that, that may be achievable.

Brady Huggett: The reduction resonated throughout Isis. Here’s Lynne Parshall, talking about what a massive layoff does to a company, and morale.

Lynne Parshall: Um, which I’ve got to say, and probably other people have talked to you about it, is one of the most awful things to have to go through. Because you’re sitting in a room with a box of Kleenex on your desk. You know, people come in and they're your friends. They’re not just your work colleagues, they’re your friends. And you have to tell them that you’re — that you had to make difficult decisions and they don’t have a job anymore. And, um, and it’s very hurtful, and then after that, the people who are left feel good that they are still there, but feel terrible that their friends are gone. And are all being asked to do five jobs, you know?

Brady Huggett: And here’s Dave Ecker talking about that day

Dave Ecker: We have a culture in the company that’s, that people behave well to one another, where people dream big. Uh, people believe that putting the patient first is what matters. And when you have a shared vision like that with a bunch of people, and you have to say goodbye to half of them? It’s traumatic. It was terribly traumatic. I mean, it had a big impact on all of us, and a big impact on Stan.

When it was disclosed to all of us what happened in the trial, we knew what was going to happen after that. And uh, we were really, Stan was very transparent with all the employees, and he said, Look, it’s not going to be sustainable at this level. We’re going to have to downsize the company.

Uh, there were tears in the hallways, I remember we had paid for a Christmas party. Holiday party. In a nice hotel here. And uh, and we got the news in November, and we had our assemblies and we talked things through, and Stan explained what was going to happen. And someone raised their hand and said, Could we cancel the holiday party — which was going to cost, I don’t know, $70,000 or something — and save one job? And I remember the head of HR raised her hand and said, We already thought of that. We can’t get our money back.

So then we debated what kind of a party are we going to have? Some people said, Well, let’s just, we won’t have music, it will be kind of like a goodbye thing. And other people said, No wait a minute here. This is life, this is how things work. We’re going to go and we’re going to have a good time. We’re going to celebrate, we’re going to have music, we’re going to have dancing. And a lot of us are going to be saying goodbye to one another at that party.

And so we had a pretty uptempo, you know, holiday party that year. As kind of a send off to a lot of the people that we couldn’t keep.

Brady Huggett: Isis cut 140 people in the first four months of 2000, about 40% of the company, for an estimated savings of $2 million. They also cut back on spending and focused only on programs that might have “significant” commercial potential. Partner Boehringer Ingelheim had paid for half of the costs to develop alicaforsen, but Isis had also dumped in millions of dollars over the years. Boehringer had given rights to alicaforsen back to Isis before the trial results — never a good sign — but it meant that Isis was alone with the compound now, in those other indications. The company ended 1999 with cash on hand of about $53 million, saying it should be able to fund operations for “at least” three years following the restructuring. But given that it had spent $66 million on R&D alone in 1999, this hardly seemed possible unless Isis set its research engine to idle, and that had never been the company’s style.

The numbers suddenly looked very grim. Since inception, Isis had earned $180 million through contracted work with pharmaceutical companies, and raised about $250 million by selling its stock. It had also borrowed $72 million to finance parts of the business. What did the company really have to show for it? An accumulated loss of $257 million, and one questionable antisense drug approved, which was now officially bringing in zero dollars a year.

Even by the more forgiving metrics of drug development, where the risk is high and success rate is low, Isis was beginning to look unseemly. Inside the company, Stan, and Dave Ecker and Rosanne, and Frank Bennett and Brett Monia and Lynne Parshall were finding it hard to constantly have to defend against the doubters. Stan, in particular, was beginning to show signs of exasperation. The failure of alicaforsen “doesn’t invalidate the technology,” he told the biotech trade publication BioWorld, and anyone else who would listen.

Stan once was described to me as “the guy who takes the air out of every room” he’s in. Partially this is because Stan was often the smartest person in that room, and he could be impatient when others didn’t automatically have his depth of understanding. But also, when the room was filled with other very smart people, as was the case at conferences and meetings, Stan sometimes seemed almost determined to separate himself.

At the end of a two-day antisense gathering in May 1997, during a final panel session convened to discuss all that the 350 attendees had heard in the previous 48 hours, Stan, on the stage, seemed irritated. When an attendee asked about the correlation between the pharmacokinetics of antisense drugs versus their cellular uptake, Stan called the idea “stupid,” saying that pharmacologists learned 60 years prior that in vitro studies taught you nothing about pharmacokinetics. When the panel turned to the reproducibility of data, Stan said that if you don’t discuss the precise dose, the time course, and the endpoint sought in each experiment, then the topic was “confusing, confounding and disappointing.”

Stan Crooke was unwavering. He worried over money, as almost all biotech companies do, but his belief in the science was as strong as ever. Even after the high-profile and costly failure of alicaforsen, he knew this was not the final verdict on antisense. And he wasn’t yet alone in his belief. Genta was still working its chemistries, and Hybridon was alive and well, as were a few smaller firms, though all were struggling under the growing public opinion that antisense didn’t work.

Paul Zamecnik had been living under this cloud longer than anyone. Skepticism had engulfed his 1978 paper when the results hadn’t been easily reproduced, and in some ways that doubt had never really gone away. He was still in the game, at Hybridon, working with his brilliant protege Sudhir Agrawal, who himself had given talks all over the world about antisense. Sometimes, during a lull in experiments, in quiet moments in the lab, Zamecnik would turn to Agrawal. “You know, we go out and we talk to these idiots, and they just don’t get it,” he’d say, almost with a shrug. “One day they will realize. But that’s OK — let’s just keep on doing it.”

Isis had failed in the lab. And in the marketplace. And now, spectacularly, it had flamed out in the clinic. Its stock had plummeted so low that raising money on the public markets seemed impossible. The perceived leader in the field, Gilead, had vacated without so much as a backward glance. None of that mattered to Stan. He was going to keep on doing it.

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Thank you to Stan Crooke, now and always. Thanks to Art Krieg, for his insight into antisense. Thanks to Dan Kisner, Lynne Parshall, Dave Ecker and Chris Mirabelli for their memories of Isis. Thanks to Steve Tighe for his recollections and analysis of the early antisense field. Thanks to Sudhir Agrawal for his knowledge on antisense and its mechanisms. Rest in peace to Antonín Holý, who died in 2012, and to John Martin, who passed away in March 2021.

Sound mix and original theme by Brian Flood. All art by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of characters, historical photos and a transcript of this, and the previous three chapters. Chapter 5 will be out in a week. Until then.

Chapter 5: valley of antisense

Brady Huggett: Chapter 5: valley of antisense

Wilhelm Bauer was born in Austria in May 1885, and initially he progressed as expected. He cut his first tooth at 7 months, he held his own feeding bottle to his mouth, and was even talking a little by the time he was 1. In the summer of 1886, however, he began to “get fat all over,” his doctor reported. Though a chubby baby was a good sign, especially then, this felt more “like dough” and the boy’s mother thought he had been stronger when thinner.

Soon enough Wilhem began having trouble sitting upright. In the autumn he contracted whooping cough. He cleared the illness, but his weakness increased and his hands took up a tremor. He lost the ability to use his legs, though he could still make slight movements at the ankle joint and flex his toes. He could no longer bring his hands to his mouth. His eyes didn’t fully close when he slept, and he began to have difficulty breathing. On April 4, 1888, the boy’s mother took him to St. Anna’s Children’s Hospital in Vienna. He had intermittent fever there the month of April, and he died May 1, not quite 3 years old.

Wilhelm had a younger brother, Georg, who wasn’t yet 2 at the time but who had already lost use of his legs. Georg followed a similar path and eventually died, too. The family’s third child, Franz, another boy, was healthy.

A neurologist named Guido Werdnig, at the Pathological-Anatomical Institute in Graz, Austria, took up the case. Werdnig didn’t know what to make of the two boys. It looked somewhat like muscular dystrophy, but that didn’t quite feel right. He performed an autopsy on Wilhelm and examined Georg, and in doing so made a key discovery — the disease, he thought, was due to a primary degeneration of the spinal cord’s motor pathways. He published a paper on his findings in 1891, roughly translated as “Two Early Infantile Hereditary Cases of Progressive Muscular Atrophy Simulating Dystrophy, But On A Neural Basis.”

Johann Hoffman, a professor of neurology at Heidelberg, Germany, was not far behind. He published his first paper in 1893 based on his observations of the same illness. Over the years the research community coalesced around the work of these two men, and for a while the illness was called Werdnig-Hoffman disease.

Today it’s broadly referred to as spinal muscular atrophy, and it’s understood to come in four severities. What these men had seen was Type 2 — bad enough to kill the children, but there are more severe cases, which occur even earlier in a child’s life. Werdnig, for all his noteworthy, early work in the field, received no real recognition in his lifetime. He became a parapalegic and was bedridden for 12 years before dying in 1919 in a sanitorium, all but forgotten.

And progress against spinal muscular atrophy, as insidious and heartbreaking as the disease was, languished. Children afflicted with it were born in seemingly good health, but then developed small symptoms incrementally, almost out of nowhere. Their muscles wasted away, they regressed, and they died. For more than 100 years, medicine could do nothing against this. Sometimes it seemed like it would always be that way. Those born with spinal muscular atrophy were just unlucky, and that was the hard truth of it. From Nature Biotechnology, I’m Brady Huggett and this is Hope Lies in Dreams.

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Brady Huggett: After the failure of Isis’s lead compound, alicaforsen, in a phase 3 trial for Crohn’s disease in 1999, the company’s stock fell below $4 per share. It had been nearly five years since the stock had been that low. In that period Isis had gotten a product approved, increased its clinical pipeline to 7 programs, and had three other compounds at the preclinical stage. It had grown its already formidable scientific talent, greatly increased its patent portfolio and established itself as a leader in the field of oligonucleotides. Yet here it was, with its stock trading lower than it had five years before, and its working capital draining away.

Stan’s response to the failure, predictably, was to throw himself into the job. That had always been his way, whether he was stocking shelves at The Tech Corner drug store as a boy, or facing a dearth of compounds in SmithKline’s pipeline. Yet in fraught times like this, he was more demanding of the team than ever, and less patient. So it’s safe to assume that in early 2000, just after the alicaforsen failure and amid the laying off of friends and rising money woes, the mood at Isis was at a historic low. They would need to raise funds, but with their stock so poorly valued on Wall Street, it wasn’t clear how that could happen.

But then a stroke of fortune arrived that had nothing to do with Isis: the Genomics Bubble. Here’s President Bill Clinton, speaking from the White House in June 2000.

Bill Clinton: Today the world is joining us, here in the East Room, to behold a map of even greater significance. We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind. The moment we are here to witness was brought about through brilliant and painstaking work by scientists all over the world, including many men and women here today. It was not even 50 years ago that a young Englishman named Crick and a brash, even younger American named Watson, first discovered the elegant structure of our genetic code.

Brady Huggett: The Human Genome Project was conceived by the National Academy of Sciences and then put into action in 1990 by the National Institutes of Health and the Department of Energy, with funding from Congress. It brought together researchers from around the world in an attempt to map all human genes. It competed against a privately funded effort to do the same, led by Celera Genomics and Craig Venter, and in the end, the two groups shared credit. The international group’s draft was published in Nature in 2001, with the genome some 90% complete, and Craig Venter’s private effort published its draft in Science at the same time.

In drug development circles, it was hoped that the genome would open the door to new targets against disease, and as the project neared completion, investors piled into biotech companies that were mining the genome. New, unknown biotechs went public at eye-popping valuations, and then watched their shares double or triple on the first day of trading. Those already public saw share prices increase by 300, 500, 700 percent over the course of 1999, and many of them took advantage by raising hundreds of millions of dollars.

Isis, savvy as it was, began to point out in its filings and external communications that sequencing the genome would likely further their antisense efforts. Eventually, that investor enthusiasm around genomics found Isis.

Stan Crooke: Um, Karen Lundstedt, who was head of corp comm in those days, and I were in LA, trying to raise money, and feeling hopeless. And about mid-day, a fund manager that we were talking to says, You know your stock is at $40. And I said, No, you mean $4. Uh, no — $40. And sure enough, the stock was at $40 a share, so we went out and raised money.

Brady Huggett: Indeed, Isis’s stock closed as high as $39 early in 2000, and the company managed to raise about $27 million in the first quarter. The money kept the engine going, kept the doors open, and Isis could turn to the pipeline.

It now owned alicaforsen outright. Though the first Crohn’s trial had failed, and Isis had shut down the rheumatoid arthritis and kidney transplant programs to save money, it pushed ahead with the drug in a topical formulation for psoriasis and an enema for ulcerative colitis.

Neither would amount to anything. So the next great hope in the pipeline was the cancer compounds it had been developing with Novartis before the discovery of the data fraud. Novartis had returned rights after phase 2 trials, saying the data were “not what we expected.” Isis, however, liked one of those compounds in non-small-cell lung cancer — the phase 2 study had shown benefit in a trial of 15 patients. In the fall of 2000, Isis dosed the first patient in a phase 3 trial of the drug, by then called Affinitak.

The problem, as usual, was money. Isis would need yet another partner to help pay for trials. It found one in Eli Lilly, which signed a deal with Isis in the late summer of 2001 that had a total potential of $400 million, including some loan money, with the two companies agreeing to collaborate on antisense for 4 years.

That year Isis also signed a 3-year deal with the biotech flagship Amgen, and one with Merck, for a second-generation preclinical antisense drug aimed at diabetes. Stan told The New York Times that the Eli Lilly deal was a “great revalidation of antisense,” and noted that 2001 was a year in which pharma companies returned to the technology because it was “coming of age.”

By this time, Isis had become the unquestioned intellectual property leader in the field. Hybridon, which had been based on Paul Zamecnik’s founding technology and helped along mightily by the chemistries of Sudhir Agrawal, was in deep financial difficulty, and Isis and Hybridon agreed to cross-license their antisense patents in the spring of 2001. The contract called for Isis to put in ~$35 million in cash and stock, but that bought access to a key advance. This is Sudhir Agrawal talking about the deal.

Sudhir Agrawal: There was, an event happened where in 2000, year 2000 late, we had a patent issued on gapmer technology. Which is very broad. And that sort of led to a call from Isis.

Brady Huggett: Then Isis called and said, We see your patent, and we want to work in this space, too. Let’s collaborate. And you guys were fine with that? Hybridon was fine with that?

Sudhir Agrawal: I think in those years, antisense really was at the bottom. Compounds had failed. Money had gotten tight. Where, um — yes, it was a very difficult and dark period.

Brady Huggett: At the time Isis had about 700 issued patents, and it picked up only about 60 in the deal. But the gem was the IP around the gapmer technology.

Hybridon had wanted to try combining, into one antisense molecule, the desirable parts of a phosphorothioate oligonucleotide with selected parts from a 2-prime phosphorothioate oligoribonucleotide. This new mixed-backbone oligonucleotide was called a hybrid, or, a gapmer, and the patents around this gapmer technology were what Isis picked up in the Hybridon deal.

Isis felt it was going to be key to its second-generation drugs. When announcing the cross-licensing, Stan told the biotech trade publication BioWorld that Hybridon had “the last meaningful patent estate in antisense that we don’t own,” and added that the deal “finishes what we set out to do, which is to own everything that is important in antisense.”

Hybridon, for its part, felt the deal would help “keep the space alive,” Agrawal told me. If Hybridon wasn’t going to be able to pursue antisense much longer, as he feared, then maybe Isis could carry the flame.

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Brady Huggett: If 2001 was a year when antisense “came of age,” as Stan had said, the maturity didn’t last long. Late in 2002, Merck returned rights to Isis’s diabetes drug, barely a year and a half after licensing it. The companies said they would continue to work on other programs, but everyone watching knew what the rejection meant: Merck saw no value in the compound.

And then, as if Isis was mired in a losing streak, its newest hope for a truly meaningful drug crashed and burned.

Stan Crooke: We put Affinitak into phase 3, unblinded it, and it was an abject failure. And, there were lots of reasons to think it was working, but it — complete failure.

Brady Huggett: In March 2003, the companies announced that the 616-patient trial of Affinitak in non-small-cell lung cancer showed no difference in survival rate between patients receiving chemotherapy versus those receiving chemo and Affintak. This was the primary endpoint of the trial.

The failure was a second, highly public implosion, yet Stan insisted to The New York Times that “the data tells you antisense works.” Then he grew defiant, saying “we pioneered antisense. We own it. We are going to complete the work we set out to complete.”

A second, similarly structured Affinitak trial was ongoing, but that would fail in 2004, just as everyone expected it to. The first trial failure was the one that battered the company’s stock, dropping it as low as $2.50 a share. This time there was no genomics bubble to rescue it.

By June 2003, Lilly and Isis had dissolved their manufacturing agreement around Affinitak, and Isis also cut staff again, releasing about 9% of its workforce, most of those positions related to manufacturing or commercializing Affinitak. To save additional money, Isis dropped a couple of earlier-stage programs from development, and would drop a couple more in 2004. At the end of that year, Isis had more than $100 million in cash reserves, but posted an annual net loss of ~$143 million. The math was very clear, and in early 2005 Isis let go another 160 employees, about 40% of the company. It also closed a research facility in Singapore, and consolidated its real estate footprint in San Diego.

Stan, as he often did, turned to Lynne Parshall. If the R&D engine was the brain of Isis, then money was the blood, and Lynne had always been responsible for the blood.

Lynne Parshall: So, we raised money at every critical time. Difficult markets, you know, creative financings, um, you know, that’s what my job was. And I think, again, in terms of the primacy of the science and the medicine — my job was to not bother the people doing the real work, the science and the medicine, with that. To just, take care of it. To just make sure that when they needed the money, it was going to be there. [laughs] And it was. And we did a great job of doing that.

Brady Huggett: I mean, he — you keep saying ‘we,’ but Stan was like, We needed the money, and Lynne went out and got it.

Lynne Parshall: Well. That was my job. [laughs] That was my job. I did a good job at it.

Brady Huggett: Lynne spent a month and a half on the road, in both the US and Europe, and got a deal done. The company raised $51 million in 2005 by selling shares at $4.25 apiece — a woefully low price. But so be it; they were alive.

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Brady Huggett: Beyond oligonucleotides, Isis was open to targeting RNA in other ways, too, and way back in 1996, Stan had seen an avenue for bringing in some government funding. He approached Dave Ecker about it.

Dave Ecker: At that time, DARPA, was reaching out to the biotech community for new ideas that related to, ah, biodefense.

Brady Huggett: Uh-hm.

Dave Ecker: Biosecurity. They were real worried about a biological weapons attacks. And they put out a — there was a fax that came to Stan. And, anybody that has an idea related to this, submit a proposal. So he said he almost threw it in the trash, but he brought it over and he gave it to me. And he said, You might be interested in this. Do you have some new ideas? We can potentially get some extramural funding from the government, as opposed to partners.

But at that time, there were a lot of revelations about RNA having these exquisite tertiary structures. And he says, Well, if we think of ourselves not as an oligonucleotide company, but a company that targets RNA, maybe we can think about new strategies to target RNA with different kinds of molecules. So I started the program — I wrote a proposal for a program, and I sent it to DARPA. And I got a rejection letter. And I remember that I wasn’t real happy with taking no for an answer. So I wrote another letter to the program manager, explaining why not funding this was going to be a bad idea.

And then on one of our business trips with one of our Japan partners, I remember I was in Tokyo, and I get this call from DARPA. It was the program manager, named Sean Jones. And he said, I like your letter, and I like your willingness not to take no for an answer. And I’m going to fund this.

Brady Huggett: DARPA — the Defense Advanced Research Projects Agency — threw some money at Isis, and Dave Ecker created a unit he called Ibis Therapeutics. He brought in some chemists, put to use some new analytic methodologies, and began work. But after the attacks on the twin towers of the World Trade Center on September 11, 2001, and the ensuing anthrax mailings in the US, DARPA fully contracted with Ibis to develop a detection device for biowarfare agents. Ibis eventually created an all-purpose device “that could detect anything,” Ecker told me, and Ecker began looking for diagnostic partners. In 2007 Ibis placed eight instruments, called the Ibis T5000 Biosensor System, around the country, and in early 2008, Abbot invested $20 million to work with Ibis on the system. This was yet another example of the ways Isis fought to keep the lights on when investors weren’t all that interested in antisense.

For these were the dark years, as Sudhir Agrawal said. The antisense field continued to shrink, and in 2005, Hybridon gave up the battle. The company had been burdened by debt, and investors weren’t interested in taking another run at antisense. They wanted “something new,” Agrawal told me, and Hybridon changed its name to Idera to highlight a focus on a technology called Toll-like receptors, which was linked to activating innate immunity in mammals, and for which Bruce Beutler would share the Nobel prize in 2011.

Genta still remained, but it had long struggled financially, and in 2004 its drug, Genasense, based on phosphorothioate chemistry targeting the production of BCL2, was rejected by an FDA panel as a melanoma treatment. And then it failed a phase 3 trial in multiple myeloma. Few had any hope left for the drug or the company.

So Isis was now clearly the king of the mountain. But that image — Isis standing on a peak, framed by the sky — doesn’t seem accurate for what was happening. Perhaps more fitting to say Isis was the remaining player, trudging alone through the valley of antisense. It was difficult to keep morale up during this long period, and Stan needed to find a way to put all that failure behind the company, and get employees looking ahead.

Stan Crooke: As soon as you get through that, then you have to generate a new dream. People live for dreams. And people like us have to dream. That’s — there is nothing else to go to work for, when you, when you do the things we do. It’s a dream, right? So you have to give people — then you have to give them another galvanic vision of, you know, here is where we are, this is where we can be, and this is what we’ve got to do to get there. And it can’t be pie in the sky. It has to be: here’s where we are, here’s the truth of where we are, here’s where I hope we can get, and here are the five steps I`m going to take tomorrow to get us there.

Brady Huggett: The new dream for Isis partially came from Brett Monia. He was head of Isis’s oncology drug discovery program at the time, and had been thinking about the company’s direction ever since Novartis revealed the data fraud around their partnered cancer program, years before.

Brett Monia: It was a difficult time for the company. It really was. But you know, something good came of this, believe it or not, Brady. It sounds crazy, but, when this data started, uh, emerging — you know, the fact that we had to go to such high doses to show activity in animal models, and we had some clinical studies not showing success — I started questioning whether or not we were ready to tackle cancer, with our technology. And, um, I started asking, Where can we apply our technology the best, for drug discovery? And one thing that I knew, that we knew, is that our drugs, our antisense generation 2 drugs, work very well in the liver. And as I was thinking about, Where can we have success? Where can we show reproducible activity at low doses? It was in the liver.

Brady Huggett: Brett put together a “small group” within the company and began to look at what diseases might be targeted through the liver. That opened up new areas — diabetes, heart disease, and cardiovascular disease — and eventually a promising second-generation antisense compound known as mipomersen. It was aimed at familial hypercholesterolemia, an inherited condition that causes dangerously high cholesterol levels.

The other part of the new dream was the second-generation antisense drugs Brett just mentioned. Alicaforsen was still in the clinic for a handful of indications, but no one expected much from it, and indeed Isis out-licensed the compound in 2007 to Atlantic Healthcare for pennies on the dollar. In fact, including the phase 3 failures of alicaforsen and Affinitak, just about everything Isis had built with its first-generation phosphorothioate chemistry had died on the vine. There was no sense in considering that version of the technology any longer.

As Stan had long said, the problem of antisense was a chemical one. Isis had not fixed the chemical problem well enough with its early efforts. But the company hoped for improvement by looking away from cancer, and also by using a 2’-methoxyethyl gapmer technology.

Here’s Frank Bennett.

Frank Bennett: Yeah, so the first generation is DNA that’s been modified, with one of the oxygens, is replaced with sulfur — it’s called a phosphorothioate modification. And that was important for, to prevent the DNA from being very rapidly degraded. And it does improve it. You know, DNA is normally degraded within five minutes. With this phosphorothioate modification, we turned DNA from five minutes to maybe 24- to 48-hour survival. And so that opened the door, that was really the critical modification that allowed us to form the company around.

And then, what we identified early on, and it was known, uh, that you could do chemical modifications on the sugar to further advance binding affinity. And so we did a whole series of chemical modifications that identified this 2-prime methoxyethyl, or MOE, modification, that gave us about a 10-fold improvement in potency of the drug. But also, it made the drug more stable. So instead of having a 1-to-2 day tissue half life, it went from, maybe even having three weeks in some cases tissue half life.

Brady Huggett: In short, their second-generation antisense was more potent and lasted longer, which meant less drug was needed per dose, and that decreased side effects. The result was that Isis’s antisense 2.0 was an improvement on three levels: potency, duration and safety.

So for all the bad news, and the depressed stock price, in some ways, Isis’s turn toward second generation antisense felt like a rebirth. A shedding of the past and moving forward. Outside the walls, though, amid the investor skepticism, it wasn’t clear anyone was still paying serious attention to a technology that had been discovered nearly 30 years ago and had posted zero success stories.

Especially because there was always a shiny new thing to be excited about in biotech. Antisense had once been that shiny thing, in the late 1980s, but the RNA field was exploding. Investors had also begun to chase something called RNA interference. A seminal paper on the technology had been published in 1998 by Andre Fire and Craig Mello, who would win the 2006 Nobel prize in Physiology or Medicine for their discovery. RNAi, as it is called, involves double-stranded RNAs that silence messenger RNA and stop protein production.

Long double-stranded RNA molecules are naturally occurring, and are called microRNAs. They act like sponges, mopping up messenger RNA molecules in cells as a form of regulation. They were first characterized in 1993. But researchers were now crafting synthetic, shortened versions of natural microRNA molecules, calling them small interfering RNAs.

The small interfering RNA method was quickly recognized as a more potent silencer of gene expression than antisense. Unlike antisense, it immediately worked in one academic experiment after another. This suddenly made Isis’s efforts “look antique,” Stan told me, and biotech investors turned their heads toward RNA interference. In 2002, a company named Alnylam Pharmaceuticals was formed in Cambridge, Massachusetts, around small interfering RNAs — an extraordinarily short period of time for Fire and Mello’s breakthrough to be converted into a commercial platform.

Isis, a science company through and through, was watching all this. Given its expertise in manipulating single-stranded oligonucleotides, Isis thought it could also block single strands of microRNA, using what was called anti-microRNAs, or antagomirs, to fight disease.

Alnylam also saw the opportunity present in microRNA, though its technology was based on double-stranded oligos. Before long, the two companies were bumping up against each other, and a patent battle loomed. To avoid this, in 2007 they formed an independent company they named Regulus, located with Isis in Carlsbad. Here is Kleanthis Xanthopoulos, the founding CEO.

Kleanthis Xanthopoulos: They came to the realization sometime in the end of ’06, the beginning of ’07 that, neither of them, the companies, felt that the microRNAs fit their overall focus that they had, in antisense and siRNA, respectively.

Brady Hugget: Uh-hm.

Kleanthis Xanthopoulos: But the opportunity was huge. And if they could find a way to combine resources they could create something very significant.

Brady Huggett: Alnylam invested $10 million into the initial company, to balance out the “overwhelming” patent estate that Isis contributed, Xanthopoulos said. Isis owned 51% of the new entity, and between the two companies, Regulus was granted a license to more than 900 patent and patent applications.

As media and investor attention moved to the RNAi technology, some observers began to wonder if Isis was attempting a rebrand to catch the investor wave, an old dog trying to learn a new trick.

Stan found this offensive. When asked in 2004 about the perception that Isis was trying to relabel itself amid a changing RNA field, Stan told BioWorld that people thinking that way were “either stupid or liars.” He added that he had not known “to call it RNAi” when founding Isis because the term “hadn’t been invented yet.” And he added, rather dryly, that one of Isis’s “central failures” was that it had not “been very good at coining exciting terms.”

These kind of direct, pugnacious comments were what made Stan Crooke’s name in biotech circles. He was always upfront, yet unbendable in his focus. He could be affable and funny both in person and on conference calls, yet the public record is also littered with the quotes of a man alternating between cocksure and exasperated. When Merck returned rights to Isis’s diabetes drug, Stan pointed the finger back at its former partner, saying the drug wasn’t given priority, that it already should have reached clinical trials. When discussing the Merck and Eli Lilly deals of 2001 with BioWorld, Stan pointed out that scientists knew the potential of antisense, “well ahead of Wall Street,” a side-eye comment for sure. After the horrendous Affinitak trial, Stan dismissed the failure to BioWorld as “just a bump in the road.”

This disgruntlement, mixed in with Stan’s at-times seemingly unfounded optimism about antisense, made it look like he was either irritated by the long list of setbacks and failures, or blithe about it. Whichever it was, it was getting hard for observers to take Stan seriously.

Of course Stan wasn’t alone in his devotion. Isis had been created in his likeness and adopted his personality. Like Stan, Isis employees were there for one thing, and one thing only: to develop antisense until the platform delivered on its grand scientific potential. The core unit that had been there in the early days still felt this, and anyone new had to buy into that dream, too, or they would not be staying long. Here is Lynne Parshall talking about Isis’s culture.

Lynne Parshal: It’s a meritocracy. So, you know, people — I didn’t have any scientists or MDs reporting to me, most of the time, in my daily functions. But people would listen to me when I had good ideas. Sometimes I had crazy ideas. [laughs] But across the board, that was sort of the nature of the company. People were expected to contribute ideas, they were expected to think hard, and say, Gosh, does that thing that somebody just said make sense to you? Does it not make sense to you? And if it didn’t, you’re expected to say that, say, Wait, I don’t understand that. Are you saying this? Or, What if we did something different? And that really is the backbone of a culture that can, No. 1, be tremendously creative. No. 2, be tremendously efficient. And really, um, persevere and pull together to tackle hard problems, and hard issues, and tough times, sometimes.

Brady Huggett: Stan had built a company of employees who constantly challenged each other. They were the world’s leading experts on antisense, and they were sure they knew what observers and analysts did not. To hear the growing skepticism, to listen to it at investor conferences, and then still keep pushing required a kind of deafness.

Stan Crooke: It bothered all of us that the technology was so demeaned, and that we were so dismissed. Uh, I mean, I think it affected every one of us. Me more than anyone else, but all of us.

Brady Huggett: And if the doubt did creep inside those walls, there was always the science to fall back on. The principles of DNA that drove life on this planet were the very assurances Isis needed to stay the course. Here’s Dave Ecker.

Dave Ecker: The ace in our pocket was the specificity that could be achieved by Watson-Crick hybridization was a fundamental law of physics. That it was — or chemistry, whatever you want to call it. As long as that was foundationally true, we were going to find a way to work on that, work around that, and be able to make specific drugs.

Brady Huggett: The “ace in their pocket” would forever guide their decisions. By never losing sight of the science, Isis could function as its own antisense cult in a sea of non-believers. Here’s Lynne again.

Lynne Parshall: Interestingly, the other thing that was fundamental to the company’s culture, um, which all of the founders contributed to, was passion about the technology. Passion about the fact that it would succeed. And extraordinary perseverance because of that passion. And I think that’s what got the company through, because you had to believe. You know, if you didn't believe, you were going to go somewhere else and find something maybe that was easier. Or, you know, not a long shot.

Brady Huggett: None of the core — save for Chris Mirabelli — had “gone somewhere else.” That was remarkable for a company nearing 20 years of existence without one success to its name, and the core kept the company stable through this fallow period.

But of course there was turnover, and it wasn’t always driven by the difficulty of the task at hand. Former employees of Isis, who did not want to be recorded, or named, told me it could also be a difficult place to work. Everyone at Isis understood that Stan was brilliant. The trade off was that he also sometimes dressed down employees if he found their work subpar, or interrogated their science in ways that left their cheeks flaming. These people didn’t deserve to be embarrassed in that way, I was told, and for certain, over the years people left the company because of it.

Stan himself knows this. “Learning to control my temper is a work in progress,” he told me, and he admitted that “people at Isis know when I’m not happy.” There have been many times that he snapped at colleagues, saying things he wished he hadn’t, then gone home and “banged his head against the wall,” he said, because he “made someone feel stupid unnecessarily.” He has started mornings by coming into the building, seeking out those employees, and apologizing. Stan likes a good joke, loves to goof off. But even he thinks that part of the reason he jokes so much is to help offset the tension and the pressure he knows he can induce in his employees.

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Brady Huggett: Stan once told me that “having an enemy can help” unite a company, but that it “doesn’t help if the enemy is the rest of the world.” That was how it was beginning to feel to Isis: that the world was against them. They were trying to do something big. People should have applauded that. Instead it felt that many were eagerly waiting for Isis to fall.

Stan Crooke: And I never dreamt that there would be so much emotion focused on hoping we’d fail. It never, in my wildest imaginings did I think that people would be rooting against us. Skeptical, sure. Laugh at us, sure. Dismiss us, sure. But to actually want us to fail makes no sense. And maybe I polarized people, maybe the whole idea was polarizing, maybe it divided people into camps — it will never work, give them a chance — who knows?

Brady Huggett: Maybe I polarized people, Stan said. The truth is, he did. Jeremy Levin, CEO of Ovid Therapeutics and former chairman of the Biotechnology Innovation Organization, told me an anecdote that perfectly embodied how Stan could come across to those who didn’t know him, and how his demeanor could split the room.

Levin was employed with Novartis at the time, as global head of business development and strategic alliances. Stan visited the Novartis Institutes of Biomedical Research, also called NIBR, to see about the companies working together on a new project. Levin doesn’t remember exactly where the companies were in their long collaborative history, and Stan doesn’t remember this incident at all, but during the discussion it became clear that Stan wanted what he always wanted, which was for Novartis to name the target it was interested in, and Isis would go develop the antisense molecule to address that target. Novartis, however, wanted to send their folks into Isis’s facility in San Diego and work alongside Stan’s group — a structure sometimes referred to as “buying the company without buying the company.” Stan wanted no part of it.

Jeremy Levin: He said, You just don’t understand. You guys will never understand. And I don’t think it’s worth my while spending time trying to convince you. I remember that so well, it was remarkable. And he said it in a very gentle but direct way. And I guess because my Israeli side likes what’s called “ישיר ”.ישיר means “direct.” I actually liked it.

Brady Huggett: Yeah.

Jeremy Levin: I think there were people around me who were shocked and thought he was rude. I didn’t. I said, He’s being very direct.

Brady Huggett: Was he right?

Jeremy Levin: He was right. It’s very difficult for a large corporation, which has got a series of multiple programs that are ongoing, to take a risk in one that they truly don’t understand.

Brady Huggett: Did he then, like, walk out?

Jeremy Levin: Pretty much. We um, this was a discussion where we’d had some really great — I was a real champion to bring this in to the company. And Stan was keen to come and visit our new site, which was in NIBR. And he arrived by himself. He was completely by himself.

Brady Huggett: Hm.

Jeremy Levin: And —

Brady Huggett: I find it so interesting that he came by himself, for some reason. Came by himself, talked, and then, when he realized he wasn’t going to get what he wanted, walked out.

Jeremy Levin: There’s a high degree of respect for somebody who does that. It means that he knew, in his mind, what he wanted for his company.

Brady Huggett: So then he says, I guess I’m going to go, and he left?

Jeremy Levin: Pretty much so.

Brady Huggett: And what did the room think? What did you think?

Jeremy Levin: Well, you know, I sort of smiled, because this was not atypical of Stan. And that type of an abrupt reaction was gentle but forceful. And, there was no screaming, no shouting, it was just, No. And you ran up against that wall and when that “no” happened, it was, No. And there was nothing more to be said.

Brady Huggett: Levin likened Stan’s decision to an “iron fist in a velvet glove.” Stan, as Levin said, had impressed some in the room, and offended others. That was common — rarely did someone meet Stan Crooke and not have an opinion.

It’s an interesting thing, to be a believer when the tide of public opinion has turned away. For Stan, antisense remained as elegant and beautiful as ever, and he was certain the chemical hurdles would be overcome. The outside world, however, had plenty of evidence to think otherwise. Isis’s many pipeline failures, for instance, and eventual washing out of its slate of first-generation drugs. The exiting of the antisense stage by the other high-profile companies, who surely must have seen something they didn’t like. The pharmaceutical partners ending research collaborations and handing back compounds. It was easy to look at all this and conclude that the antisense technology was a mess.

And yet here was Stan Crooke, 62 years old now, still talking it up, still crowing about it. Still seeking, and getting, new pharmaceutical partners, and then telling the press that the next drug was the one. His persistence made him seem like some sort of aging carnival barker, holding open a tent flap, endlessly shouting to passersby to come see the greatest show on earth. But he’d been saying the same thing for nearly two decades now, and those within earshot had already stuck their heads into the tent and seen all they needed to see. And now they were just tuning him out.

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Thank you to Stan Crooke, now and always. Thanks to Sudhir Agrawal, for talking about Hybridon. To Dave Ecker, Lynne Parshall and Brett Monia, for their memories of Isis. To Kleanthis Xanthopoulos for his thoughts on Regulus. To Frank Bennett, for discussing antisense chemistries. To Jeremy Levin, for his insight.

Sound mix and original theme by Brian Flood. All art created by Erin DeWalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous four chapters. Chapter 6 will be out in a week. Until then.

Chapter 6: lone voice in the wilderness

Brady Huggett: Chapter 6: lone voice in the wilderness

Darryl De Vivo was a junior at Amherst College in the late 1950s, when his brother, younger by 3 years, contracted transverse myelitis. That’s a swelling along a portion of the spinal cord, causing paralysis. His brother was transferred to the Massachusetts General hospital, and there he was treated by Phil Dodge, a renowned pediatric neurologist. Because Darryl was not far away, he frequently checked on his brother, and he got to know Dodge. He admired him, found him charismatic and deeply empathetic, as many pediatric doctors seem to be. Darryl was already considering going to medical school, and Dodge connected with that, and he invited Darryl to spend a year with him, learning at Mass General.

Beyond his rounds at the hospital, Dodge would also see private patients in his office on Fridays, and he often brought Darryl in to see interesting or complex cases. That’s where Darryl first encountered spinal muscular atrophy.

Darryl De Vivo: And so on one occasion, now, uh, 60 years ago, in 1960, he said, I want you to see this patient, who has a rare neurological disease. It looks like muscular dystrophy, but it’s different. And we don’t know as much about it as we would like, but I think it’s a particularly interesting problem.

And that was my first experience with a patient with spinal muscular atrophy. I was quite fascinated by it and Phil Dodge pointed out a number of things, including the fact that this is presumably a disease that affects the nerves, the motor neurons, but in fact clinically, it seems to affect the proximal muscles, the girdle muscles, the pelvic and shoulder muscles, to a greater degree than the distal muscles. So it’s a curious phenom — and Phil focused on that and spent some time talking with me about that, and was puzzled himself as to why that in fact seems to be the case.

Brady Huggett: Spinal muscular atrophy, more than 65 years after Werdnig and Hoffman had published their initial papers describing the disease, was still in the dark ages. Little was known about the causes, and certainly there were no treatments. Darryl went on to medical school, and became a celebrated child neurologist. He has contributed hundreds of peer-reviewed articles on pediatric disease to the medical community, and served as co-editor of a staple textbook in the field, titled “Neuromuscular Disorders of Infancy, Childhood and Adolescence.” He has seen SMA cases throughout his career, and for much of it, the interactions with patients and their families were among the bleakest, most heart-wrenching of his life. For the most prevalent type of SMA, three-fourths of the children die before their second birthday. So to Darryl it always felt the same: first explaining the diagnosis, then admitting to parents that medicine could do nothing to prevent the disease’s progression, and then offering some palliative care until the end.

He hated it. It’s not exactly what he envisioned when he went to medical school. This isn’t the way doctors like to spend their time.

From Nature Biotechnology, I’m Brady Huggett, and this is Hopes Lies in Dreams.

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Brady Huggett: After the alicaforsen failure just before 2000, and the investigation around the data fraud from the Novartis partnered program, Isis had understood its second-generation drugs were more easily reaching and staying stable in the liver, and that had opened the door to diseases that could be treated by targeting that organ.

The company needed someone to head up this program, and Stan turned to Rosanne.

Stan Crooke: And, then the decision to put Rosanne in charge of it was quite controversial, because, you know, she wasn’t trained as a cardiovascular pharmacologist. But I knew she’d do a good job with it.

Brady Huggett: There were people in the company with experience more aligned for this new program than Rosanne, but Stan wasn’t convinced anyone else was “up to the task,” he told me. Or, Isis could have gone out and hired someone, but Stan had learned that it took longer to teach a newcomer the intricacies of antisense technology than it did to refocus that knowledge on a new indication. And he knew what Isis had in Rosanne: someone who would manage a team well, and push for innovation. And finally, he understood his decision could look like nepotism, but he was the one in charge, after all, so let them talk. He named his wife the head of the cardiovascular program.

Rosanne put together a small team and began to consider their next steps.

Rosanne Crooke: So, I spent, probably the first six months — so that was 1999, December, that happened. And so I spent about six months, you know, better understanding what the liver does. Of course, I knew it was wonderful and did so many wonderful metabolic things.

Brady Huggett: Uh-huh.

Rosanne Crooke: And, just researched the liver and realized that the liver made these wonderful little things called apolipoproteins, which carried all of the fats throughout the body. Lipids. And realized that there were a ton of apolipoproteins that I could target.

Brady Huggett: With two people in her group, they identified 20-30 targets they might hit with Isis’s second-generation antisense oligonucleotides. One of the early targets was the gene product apolipoprotein B, nicknamed apoB. Building an oligonucleotide that inhibited the synthesis of the isoform apo-B-100 showed immediate benefit in animal models, quickly reducing lipid levels in the blood. That benefit translated to human studies in phase 1. It was “remarkable,” Rosanne said, a straight line from conception of the drug to patients. The company was certain mipomersen, as they called the compound, was a winner.

But developing it would cost money — the constant thorn in Isis’s side. Isis turned to Symphony Capital, which formed a unit called Symphony GenIsis and seeded it with $75 million, to be used for mipomersen and other products focused on metabolic disease. In return Symphony held all drug rights. This was a somewhat unusual setup for a biotech, but then again Isis was used to getting money any way it could.

The company’s second-generation drugs in general were beginning to show promise. At the top of that was mipomersen, but the full pipeline — across cardiovascular indications, metabolic disease, cancer and other areas — was more than 15 deep. And these early programs were helping to produce the one thing Isis needed to convince an unbelieving public. Here’s Stan.

Stan Crooke: And, as you know, there was, what? Fifteen, 20 years of extreme skepticism about antisense? And we were the lone voice in the wilderness. So, everything — everything — rode on both advancing the technology and proving to skeptics that we were having antisense effects in the clinic. And so, it was mipomersen, the clinical data with mipomersen, and then the backup information with various other drugs, that we had in cells and animals. That convinced at least some skeptics — actually a small fraction — that antisense was real.

Brady Huggett: With these new data being produced, Isis again drew interest from pharma. In May 2007, it announced a 3-year partnership with Bristol Myers Squibb to develop antisense drugs around the target PCSK9, which is linked to cholesterol levels. That deal brought Isis $15 million immediately, and a promise of research funding. It was followed by a licensing with Johnson & Johnson unit Ortho-McNeil, in which Ortho got rights to two of Isis’s diabetes drugs and paid $45 million up front, and potentially five times that much in later payments, based on milestones.

Isis used that money to help buy back rights to its metabolic drugs from the Symphony agreement. It cost Isis $120 million to do so, but when rights were back in house, Isis was free to license it to a partner.

Then in a deal announced early in 2008, Isis signed with Genzyme, a biotech company in Cambridge, Massachusetts, which had made its name developing therapies for rare diseases in children. It had 10,000 employees worldwide and pulled in ~$3.5 billion in sales that year, the majority of it coming from its ground-breaking, life-saving enzyme-replacement drugs. It was run by a well-known and well-liked CEO, Henri Termeer. Genzyme, in other words, was a biotech success story, flying high and flush with cash, looking to expand its pipeline. It seemed the perfect partner for Isis.

The deal centered around mipomersen, after its promising phase 2 studies. Genzyme bought $150 million in Isis stock, and paid another $175 million as an upfront fee. There was more than $1.5 billion attached to development and sales milestones, if and when mipomersen got approved. Sales revenue would be split between the companies. Though the contract called for Isis itself to invest $75 million in developing mipomersen, afterward Genzyme would fuel the rest.

The deal had the largest potential payout, ever, for Isis, and was one of the largest in biotech at that time. It was also Rosanne’s stamp on the company, her mark on its history. Mipomersen “was my drug” she told me. She’d found it, nurtured it, readied it for partnering. The Genzyme deal, and all that money, does not happen without Rosanne. Mipomersen, Stan told me, saved the company. Poetic, he said, considering some had doubted his decision to name Rosanne as head of the cardiovascular unit.

On the strength of the new deals, and all the money they brought in, Isis finished 2008 with a net loss for the year of just $12 million. There was more good news. The Ibis unit, now called Ibis Biosciences, had progressed into something of tangible value, with needs greater than Isis could fill. Here’s Dave Ecker.

Dave Ecker: We decided it was time to spin it out, or have it acquired. And so, this is now all the way up to 2009, after, you know, $100 million worth of government investment — we had investments from CDC, from NIH, a lot from DARPA, a lot from other agencies of the government. And eventually Abbott raised their hand and said, We’d like to buy this. So that’s when I left the company, because it was part of the expectation of Abbott that I would go there and take my whole research group and take all the technology.

Brady Huggett: Here’s Stan, talking about that transaction.

Stan Crooke: We then put a campaign together to sell it, and Abbott was keenly interested. And at that time we were running out of money. And so we sold it for $215 million and some residual rights. Both because we weren’t capable of doing it — we didn’t have the money — and we needed those dollars to fund mipomersen. We would have failed without that $215 million, we would have run out of cash.

Brady Huggett: If Lynne Parshall saved Isis through her fundraising efforts after the clinical blow ups, and if Rosanne saved the company by developing the mipomersen program that earned the massive Genzyme deal, and if Dave Ecker’s Ibis unit saved the company from running out of cash, then this tells you that Isis was in constant need of saving. The company could always see its own demise, just beyond the horizon. Indeed, at the end of 2008, 20 years after founding, Isis had accumulated a net loss of $840 million, without a single viable drug to its name. No wonder the general public was so dismissive. No wonder antisense was so doubted. No wonder Isis was the lone voice in the wilderness.

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Brady Huggett: Unfortunately, the high point of the Genzyme-Isis partnership might have been at the announcement. Before six months had passed, the companies had already shuffled the terms, calling for Isis to pay $125 million toward development, instead of $75 million. Indeed, Isis did need the money from the Ibis sale. And there were problems arising in the mipomersen trial data. The drug was being developed for familial hypercholesterolemia, sometimes called FH, a genetic disorder where those afflicted struggle to metabolize low-density lipoprotein cholesterol. The disease comes in two forms — heterozygous and homozygous — with the homozygous version occuring in just 1 in 1 million people, and the heterozygous 1 in 500. Those with homozygous FH can have LDL cholesterol levels as high as 600 milligrams per deciliter, and they are at risk for coronary events, heart attacks and early death. Heterozygous patients have LDL levels about half of that.

During the drug’s four phase 3 trials, its profile slowly came apart. It hit all endpoints in both the heterozygous and homozygous FH indications, with the expected injection site reactions and occasional flu-like symptoms as side effects. But there were also troubling elevations of liver transaminases, and when the companies presented data, Isis’s stock sank each time. Analysts and Wall Street weighed the hepatotoxicity against the benefits of the drug, and took into account the cheap, abundant supply of statins already available for patients, and didn’t like the chances of market uptake.

But it was clear mipomersen actually worked. In the homozygous FH trial, where the patients were most at risk, enrollees saw a 25% decrease in LDL cholesterol vs placebo — an average drop of more than 100 milligrams per deciliter. This was real progress, and Genzyme and Isis prepared the regulatory filing in that indication, thinking the FDA would be lenient about the liver issues when the need of the patients was so high.

They were right, mostly. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted in October 2012 in favor of the drug, by then branded Kynamro, but by a thin 9-to-6 margin. The underwhelming vote sank the mood around Kynamro, and it sank further that year when the European Medicines Agency panel voted against it, saying that the liver toxicities overshadowed any benefits Kynamro presented.

The drug’s prospects suddenly seemed so grim that a class-action lawsuit was filed against Isis, claiming that executives made “false and misleading” statements about Kynamro’s safety and efficacy, causing stockholders to believe the drug would be approved when surely Isis had known it would not.

Yet the suit was made irrelevant, in January 2013, when the FDA approved Kynamro in homozygous FH. The drug was given a “black box” warning — a bolded square up front and center on the label, loudly flagging the risk of hepatotoxicity.

It is the FDA’s way of alerting prescribers to serious side effects, and never what a company hopes for. Still, Kynamro was the first approved systemic antisense drug, as the media correctly noted, and it had a clear mechanism of action that could be attributed to nothing but antisense. That was not lost on Stan and the people at Isis who had worked on it for years. And it was certainly not lost on Rosanne. Since the fourth grade she had wanted to make drugs that would help patients, and now she’d done it.

Rosanne Crooke: How many, how often does a scientist in pharma get to have a drug approved. I think it’s very rare.

Brady Huggett: It is very rare, yeah.

Rosanne Crooke: And so it’s really cool that I was able to do that, and my small team, and it’s very validating. It’s really — it’s an amazing thing, actually. Um, it’s the most rewarding feeling, it makes me tear up, thinking about that we actually do help sick people, and it’s not just in an abstract way. People say, You let me live a life. And you help my family do this, it’s incredible.

Brady Huggett: Participants from the clinical trials visited Isis and walked up to her, thanked her for what she’d done for them, thanked her for the years of effort. And even beyond that, the approval was a “stake in the ground” for antisense, she told me. Kynamro had changed theory to fact: second-generation antisense could work. They’d just proved it.

The drug was also cleared in Mexico, Argentina, South Korea and Peru. Isis had $825 million tied to commercial milestones for it, and they awaited the windfall. But sales were never there. The black box warning plagued the drug, and patients had other ways to deal with their condition, including statins, and, by mid-2015, the first PCSK9 inhibitor — Alirocumab, an antibody drug sold as Praluent by Sanofi.

Regardless, Isis’s hopes for the heterozygous FH indication never materialized, and Isis and Genzyme dissolved their agreement in January 2016.

The drug was finished, a second antisense product approved that never went anywhere. There were a lot of reasons it played out this way, including mipomersen’s poor safety profile, but Stan had a ready culprit at hand: Genzyme.

Stan Crooke: I do blame them. I think they didn’t understand the market, didn’t understand what was required, lost commitment well before they should have. But you know, we argued, we pleaded, we did everything we could do, and they finally gave up on it. And then we tried to find other partners, but it was hopeless. So, Kynamro was lost.

Brady Huggett: By the time the partnership ended, Kynamro had a bad reputation, and Isis sold it to Kastle Therapeutics for a paltry $15 million.

To be fair, by the end of the partnership, Genzyme had become a very different company. In 2009, it discovered a contamination issue at the production sites for two of its biggest selling, and revenue-generating drugs, Cerezyme and Fabrazyme. The company was forced to invalidate entire batches, and that news, plus the lost revenue, hammered Genzyme’s stock. Activist shareholders moved in, including the notorious corporate raider, Carl Icahn, who began to call for Henri Termeer’s head.

Though the contamination issues were eventually resolved, Genzyme’s shrunken market cap brought bidders, and by 2011, pharma giant Sanofi-Aventis had purchased Genzyme for more than $20 billion dollars. After the buyout, Genzyme remained a stand-alone unit of Sanofi, but Termeer, who had run the company for 25 years, resigned as CEO.

Stan and Henri had liked each other, had a mutual respect, and with him gone the relationship between Isis and Genzyme seemed to sour.

Stan Crooke: And we really didn’t get along with Genzyme. We, we interacted as negatively as any, as we have with any company in all the deals we’ve done. Way more negatively, across the board. Every element of the company. And so it was constantly fighting.

Brady Huggett: The antisense field took another hit in August 2012, when Genta filed for bankruptcy, finally stepping off the stage completely. It was the last of the core companies formed in the initial rush of interest around antisense. With it gone, Isis was truly the sole survivor.

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Brady Huggett: Hidden in the original Genzyme Kynamro deal were a handful of Isis’s central nervous system programs. They were early stage, without much yet in the way of data, and Genzyme never seemed to take them seriously. When it came time to consider picking up the options, it made a half-hearted bid.

Stan Crooke: The actual CNS program was actually owned by Genzyme.

Brady Huggett: The original CNS program?

Stan Crooke: Yeah. It was part of the, just, you know, things Henri wanted me to throw in to sell the deal, more broadly, to the public. They had rights to Spinraza, and the SMA program.

Brady Huggett: Oh, I did not know that.

Stan Crooke: They had, and they offered for Spinraza — and now they were in hard times. Because they had that, uh, FDA, you know, problem with their manufacturing and they were getting beaten up and they had no money. So they offered us $5 million, and we laughed at them. And we wouldn’t work with them anyway, so we walked away.

Brady Huggett: So they had an option to pick up Spinraza —

Stan Crooke: They certainly did.

Brady Huggett: They offered five, and you said no.

Stan Crooke: And a couple of others. And, had they offered us $100 million, they would have had Spinraza really cheap.

Brady Huggett: The central nervous system. It was a brand new area for Isis, and for antisense. Isis’s CNS programs included a “skunkworks” project being run by Frank Bennett, aimed at spinal muscular atrophy, and it would produce a compound eventually named Spinraza. No one at Isis thought much of the program yet, and certainly they didn't at Genzyme. But Frank did. Understanding why requires going back 25 years.

Before 1995, about three-fourths of the Type 1 subset of SMA patients, which is the most prevalent type, died before 2 years of age; the remaining quarter died after that two-year period. Doctors focused on palliative care, but still the children tended to struggle with eating and breathing, due to weak thorax muscles. They suffered from respiratory infections, and were often under-nourished, and these were the issues that led to their deaths.

It had long been known the disease was hereditary, but in 1995 a research team at L’Institut National de la Santé in France, led by Suzie Lefebvre, published a paper titled “Identification and Characterization of a Spinal Muscular Atrophy-determining gene.” Suddenly, there it was. It was a watershed moment in the history of SMA. Forever the healthcare field had been treating the symptoms, and now, laid out in that paper, they had the cause.

The gene is survival motor neuron 1, or SMN1, and in healthy individuals, it produces high levels of the survival motor neuron protein needed for normal muscular function. When this gene is defective, it does not produce the SMN protein, and spinal muscular atrophy arises. Muscles are not able to function, they atrophy, and in the strongest cases this leads to death.

But there is a backup copy of that gene, called SMN2, and it is capable of producing very low levels of the protein. The prevalence of that backup gene is what defines the severity of spinal muscular atrophy. Type 1 patients, who have one copy of the backup SMN2 gene, tend to be diagnosed in their first six months, and often die before their second birthday. This group makes up 60% of all cases. Type 2 have two copies, and are usually diagnosed later, when they fail to meet progression milestones. These children usually are unable to walk, and require a wheelchair. Type 3 can sometimes be diagnosed as late as the teenage years, and those afflicted often regress to life in a wheelchair. Type 4 is the rarest version, and is diagnosed in adulthood, usually after 18 years of age but before 35. These individuals have mild motor impairment.

The discovery of the gene was hope. Here’s Darryl De Vivo.

Darryl De Vivo: So after 1995, people became more optimistic. Wow, we found the gene, now we might be able to find a treatment. So let’s step in and do what we can to support these babies. So now we were increasingly being proactive in supporting their respiratory needs before they had respiratory failure. And also putting in gastronomy tubes to nourish them, so they wouldn't run the risk of not being able to chew or swallow, or aspirate into their lungs because they couldn't swallow it very satisfactorily. And those two changes alone changed the mortality from 75% to 25% in the two-year period.

Brady Huggett: And now, researchers and specialists like Darryl De Vivo began to push the National Institutes of Health for more attention on the disease.

Darryl De Vivo: At that time, in 1999, we said, You know, you should have a study, a seminar, a, kind of a brainstorming session for spinal muscular atrophy. It’s the second most common autosomal recessive disease. It’s monogenic. We have a second target. We have a primary gene that’s mutated that causes this disease. We’ve got a backup gene that modifies the phenotypic severity — the SMN2 gene. It’s ripe for study and development of an effective treatment.

And so Story Landis said, We agree with you. And John Porter, who was there at the time, said, Let’s create a one-day meeting, and we’ll invite people, including a fellow named Adrian Krainer. Very good in RNA biology, but he doesn’t know anything about disease or anything. So we’ll invite him to come.

Adrian came to the meeting, and he sat there and he listened and he said, I was fascinated, listening to this. And then learning that this disease is a result of something wrong in RNA splicing.

Brady Huggett: Adrian Krainer was born in Uruguay. During his high school education, he came across Gregor Mendel, the scientist from Brno, Czech Republic, who is sometimes called the father of genetics. Mendel’s work and theories hooked Krainer, and confirmed his desire to be a scientist. He won a scholarship to Columbia University, where he majored in biochemistry, and then went to Harvard for his PhD and studied biochemistry there, too. While there, he worked with Tom Maniatis, who was studying the mechanisms of RNA transcription and splicing.

That led Krainer to a career of “trying to understand RNA splicing,” he told me, almost the entirety of which has been spent at Cold Spring Harbor, in New York. Krainer had been unofficially mentored by Richard Roberts, who shared the Nobel Prize in Physiology or Medicine in 1993 with Phil Sharp for the discovery of introns in eukaryotic DNA and the mechanisms of gene splicing.

This background made Krainer a perfect invitee for the one-day symposium on SMA. At the event, he got an early look at a paper that would soon be published in the Proceedings in the National Academy of Sciences, titled, “A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.”

The paper turned a light on in Adrian’s head.

Adrian Krainer: And I went to this meeting, and it was before the papers were published, so it was a good opportunity to find out about it early. And I knew right then that it made a lot of sense for us to work on SMA.

Brady Huggett: The mechanism of splicing is a normal occurrence that underlies the expression of almost every gene. Krainer himself uses an analogy of books and a library to explain it. Consider the genome to be a library, containing some 25,000 books. Each book is a recipe for a protein, and reading the chapters of that book provides instructions on how to make it. Yet there are also nonsensical pages that do nothing but separate the “chapters,” he said. In the normal process leading up to protein production, a mechanism removes those nonsensical pages, and allows the “recipe” to be read cleanly and in sequence, and a protein to be produced.

Those nonsensical pages, the non-coding segments of a gene, are called introns. Exons are the coding segments used to create mature RNA that is ready for translation. The process of removing introns is called splicing.

It is a crucial element of protein production, and Adrian Krainer had spent nearly his entire career studying it. Adrian left that meeting in 1999 with the understanding that between the two SMN genes there was just a single nucleotide difference in exon 7, and that resulted in a different splicing pattern. This single splicing defect, in this single gene, made SMA the number one genetic killer of babies less than 2 years of age.

Adrian Krainer began to immerse himself in the disease and its communities, attending meetings sponsored by groups like FightSMA, learning all he could.

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Brady Huggett: If the discovery of the gene behind SMA brought new attention to the disease, it didn’t bring enough. Or that was the feeling of Dinakar Singh and his wife Loren Eng.

In March 2000, the couple had a daughter. They named her Arya, and she developed normally, as SMA children do, sitting and crawling in line with other kids her age. When she lagged in learning to walk, her pediatrician thought Arya was simply a late bloomer. Yet in August 2001, while at a party in New York, a doctor friend of Loren and Dinakar’s saw Arya stumbling around the room and was worried enough to recommend they take her to a neurologist.

A month later the parents had their diagnosis. Loren and Dinakar, like many, many parents before them, were crushed when they learned there were no treatments for SMA, and little being done to generate one. What made it worse was that Loren was already pregnant with their second child.

But what set them apart is that they were wealthy, well educated and well connected. Dinakar was a trader for Goldman Sachs. Loren had been an investment banker and had an MBA and a master’s in education, and the couple was active in elite New York City circles.

And, now, they were desperate. They began seeking out the best for Arya, and made their way to Darryl De Vivo, at Columbia.

Darryl De Vivo: I had just gotten back from a trip to China with my wife.

Brady Huggett: Uh-hm.

Darryl De Vivo: And we actually flew back into New York just after 9-11. It was a terribly depressing moment. We arrived, and I went back to the office, and a few weeks later, the president of the hospital, who had been the former dean, Herb Pardes, called me and he said, Darryl I have this family, they called me last night. They’re important family members, important people here in New York. And they have an urgent need to see you. And I said, Well, have them come tomorrow morning.

And, the father was upset, when he told me this story. He said, Yesterday, or the day before, I got a call from an orthopedist, saying, We know what your daughter has. She has spinal muscular atrophy. It’s not going to affect her brain, she’s just not going to be able to play baseball or anything.

And he was really offended by that. He said, My goodness, what a way to announce on the telephone that our daughter has something that I’ve never even heard of!

Brady Huggett: Yeah.

Darryl De Vivo: And the mother and father, being just remarkably intelligent, you know, just immediately went on the internet. They’d digested everything they could overnight. And so the next day they came to see me. They were already remarkably informed on the subject of SMA.

And I examined this young girl, who was 18 months old, and she could walk but just barely. So she was really a rather severe Type 3a. In any event, I saw her and I talked with the mother and the father. And I said, Well gee whiz, yeah, your daughter I think does have spinal muscular atrophy. There are some tests we can do to, you know, be absolutely certain. But I explained, you know, it’s an autosomal recessive —

They said, yes, we know all about that, we’ve read all about it. And the mother is sitting there fully pregnant, ready to deliver in a few days. And that was the beginning, I think, of a very meaningful interaction with the parents of this young girl.

Brady Huggett: A Type 3a meant symptoms usually show up before age 3, and the patient will eventually lose the ability to stand. This was terrible news, softened somewhat by the confirmation that their second child — a boy born not long after this initial meeting — inherited both normal alleles and was free of SMA. When that fear was alleviated, Dinakar and Loren focused on doing whatever they could for Arya.

Darryl De Vivo: And so Loren and Dinakar came to me and said, What else can we do to, you know, move things along? To see if we can do something to help Arya and the other children with this? And I said, Well there’s this organization called Families of SMA.

So they went and actually spent a year interacting with the Families of SMA. Loren and Dinakar thought they wanted to go more central and go directly to federal government. And they were well connected so they had contacts in the White House and in Congress, and increasingly they got to know everybody at the NIH.

Brady Huggett: Families of SMA was a grassroots organization. It put on road races and had bake sales to raise funds. It built a much-needed community around the disease. But Dinakar and Loren wanted something different, something specifically targeted on drugs and a cure.

Darryl De Vivo: And then they came back to me and said, You know, we want to create our own foundation. I said, You know, that’s a lot of work. I said, Not only that, but you’re living with this disease 24-7. Not only with your child, but with everybody else related to the foundation. And they said, I know, we’ve thought about it, and we’ve talked with other people, and so forth, and we’re going to do it.

So in 2003 they created the SMA Foundation, which was based in New York City. They headquartered it at Columbia, and asked me to direct it.

Brady Huggett: With Darryl directing, the SMA Foundation founded the Pediatric Neuromuscular Clinical Research Network, which brought together SMA clinical experts from Columbia University Medical Center; from Children’s Hospital of Philadelphia, where neurologist Richard Finkel presided; and from Boston Children’s Hospital with Basil Darras, and also a data coordinating center at the University of Rochester. They enrolled patients, and established a standard of care across sites. Referrals came in from all over the northeast, and soon they had 500 patients in the network.

The foundation began to put money into generating mouse models for SMA for preclinical testing, available for whomever needed them. And they also recruited evaluators — physical therapists who would be able to gauge how these patients were doing, if they were getting weaker, or stronger. And they established better outcome measures, so they could more easily collect data on all three prevalent types of SMA patients.

All of this was preparation. If a drug came along, if some company could conceive and develop a compound that could make any difference against this disease, they would be in a position to recruit patients, to run trials, and collect the information that might, one day, win an approval from the FDA.

Loren and Dinakar began to work this second angle. They didn’t think SMA got enough funding from the NIH — it was just $13 million a year at the time. When Loren and Dinakar went to Congress to lobby for more, they were sometimes told they would get better traction if they had a celebrity face at the front of the disease, like Michael J. Fox with Parkinson’s, or Christopher Reeves had been for spinal cord injuries.

SMA didn’t have that. Where would the celebrities be, considering the disease killed so many children before they ever got a start in life? But Loren kept hammering anyway. She got 50 scientists, including Nobel winner James Watson, to petition the NIH for more funds for SMA. She paid a lobbyist to combine efforts from various SMA support groups, and they sent more than 400 pieces of mail to Congress. Loren and Dinakar met with US Senators Arlen Specter and Tom Harkin. And they told their story wherever they could. The New York Times. Forbes. The Today Show. Nightline. The Pittsburgh-Post Gazette.

Dinakar bankrolled all of it. He had quit Goldman Sachs and started a new fund, and told Forbes magazine in 2005 that he would “put every penny” from that fund into SMA research if he thought it would hasten a cure.

That was not hyperbole.

Bloomberg anchor: Former Goldman Sachs partner Dinakar Singh is racing to find a cure for his daughter, before it’s too late. She’s suffering from a disease that was largely ignored by biotech firms, even though a number of breakthroughs made it ripe for drug development. Singh’s efforts are featured in the current Bloomberg Markets magazine, Gigi Stone is here to tell us all about it. Gigi?

Gigi Stone: Eric, imagine having all the money in the world practically, and not being able to fix the one thing in your life that matters most to you: the health of your child. Well it’s a life calling for Dinakar Singh, founder of TPG Axon Capital, a hedge fund with more than $8 billion in assets. And Singh has spent nearly $100 million of his own money to create and fund the Spinal Muscular Atrophy Foundation.

Brady Huggett: And now, finally, some threads began to braid.

Adrian Krainer, upon leaving that NIH meeting in 1999, was focused on the disease. Neurological disorders are notoriously hard to crack, but this was a problem worth studying. He started looking for funding, and earned a grant from Fight SMA in 2000. While attending a Fight SMA meeting some time around the end of 2001, he met Loren Eng, who had recently gotten Arya’s diagnosis. They stayed in close contact, seeing each other at community meetings, and after Loren and Dinakar launched the SMA Foundation, he attended those events, too.

The SMA Foundation in all provided ~$200,000 to Adrian’s lab. Along the way he secured money from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and Fight SMA, among others.

And he began to publish his findings. In 2002, his lab published their first paper on SMA in Nature Genetics, titled “Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.” In 2003 they published in Nature Structural Biology a paper showing a proof of concept for a potential therapeutic, titled, “Correction of disease-associated exon skipping by synthetic exon-specific activators.” The group also filed for a patent around the discovery.

Frank Bennett, laboring over his skunkworks project in Isis’s small CNS program, saw the paper and the patent. This was close to what he was working on, and he’d long admired Krainer’s research.

Frank Bennett: So, I’ve known Adrian’s name since I was a graduate student. We worked on similar projects. Um, and he was a graduate student in Tom Maniatis’s lab at Harvard and I was a graduate student in a lab in Baylor. And the work that they were doing on characterizing the mechanisms of splicing was very visible work, and, uh, you know, I had a tremendous amount of respect for the work that they were doing.

And so I’ve known about Adrian for, since, like, early ’80s. Then you fast forward a number of years, to when we started working on antisense technology, and he had published a paper on SMA. Using a very similar technology to what we’re using, that we owned at the time. And he had done a proof-of-concept study that was published. So it caught my attention. And, uh, at the same time we were working in the CNS, with Don Cleveland, that had already generated some data that showed that we could get effective delivery. And so between those two data points, I decided to reach out to Adrian to see if he’d be interested in collaborating.

Brady Huggett: A horrendous disease without a single therapeutic had finally been given a root cause, and it included a splicing error. That discovery had attracted one of the world’s thought leaders on splicing. His work, in turn, had attracted the attention of a company that had worked for 25 years to make antisense stable and potent in the body, and a researcher there working on delivering drugs to the central nervous system.

They didn’t know it yet, but pieces were dropping into place to do something monumental. There were a lot of other people who would need to put their blood, sweat and tears into this, but it was getting close.

[theme music]

Thanks to Stan Crooke, now and always. Thanks to Rosanne Crooke for her memories on developing Kynamro. To Dave Ecker, for his memories on Ibis. To Darryl De Vivo for discussing his career and treating SMA. To Adrian Krainer for sharing his expertise on splicing. To Frank Bennett, for providing the details on the CNS program. Audio clip on Dinakar Singh and the SMA Foundation taken from Bloomberg. Of particular use to this chapter was an article in Forbes titled, For Arya, written in 2005 by Robert Langreth.

Rest in Peace to Henri Termeer, who died in 2017. If you’re ever in Cambridge, look for the statue of him in Henri A. Termeer square. Rest in peace Paul Zamecnik, who died in 2009. Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous five chapters. Chapter 7 will be out in a week. Until then.

Chapter 7: the SMA gang

Brady Huggett: Chapter 7: the SMA gang

In February 2013, in Long Island, New York, Dianne Larson and her husband Matthew had their first child. A girl, and they named her Emma. It had been an uneventful, healthy pregnancy, and for months everything was fine. Emma was crawling by her first birthday and at her one-year checkup with her pediatrician, nothing seemed abnormal.

But then things changed.

Dianne Larson: And literally at 13 months, it was like her legs just stopped moving. It was, it was strange. The bouncy? The exer-saucer, they call it?

Brady Huggett: Yeah.

Dianne Larson: Uh, she wasn’t bouncing anymore. You’d just put her in, and she just wouldn’t move. So, like, OK, something’s not right here. So we took her back to the doctor, and they’re like, Oh, it might be just, like, lazy. Take her to early intervention. Go through them, talk to them. Maybe there is some physical therapy. We did that.

So she was getting physical therapy, but we still decided to go through other doctors and see what was going on. We went to Stony Brook, and Stony Brook did an MRI on her, and a couple other tests, and said, No, she’s fine. She was still crawling at the time. So they’re like, Just give it a few more months.

Brady Huggett: So this physical therapy wasn’t really helping.

Dianne Larson: Well, the thing was, it’s amazing, because her physical therapist is the one who pushed me to say, hey, something’s not right here. Uh, she’s a great therapist and she said, Listen. She goes, I’m not supposed to give advice, but if this was my kid — you know, don’t listen to Stony Brook. You need to do something. And you need to do it quick. She’s getting weaker.

Brady Huggett: If she was getting weaker, it was happening so slowly that it was hard to tell. So Dianne pulled up videos of Emma, taken during the previous months, and began to go through them. Those videos over time, when viewed side by side, showed a clear regression.

Dianne Larson: And I pulled my husband aside, I was just in tears. Because I guess I didn’t realize it, the thing with SMA. It takes just a little each day that you don’t really notice it. It took so little. And then one day, it was like — Bam! What happened here? Something’s not right.

Brady Huggett: Yeah.

Dianne Larson: So when we looked back on the videos, I had to pull my husband in, because he was still, like, on the fence. You know, maybe she’ll be OK. And I showed him the videos of her crawling at 11 months, and now at 14 months. And he was like, Wow.

Brady Huggett: Her physical therapist recommended a doctor at nearby St. Charles Hospital, but when Dianne called, she was told the wait for a new appointment was five months. By now Dianne was “hysterical,” she told me. Emma’s crawling had become even more labored, the distance she could cover had shrunk down to four or five feet. When her daughter lifted her bottle to her mouth, her core was so weak she’d topple over.

“We don’t have five months,” she told the receptionist.

The hospital fit Emma in on the coming Friday. The doctors spent four hours with her, and she was seen by a visiting neurologist who happened to be in the building that day. They drew blood, and told the Larsons they’d have results in two weeks.

Dianne spent that time online, googling neurological conditions, everything she found adding to her spiraling anxiety. Then they got a call, asking them to come back to St. Charles.

Dianne Larson: You know, they sat us down, they said, We have really bad news that your daughter has spinal muscular atrophy. We think she has Type 2. We don’t know her life span, maybe 20 years. Uh. She’ll never walk. She’ll probably lose her upper body strength. If there’s no intervention, she’ll basically get to a point where they said she wouldn’t be able to lift a cup. Or a fork.

And the craziest things, and thoughts, go through your head. I’m like, I have to sit here and watch my daughter slowly waste away?

Brady Huggett: Yeah.

Dianne Larson: Like, that’s what I’m going to do? [sighs] It’s still hard to talk about it. [sighs]

Brady Huggett: That’s OK.

Dianne Larson: Um. I don’t — it’s. It’s literally hell on earth. I don’t think there is anything. I mean. It’s pretty — it’s almost as bad as you could possibly, you know, things could possibly get.

Brady Huggett: It’s almost, like, um, if the diagnosis was for yourself, you’d find a way to handle it. But when it’s for your kid, you really can’t handle it.

Dianne Larson: No. No, you always, as a parent, would wish it would be you, rather than your kid.

Brady Huggett: That diagnosis came on July 22, 2014. The Larsons still call it D-Day. They were told there weren’t any medications, and there was no cure. They had “no hope,” leaving the doctor’s office, Dianne said. In the following weeks — Dianne called them “a blur”— she stopped eating, and couldn’t sleep. She lost weight. She slipped down into a kind of hole, grieving, and feeling lost and desperate.

Dianne Larson: There’s a lot of things that you learn when you are hit with something like this. Of how I could now relate to how people do crazy things. Because it is — until you’re put in that predicament, um, like you really would go to the end of the earth for your child. So you just become crazy. You look on the internet for anything.

Brady Huggett: It was difficult to snap out of that depression, but she did it. I can’t stay like this forever, she thought. She needed to move forward, in whatever way she could. The first part was sharing this terrible news with loved ones. But rather than retelling it, painfully, over and over, she put together a Facebook post and shared it with her circle. And then she and Matthew started thinking about where they could go, and what they could do that would be best for Emma.

From Nature Biotechnology, I’m Brady Huggett and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: The central nervous system program at Isis didn’t start with SMA. Frank Bennett, as chief scientific officer, had the job of figuring out where and how to apply antisense technology. Though Isis was strapped for money, it still allowed for what’s called “blue sky” research — that’s work driven by curiosity, where the main goal is to simply consider what’s possible. This was part of the culture Stan Crooke had wanted and instilled at Isis, and it was one of the reasons scientists like Frank stayed around all those years. The chance to explore.

What Frank wanted to explore, was the central nervous system. In his blue sky research, he was collaborating with Don Cleveland, from the University of California, San Diego, and Richard Smith, who is now director at the Center for Neurologic Study in La Jolla, California. Those two men thought the way to deliver drug for CNS diseases might be via lumbar puncture. This technique is also called an intrathecal injection, and it administers drug into the cerebrospinal fluid at the base of the spine. The fluid then carries the drug along the spinal cord and into the brain. This method had been used by others in the field, and Frank and his collaborators set up some animal experiments to try it themselves.

Here’s Frank.

Frank Bennett: The original experiment was, um, you know, let’s see what happens. I didn’t have a preconceived idea that it would work or wouldn’t work. It was just, you know, until you do the experiment, you don’t know the answer. Once we started seeing some encouraging data from the animal experiments that we were doing, then it became clear that this could be broadly applicable for a variety of CNS diseases. And so we focused on one disease to really establish all the proof of concept.

Brady Huggett: What was the first disease?

Frank Bennett: It was ALS, due to mutations in a protein called superoxide dismutase.

Brady Huggett: The superoxide dismutase gene, also called SOD1, had already been directly linked to a rare, aggressive form of ALS, so that helped derisk the program, and made it a good place to start. Quickly, in these mice experiments, the team saw evidence that antisense drugs have a longer half life in the central nervous system than they do in organs, such as the liver. This was encouraging, but expanding the work and exploring other diseases would require a proper budget, and when Frank asked Stan about using in-house funds, the answer was no.

Stan Crooke: I was very skeptical. I didn’t believe that the technology would work, because of inflammation in the central nervous system. And I believed that if it did, there was no market. Well I was 100% wrong.

Brady Huggett: Stan told Frank he would need to find external resources. Frank did. He received grants from the ALS Association and the Muscular Dystrophy Association, both of whom provided “critical” funding, he told me. Without that money, it’s likely the CNS program never goes anywhere.

Generally, intrathecal injections were administered by a pump implanted under the skin, giving a constant, slow infusion. But for the SOD1 mice and rat studies, the group delivered the antisense oligonucleotide via minipump into cerebral ventricles instead — right into the brain.

The next step was to compare those results against intrathecal injection. In monkeys, intrathecal delivery gave comparable results to what was seen with delivery to the brain, with less toxicity issues. From that point on, Frank and his team focused on lumbar puncture, though they eventually switched away from pumps to a bolus injection, which proved more efficient.

These early experiments “worked far better than I expected them to,” Frank Bennett told me. They established proof of concept for the delivery method and documented that the drug was widely distributed into the spinal cord and brain tissue. They were getting someplace.

Then Adrian Krainer’s lab published a paper on SMA and splicing.

Adrian Krainer: And so we began to do some early antisense experiments. We based those initial experiments on the, what we knew about the protein that’s failing to bind. And so that protein has a modular structure, so we were trying to create a synthetic molecule that will function like that, like that RNA-binding protein. So it had an antisense part, and a peptide part attached to it. And so those are experiments that we did in the test tube, which worked quite well. And, uh, so we published them, and so we also had a patent on this concept. And then, that actually opened a lot of doors.

Brady Huggett: Frank saw the paper, and the patent, and reached out to Adrian in 2004. Here’s Frank.

Frank Bennett: We set up, uh, a call, and invited him out to visit the company. And in his visit we sort of mapped out a plan of how we’d go forward. That sort of started the collaboration.

Brady Huggett: The 2003 paper by Adrian and his lab attempted to deal with the single nucleotide substitution in exon 7 of the backup SMN2 gene. That substitution weakened the binding of splicing activators, and caused only a small portion of SMN protein to be produced — not enough to make up for the lack of SMN protein caused by the deleted or mutated SMN1 gene in spinal muscular atrophy sufferers. Adrian and his group engineered an antisense oligonucleotide and covalently linked a peptide that mimicked a splicing activator. This promoted exon 7 inclusion, and that was the basis for his paper.

But when the two groups began working together and tried to produce the peptic nucleic acid meant to be linked to the antisense molecule, Isis found them hard to synthesize. And anyway, they didn’t work as well as they’d hoped. Frank suggested they use the MOE second-generation chemistry that Isis had built, and Isis sent over about “100 antisense oligonucleotides” for screening, Adrian said. Immediately they got good results, and it was clear the peptide was “not necessary.” The group began working in that direction.

But by now Isis had had the massive Affinitak failure, and the downsizing that followed, and money had gotten even tighter than usual. Even Adrian could feel it.

Adrian Krainer: The first time I went out there, early in our collaboration, I was kind of blown away by the whole setup and, you know, for oligo synthesis — it was very impressive. Then they went through some difficult times. So, on another trip, they had shrunk. I mean, they had got rid of a lot of personnel. They moved to a smaller premises. I was thinking, Oh my god, are they to survive [laughs] long enough for this project to be successful?

Brady Huggett: In early 2008, Isis signed the big deal with Genzyme on Kynamro, and Henri Termeer asked Isis to throw in the burgeoning CNS program. The research scientists there were “wonderful” to work with, Frank told me, and Frank and Adrian published in 2008 a paper showing that antisense could modify pre-mRNA splicing and kickstart the modified copy of the existing SMN1 gene.

Their experiments in SMA mice models were encouraging. The drug development path is littered with failed compounds that once looked promising in mice, but still, their results opened eyes.

Adrian Krainer: I think it looked pretty promising, because, you know, it was very striking. I mean, we had mice that, if you don’t do anything, they drop dead in 10 days. And then we do these treatments and they are surviving 250 days, running around normally. So, we’re talking, not-subtle effects.

Brady Huggett: Yeah

Adrian Krainer: It was pretty striking.

Brady Huggett: By 2009, Isis had officially elevated the spinal muscular atrophy program to its public pipeline. Along with the growing SOD1 experiments in ALS, Isis knew it needed help with its clinical aspirations.

They hired Kathie Bishop. She grew up in Canada, where she had a great high school teacher in an advanced biology class, who opened a passion for science in Kathie that has never dissipated. She studied genetics in undergrad, eventually earned a PhD in neuroscience at the University of Alberta, and then did her post-doc at the Salk Institute, in San Diego, studying molecular neurobiology. She published a high profile paper in Science while at Salk that could have led her to an academic career, but she knew she wanted to go into industry, in particular to work on therapies for neurological diseases. Something about academic work, she’d realized, felt too theoretical. For every research grant she’d ever applied for, or won, she’d needed to describe how the proposed work would help patients, and it always seemed a bit fanciful, and far off. She wanted to work on disease in a more near-term way.

She was hired into a startup gene therapy company, called Ceregene, as its first scientist. For more than 8 years she worked on neurological disorders there — Parkinson’s, Alzheimer’s, ALS and Huntington’s disease — and took two drugs into the clinic. But after a phase 2 trial in Parkinson’s failed, Ceregene was forced to narrow its focus, and that also narrowed the projects Kathie could work on, so she left.

Isis hired her at the director level for clinical development. Much of the company was occupied with the Kynamro phase 3 trial, and Isis needed deep experience in neurology clinical work. Here’s Kathie.

Kathie Bishop: When I started, the ALS drug was going into the clinic. Um, but Frank and Adrian Krainer had already done some of the early mouse work on the SMA drug. So, my job was also to start to think ahead to the clinical trials, to SMA.

Brady Huggett: It was a disease she’d never even heard about, but she got a crash course in it immediately.

Kathie Bishop: I actually remember really well, my first week — it was my first or second week — we had a visit from the SMA Foundation. Um, from Karen Chen, their CSO, to come and for us to learn about SMA. So I remember that really distinctly.

Brady Huggett: Kathie brought in a panel of experts to help Isis think about delivery. Isis ran a phase 1 trial in the ALS program in 2010. Officially, an antisense drug had been delivered to the central nervous system — another first for Isis. That helped ease anxieties around a clinical study in SMA patients, because the SOD1 trial showed that delivery into the spine was safe. Still, sick children were an entirely different proposition. Here’s Stan.

Stan Crooke: It was the riskiest decision I ever made in my life. And we certainly had never treated a child, of any sort. In any way. Uh, so, you know, I know bad things can happen. I worried that, somewhere along in the first couple-three patients, one of these patients has, uh, some bad event when getting his injection, dies, and our company’s finished.

Brady Huggett: With these expensive trials looming, Isis would need financial help. But beyond the money, given the risks with these vulnerable children, Isis also “needed knowledge,” Stan told me. They needed another corporate partner, a company active in the space. Here’s Kathie.

Kathie Bishop: So Frank and I sat down with business development, and kind of wrote out a list of all the companies that we thought might be interested, and all the people that we knew at those companies. And then set out to, within that year, find a partner.

Brady Huggett: One of those companies was Biogen. It was one of the original flagship biotech companies, initially founded in 1978 in Geneva, Switzerland, though it moved headquarters to Cambridge, Massachusetts in 1982. It had developed a successful multiple sclerosis franchise over the decades, and by 2010 it had four products on the market, including two for MS, and pipeline programs in ALS, Parkinson’s and Alzheimer’s disease. It had total revenue that year of more than $4.5 billion, and cash on hand of nearly $2 billion. It understood treating the central nervous system, but it was in a period of upheaval. Its success in multiple sclerosis had been difficult to replicate, and its stock had weakened in recent years. Carl Icahn, the activist investor who would soon be after Henri Termeer at Genzyme, had taken to publicly criticizing Biogen CEO Jim Mullen, telling The New York Times in 2009 that Mullen would “have to work harder” in the face of Biogen’s sinking stock, which had fallen by nearly a quarter over a five-year period. And after Icahn secured two seats on Biogen’s board in 2009, Mullen left the company in early 2010.

Stelios Papadopoulos was on the Biogen board at the time. Here he is discussing that event.

Stelios Papadopoulos: In 2010, we had a change in management at Biogen. George Scangos took over, um, following Jim Mullen. And when he showed up, when he became the CEO of Biogen, there was an opportunity — and that’s fairly common in this business — to, you know, redefine the management team, personnel, priorities, strategy, vision. And at the time, one position that was particularly important was that of R&D.

Brady Huggett: Uh-hm.

Stelios Papadopoulos: Which was vacant. Immediately both George and I thought that the best person for that would have been Doug Williams.

Brady Huggett: Doug Williams was a sharp scientist and had been CEO at a company called Zymogenetics, but it had been recently bought by Bristol-Myers Squibb, and post-merger the executive team was not retained. Stelios and George Scangos convinced Doug to join Biogen. He was officially announced as the new head of R&D in early January 2011.

Frank Bennett knew Doug Williams, and Biogen was already on the list of companies he and Kathie had put together as potential partners for the SMA program. Frank reached out to talk about spinal muscular atrophy, and the work he’d been doing with Adrian Krainer. It caught Doug’s interest. Here’s Stelios again, talking about Doug Willliams.

Stelios Papadopoulos: Somewhere early in 2011, he started bringing out this notion of wanting to do something with antisense oligonucleotides, largely driven by his own appreciation of the value of the science, as well as his friendship and mutual professional respect with Frank Bennett.

Brady Huggett: Yeah.

Stelios Papadopoulos: And really, it was the Frank Bennett-Doug Williams relationship that drove the vision, defined the vision, and drove the process.

Brady Huggett: There were other companies expressing interest, but Frank liked what he saw in Biogen. Though he’d gotten along with the researchers at Genzyme, before the money got tight and the mood changed, he felt Isis and Biogen were almost spiritually matched, and that was his pick for the partner, if he could make it happen.

Frank Bennett: I was a very strong advocate that we had to do this with Biogen. It’s just, our two companies were so aligned in our cultures. And, the people we were interacting with were people I actually enjoyed talking to. And so, you know, that’s in part what makes a good collaboration, is if you enjoy your partner, interacting with your partners. That’s important.

Brady Huggett: Perhaps others saw a synergy between the companies, too. The SMA Foundation, now well established in the community behind Loren Eng’s tireless efforts and Dinakar’s financial clout and contacts, often put together scientific meetings on the disease. At one of those, Loren carefully arranged the dinner seating, like chess pieces on the board.

Frank Bennett: Well, Loren plays matchmaker. So, they would have these scientific advisory meetings, where, uh, really what they would do is talk about the latest research. And they invited us to present at a couple of those meetings. And at one of those meetings, they would do a dinner afterwards. And Loren set me next to Al Sandrock, at Biogen. And, you know, I knew exactly what Loren was trying to do. [laughs] It was obvious, but I appreciated it. You know, it was an opportunity for me to have dinner with Al. And Al and I have very similar personalities, and we got along fabulously.

Brady Huggett: I mean, how long into the dinner before you were talking about SMA?

Frank Bennett: Oh, immediately. And then we — as I said, I think both Al and I have very similar personalities and, you know, love for science, and what medicine is doing. And then, he just said, We gotta do this deal.

Brady Huggett: The dinner helped “seal the deal,” Frank told me. But it was not exactly a slam dunk. Obviously Doug Williams wanted it, and he’d convinced George Scangos. And after that dinner, Al Sandrock wanted it, too. But this was before Kynamro had been approved, and Isis’s entire drug portfolio, after more than two decades, was a questionable CMV retinitis product that never sold. Many, many people remained skeptical around antisense oligonucleotides. Here's Stelios.

Stelios Papadopoulos: So, there was broadly a perception in the industry that, yeah, ASOs are interesting, but I’m not sure they’ll be drugs. And that point of view was shared by a number of people on our board.

Brady Huggett: Stelios believed in it — he’d had a relationship with Stan and Isis nearly since inception, and he knew those feelings around ASOs were “dated,” he said. Eventually the positive opinions won the day, but the doubt about the program still lingered in the halls of Biogen.

The deal was announced the first week of January 2012. It was a single-asset collaboration. Biogen signed to develop and commercialize what by then was named ISIS-SMNrx. It meant that Biogen would use their years of experience with CNS drugs to offer valuable input on trial design, and interactions with the FDA and other regulatory authorities. The deal called for an upfront payment of $29 million to Isis, and another $45 million in milestone payments linked to achievements in clinical developments. If Biogen licensed the drug outright, it could pay up to $225 million more in fees and milestone payments, and Isis would get royalties on sales in a “double-digit” percentage.

The $29 million upfront exposed Biogen’s cautious nature around the program. The fact that Isis accepted it showed its still-moderate expectations, too. Frank and Adrian had done remarkable things in cell tissue and in mice, but that is eons away from solving anything in humans. One look at the history of SMA, and at the way the bodies of these children were betraying them, and anyone could see how difficult the task would be.

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Brady Huggett: Just before the announcement of the Biogen collaboration, Isis entered the clinic with ISIS-SMNrx. Moving it into humans contained many anxiety-producing elements. The first was the patient population, in particular the severe Type 1 SMA patients who were already in a slow, terminal cycle. If one of those babies died while getting injected, the trial could end right there, halting the forward progress that Frank and Adrian had made.

But there were other concerns. Antisense had never been dosed this way; the ALS SOD1 phase 1 trial has used the pump method, and this would be bolus injection. It was also the first time antisense as a modality has been put into kids. And there had been very little done, historically, with delivering antisense to the brain. Kathie remembers a trial in France, but nothing else in the literature.

There was also the fact that there had never been a drug developed for SMA. A few academic groups had repurposed old drugs in SMA infants, but that had failed, and put some babies into the hospital, so the clinical pathway was fully unclear. And the FDA itself didn’t particularly understand the disease, or how desperate the need was. Isis met with the FDA “several times,” Kathie told me, in order to help educate the regulatory authority, with people from the SMA Foundation, and clinicians coming along to add their expertise.

Then there was the complexity of the disease itself. The severity is spread across the four categories, with the vast majority of sufferers falling into types 1, 2 or 3. Diseases always manifest differently in the individual, but not quite like this.

And finally, there was the drug Isis and Biogen were putting forth. Isis had crafted a 2-methoxyethyl antisense oligonucleotide designed to bind to SMN2 pre-messenger RNA. That binding would then promote the inclusion of exon 7 in the messenger RNA transcript, which would, in turn, lead to production of higher levels of working SMN protein. Theoretically, that would arrest the disease’s progression.

This wasn’t exactly aspirin. There were raised eyebrows from regulators, and at the hospital level, too. Here’s Kathie.

Kathie Bishop: And there were a lot of skeptics, I’ll say, at the institutional review board. Um, I spent a lot of time answering questions and providing arguments for why this should go forward, with those people. And I think in that case, too, it was just because they didn’t know about SMA, and the drug was complicated.

Brady Huggett: With so much in front of them, and so much on the line, Isis made the decision to not start with the sickest, youngest children, though they were the most in need.

Kathie Bishop: In the clinical development of SMA, we didn’t start in the infants. So, the first trial was in children, um, between 2 and 14 years of age.

Brady Huggett: Uh-hm.

Kathie Bishop: So we didn’t, because we thought it would be so risky to do the trial in these infants, and maybe they get hospitalized, not because of the drug but because of their disease, and we couldn’t complete the trial. That maybe then we would never be able to develop the drug in that scenario.

Brady Huggett: They launched a phase 1 in “medically stable” Type 2 and Type 3 kids, and announced it publicly December 19, 2011. It began as a single-dose, dose-escalation trial, with 1-, 3-, 6- and 9-mg doses across four cohorts, the largest being at Columbia. The drug was delivered by bolus injection into the spinal fluid, and the study gathered safety and tolerability data, and the pharmacokinetic profile of the drug.

Kathie Bishop: And um, the other thing is that the FDA required us to start at a low dose. So we had to start at a dose that may not have an effect, and then — because they were very concerned about safety. So they had us start quite low, and then we kinda worked our way up, dose-escalating in that first trial. And we actually added on a higher dose.

Brady Huggett: Amid Stan’s anxiety about dosing children, Kathie helped inject a measure of calm. She had worked CNS clinical trials before, at Ceregene, and she was in close contact with the clinicians at Columbia. They were comfortable with what was about to happen, and that made her comfortable, too.

Still, when the trial started, and the first dose was administered, her mind raced.

Kathie Bishop: That is what I remember. I remember the first patient, at Columbia. And I remember, like, almost staying up all night, the day after we dosed that patient. Wondering if things were going OK, and how it was going.

Brady Huggett: There had been so much discussion, so much worry over dosing levels, and delivery route, and toxicity, and the strength of these children, that it was impossible not to be anxious. It had been more than a decade since Adrian Krainer attended the NIH meeting on SMA, and more than seven years since Frank and Adrian had first talked of collaborating. Finally, the moment was at hand, and every step would be determined by whatever happened next. The folks at Columbia called Kathie nearly every hour to give updates. When the night was over, the patient — a two year old — was doing fine. The drug had passed a first, small test.

This phase 1 trial enrolled 28 patients, each of them confirmed to have the deletion of the SMN1 gene, to have clinical signs of SMA and a life expectancy greater than 2 years from time of screening. Importantly, the trial also needed to exclude patients. In this case, it meant turning away weaker children who might die during the trial, and those with gastric feeding tubes, those with a current infection that would require an antiviral treatment, those with a history of bacterial meningitis, and other criteria. The study had four arms, across Columbia, Children’s Hospital of Philadelphia, the University of Utah School of Medicine, and UT Southwestern Medical Center - Children's Medical Center Dallas.

Less than a year later, on November 1, 2012, Isis and Biogen announced a phase 1b/2a trial, again in children, this time aged 2-15. The slight increase in age was due to a girl who had been slated to participate in the phase 1 as a 14-year-old, but got sick. She was 15 now, and by changing the parameters, Isis was able to include her in the trial. This new study was multiple dose, and dose-escalating, meaning patients would receive 2 or 3 injections over the course of the study, and there would be cohorts for 3-, 6- and 9-mg doses of ISIS-SMNrx.

No red flags were raised there, either. Here is Richard Finkel, who was chief of the division of neurology at Nemours Children’s Hospital in Orlando, talking about the results.

Richard Finkel: It showed that these older children could handle the, the spinal taps. It seemed to be safe. We were seeing some improvement, uh, in their muscle function and in their motor activities.

Brady Huggett: All 34 patients in that trial completed dosing, and the drug was well tolerated over multiple injections. It promptmed Isis, roughly a year later, to add a 12-mg arm to the trial, and it said it would offer a 12-mg dose schedule in the open-label extension trials for children who completed the earlier phase 1.

Meanwhile, in April 2013, Isis announced a phase 2 study in infants. It was spread across four sites: Stanford University Medical Center, Nemours Children’s Hospital in Orlando, one again at Columbia, and also at The Hospital for Sick Kids, in Toronto, Canada. The study tested two doses — 6 mg and 12 mg. It aimed to enroll 8 babies, but by completion, it had enrolled 21, all between the ages of three weeks and 7 months, all confirmed to have SMN1 gene deletion or mutation, and “clinical signs and symptoms consistent with SMA.” The trial measured change in neuromuscular electrophysiology, level of motor function, survival, and serious adverse events, as well as the amount of drug found in plasma, and other outcomes.

These babies were in a delicate position already, given their severe, infant-onset type of SMA. After two trials in children, the team at Isis, and Biogen, had gained experience, but the move into the youngest, most ill patients still twisted up their nerves. Here’s Stan.

Stan Crooke: And these babies were, dying.

Brady Huggett: Yeah.

Stan Crooke: And so, you know, what happens if one of the babies just, you know, chooses to die while they’re getting an injection.

Brady Huggett: It’s terrifying.

Stan Crooke: And then, most of all, I was terrified that we’d do harm to these babies. I mean, these poor babies are dying, they’re suffocating, and they’re dying by the time they are six months old. The thought that we could hurt one of them, was awful.

Brady Huggett: Yeah.

Stan Crooke: And the only way to figure it out was to take the risk. And, um. And, you know, that first study, I couldn’t call those babies numbers, so I gave them all names. I mean, we’re not allowed to know their names, but I gave them all names.

Brady Huggett: This phase 2 trial would gather information that Isis hoped to feed into a registration study to begin in short order, and it also planned a parallel study in children. All along the way they planned to discuss with the FDA what data they would need to submit in order to win approval.

Traditionally in its history, Isis’s press releases contained information about the news at hand, and then a company-sanctioned statement from Stan or another executive. But the releases around the ISIS-SMNrx trials were different. They had statements from Stan, Lynne Parshall, and Frank Bennett. But also from Columbia’s Darryl De Vivo, and Adrian Krainer, and Richard Finkel, and the SMA Foundation’s Karen Chen, as well as representatives from Families of SMA and the Muscular Dystrophy Association, and others. Even a comment from the University of Massachusetts Medical School, which had supplied a small piece of intellectual property for the drug. It makes the press releases sound less like company statements, and more like the voice of a gang. A group of people who had coalesced around a common goal: to develop a drug for these children.

[music]

Brady Huggett: After Dianne and Matthew Larson put up their Facebook post, telling their family and friends the terrible news about Emma, they tried to move ahead, in whatever way they could. But through that social network, someone reached back.

Dianne Larson: It was somebody through my husband’s family, said, Hey, there’s a doctor here, a scientist, who is working on a treatment for SMA. Why don’t you come down?

It was Dr. Krainer. It was one of the people who worked at the lab. So we’re like, Oh my god, this is great. So, we went down to the lab, I think within that week.

Brady Huggett: The Larsons were able to meet with Adrian. He explained the drug, what it was meant to do and how it was designed to work. He told them what he and Isis were observing in the mice experiments and early studies. He told them that if they were interested in clinical trials, they would want to speak to the folks at Columbia.

The Larsons met with Darryl De Vivo. There would be a phase 3 trial starting soon, he said, and Emma would be a good candidate for the drug. But the study had a lower age limit of 2, and Emma was only a year and a half. That meant waiting six excruciating months. And even then, if she was taken into the trial, there was no guarantee she’d receive the drug, since the phase 3 would be blinded and have a placebo arm. And of course there was no guarantee the drug would work, even if she got it. That was a lot to think about, even without considering all the hospital visits, and multiple injections into Emma’s spine. The phase 3 was a glimmer of hope, but the details around it were enough to wring the Larsons out.

Dianne Larson: [sighs] So, we’re like, Oh my gosh. You know, it’s — to think about, to do this and have her go through all the injections and all this crazy stuff. I’m like, to me, it’s like, what choice do we have? And I said to my husband, putting her through — which she’d be put through a lot — even if she doesn’t get the medicine, or even if it doesn’t work. I said, the only way we’re going to, the future is going to change is if somebody takes a chance with their child. I mean, it’s a big decision.

So I said I don’t want anybody to go through what we’re going through, if we can help prevent it. So I told Columbia, I said, We will be here on her second birthday.

Brady Huggett: Make the appointment now, Dianne told the people at Columbia. February 6, 2015, we’ll be here. And then Dianne and Matthew, and Emma, began a fight “against the clock,” she said. Over those six months, Emma completely lost the ability to crawl. When she was on all fours, she couldn’t hold her head up, and her legs were like “noodles,” Dianne said. The disease, she told me, “doesn’t wait around,” and every day they watched their daughter weaken. Six months of “hoping and waiting,” she said.

“The only way the future changes is if someone takes a chance with their child.” That was Dianne’s thinking. The status quo was not working here, not for her, or Emma, or anyone else in the SMA community. The Larsons were going to take that chance.

[theme music]

Brady Huggett: Thanks to Stan Crooke, now and always. Thanks to Dianne, Matthew and Emma Larson. Thank you to Frank Bennett and Adrian Krainer, for their memories on developing ISIS-SMNrx. Thanks to Kathie Bishop, for her insight into the clinical trials. Thanks to Stelios Papadopoulos, for his incredible memory. Thanks to Richard Finkel, for his recollections as a clinician.

Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous six chapters. Chapter 8 will be out in a week. Until then.

Chapter 8: part of something big

Brady Huggett: Chapter 8: part of something big

Because Isis’s spinal muscular atrophy product was the first antisense drug in kids, and the first antisense drug that got delivered to the brain, and the first antisense drug given via bolus injection into the spine, there were myriad ethical questions to work through in the phase 1 and 2 studies. Many of them had to do with enrolling babies into clinical trials, these tiny humans who could not speak for themselves. But some questions had to do all those firsts — there were a lot of unknowns, and anything unknown in a clinical trial is a risk. The risks meant the FDA wanted Isis to start at low doses, yet Kathie Bishop, and Frank Bennett and Adrian Krainer, and the rest of the people working on this drug were skeptical that the low doses would have any effect. In essence, that meant the clinical trials would subject sick children to an uncomfortable lumbar puncture, and an unproven drug that would reach their brain, given at a dose level that was unlikely to help them. That seemed all risk, and no benefit. Was that ethical?

Time and time again, the team worked their way back to the same position: nothing was going to change for the SMA community without risk, and sacrifice. The clinicians knew it, Isis knew it, and the parents knew it, too. As Dianne Larson said, “The only way the future changes is if someone takes a chance with their kid.”

But new questions arose as the drug advanced toward phase 3. These would be blinded trials, not open label. And there would be a placebo, or “sham” arm, in which children were given only a needle prick at the base of the spine, and were not injected with drug. Placebo-controlled studies are the hallmark necessity of clinical trials, but this deepened Isis’s ethical quandary. Now, for certain, some already weak children would be subjected to the rigors of a trial but would not receive any potential benefit. Here’s Richard Finkel, who was chief of the division of neurology at Nemours Children’s Hospital in Orlando, one of the clinical sites.

Richard Finkel: This is where I had to have several sit down talks with ethicists, and with colleagues, in medical ethics at other institutions and at the NIH, and really think about, how does one do this properly? Because the parents are desperate. They know that without this potential treatment, that their baby’s gonna die.

Brady Huggett: Uh-hm.

Richard Finkel: And it’s just a matter of when. And we know that parents go into these clinical trials really with one eye closed, looking at it from the point of view as a treatment option, not really focusing on the fact that it’s an experiment. It’s an investigational study. So I think the challenge to the clinician, when faced with this situation — OK we have this drug that looks very promising, and we have these desperate parents who will sign on the dotted line, for anything, because they know what the alternative is, but how do you do it in an ethically sound way? And in the end, I think, as difficult as it was for the parents to get their head around the idea that there was this sham control group, and that their child had a 1-in-3 chance of being assigned, randomly, to that group, they flocked to this study. There were very few who balked and said, No, I’m not going to do this.

Brady Huggett: Some parents did balk, of course. There were “a small number” who thanked Richard, and then took their child home, to provide as much comfort as possible. But to his surprise, “almost uniformly,” Richard said, most parents saw a chance to throw themselves actively into the fight against SMA, and they took it.

Richard Finkel: It’s hard for me to put myself in those parents’ shoes and think if I would be as magnanimous as they were. To be able to even think beyond their own little baby and how horrible the situation was, and to be able to look at the broader picture, and the fact that, yes, this is an experiment. And my baby may not benefit, but mankind hopefully will. And maybe the next baby that comes along will be able to benefit — I was just astonished by how frequently the parents, uh, independently would come to that realization.

Brady Huggett: If spinal muscular atrophy, and the slow death of a child, is one of the worst things that can befall us, then the response of these parents is its antidote. They were able to recognize the possibility of helping others, even when facing the worst event of their lives. It is remarkable, but this sort of magnanimity happened more than once during the trials.

From Nature Biotechnology, I’m Brady Huggett and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: Though Biogen had its doubts early on about the SMA program, it was becoming convinced that, in general, antisense drugs might be effective against central nervous system diseases. In late June 2012, Isis and Biogen announced a collaboration on a drug for myotonic dystrophy 1, a genetic neuromuscular disease that leads to muscle atrophy, weakness and spasms. Kathie Bishop would lead that program. Then, in December 2012, the companies signed another, similarly structured deal, this time around three undisclosed targets.

The next year, in 2013, they signed their fourth collaboration with Biogen, this one the richest yet. It was set for six years, and aimed more broadly at neurological diseases. It garnered Isis $100 million upfront, with as much as $220 million more tied to specific achievements, and payments to help with any eventual clinical trials. The deal was big enough to make the business shows.

Squawkbox: Biogen Idec and Isis Pharmaceuticals announce a strategic collaboration to advance the treatment of neurological disorders. Here now with more is Dr. Stanley Crooke, chairman and CEO of Isis Pharmaceuticals. Ah, Dr. Crooke, congrats. It’s a nice chunk of change to help you further your technology. You’ve been on so many times over the years and I’ve watched the development of antisense technology and I’ve watched some of the setbacks. Some of the stuff that has happened in the past. There have been times when I wondered if it was a viable technology. Do we know now that, that antisense works and will be part of therapeutic, um, biotech in the future?

Stan Crooke: Absolutely. I think, uh, Isis invented it and we validated it. You know we just had a drug approved for the treatment of high cholesterol. Uh, and we have evidence in multiple organs, multiple targets, multiple diseases, multiple routes of administration, that antisense works. And obviously, one of the reasons that Biogen has invested — now in the fourth deal, which is the strategic deal, that we’ve done with them in the last two years — is that it works.

Brady Huggett: Doubters still existed, as evidenced by that Squawkbox clip. But Biogen had seen enough, and it tightened the working partnership between the companies. The two groups were culturally similar, with comparable thoughts about science, and innovation, and patients. They recognized that in each other, and they valued it.

Yet Biogen still had not officially licensed the SMA program. Though it worked closely with Isis, it was waiting to see how the drug did in a fully controlled, blinded study in a larger patient population.

And Isis thought the drug was ready for that step. Nearly all indications suggested ISIS-SMNrx was safe, and was providing some level of benefit for these sick children. Yet Isis needed the bigger study in order to prove it. A lot hung on that trial. Here’s Kathie.

Kathie Bishop: And we really felt like we only had one chance at it.

Brady Huggett: Uh-hm.

Kathie Bishop: If we designed the trials wrong, we wouldn’t be able to redo it. People then would lose their faith in the drug and not want to commit to doing it again. Because I think at the time we were still really, um, a lot of people had doubts about the drug. And, so although at that point we’d done the phase 1 safety trials, and we had shown some improvement, because they were open-label trials people didn’t quite believe in it.

Brady Huggett: But before it could start, the team needed to deal with a crisis. In the phase 2 trial in infants, three babies died. Infants diagnosed with symptomatic SMA are by default the sickest. They have the most severe form of the disease, with prognoses that generally do not extend beyond two years. Even something like pneumonia might put the infant onto a ventilator, which can start the downward slide toward death. It had always been a possibility that children would die in the trial; Isis and Biogen knew that going in.

Now it had happened. As unproven as ISIS-SMNrx still was, Kathie Bishop didn’t think the drug had caused the deaths. Doug Kerr, a neurologist and the global medical director for the SMA program at Biogen, didn’t think the drug was to blame, either. But without proof that the deaths were a result of the disease and not the drug, the program was in danger. Phase 3 trials take a huge time commitment, and a lot of money. Any remaining skeptics on Biogen’s board might latch onto the deceased babies and suggest the company’s money go someplace more promising.

The only way to get to the truth of the deaths was with an autopsy. The realities of the trials had been discussed with parents before enrollment, but it was impossible for them to not have hope when signing their babies up. Now, for three families, that hope had been dashed, and their children lost. In the midst of this grief, this heartbreak, they were confronted with having to consent to an autopsy. It was a situation Kathie could barely envision, and something Doug still thinks about.

Kathie Bishop: If you can imagine, you have this baby in the trial, you have all this hope from being in the trial. Um, and then your child dies anyways. They were under such stress, but they agreed to donate their babies’ brains for the autopsy.

Brady Huggett: Why do you think the parents agreed to that?

Kathie Bishop: Yeah, and they had to agree right away. Because the brains —

Brady Huggett: You can’t wait.

Kathie Bishop: You can’t wait. You need the tissue that’s fresh, that’s still, um — so they had to agree basically within 24 hours of their child passing away. So, I just can’t imagine what that would be like.

Brady Huggett: Here’s Doug Kerr.

Doug Kerr: The courage that they showed, um, to go into the study, and of course those who consented to the autopsy, was amazing. Just, one of the more amazing, dramatic moments, certainly of my life.

Brady Huggett: The autopsies gave the SMA team exactly what it needed. Results confirmed that ISIS-SMNrx was reaching the motor neurons of the spinal cord at levels that were “predicted to be meaningful,” and that the drug was acting through its intended mechanism of action. The autopsies also revealed that splicing of pre-messenger RNA was corrected, resulting in an upregulation of the SMN protein.

These findings cleared the drug of causation for the deaths, but it also helped with dosage planning for the phase 3 study. Here’s Doug.

Doug Kerr: And, the two things that it suggested was, one, get patients earlier. I mean, come on. You know, once they are in this phase, it may be really hard to pull back from this. Because it’s such an apocalyptic decline. And two, get more drug in faster. And that’s one of the things that we did as we went to the phase 3. Instead of a slow, um, titration of three doses over, I think it was three months, it’s four over two.

Brady Huggett: Though there had been no placebo-controlled trials, the clinicians involved in the earlier studies, like Darryl De Vivo and Richard Finkel, had noted that the drug appeared to arrest the decline in these babies, and in some cases they seemed improved. Knowing this, it was difficult to consider including a sham arm in the trial, where a sick baby would get nothing during these crucial months of their disease, especially because Isis already thought it had a drug that might help. So the team turned to the FDA for advice. Here’s Richard.

Richard Finkel: To the FDA’s credit, they said, Look, if you do a randomized, controlled study, and you put sufficient number of patients in the study, and you pick an outcome measure that is very robust. Something that we’re never going to see in this population, such as sitting. You just don’t see Type 1 babies sit, and by definition they don’t. But if you can just show us that a certain percentage of these babies achieve sitting, and that you have improved survival, and you have an internal control group, and the drug is safe and well tolerated, and you do an interim analysis, then we are going to be more inclined to pass judgment early. And you would gain regulatory approval and be able to then have the drug prescribed widely for children with SMA.

Brady Huggett: At the beginning of August 2014, Isis announced it was starting its phase 3 program, first with a trial called ENDEAR. The study was double-blinded, meaning neither clinician nor patient knew if they were getting drug, and it had a sham-procedure arm. The study was set for 13 months across 31 clinical sites. It had the primary endpoint of the proportion of babies that died or were put on a permanent ventilator, and it also gauged improvements across a range of motor milestones, such as rolling, sitting, and crawling. There would be an interim analysis, as the FDA had suggested.

It had taken some 25 years of developing antisense chemistry to get to this point. It took more than a decade of Adrian Krainer’s efforts. At least $100 million from the SMA Foundation, and the attention and efforts of all the other SMA groups. But perhaps most importantly, it took the courage of parents, and their sick children, who stepped forward in the name of progress.

The study enrolled 122 babies. Forty-one of them got the sham pinprick at the base of the spine. Eighty-one of them were scheduled to be given 12-mg doses of ISIS-SMNrx on day 1 of the study, then again on day 15, day 29, 64, 183 and finally day 302.

In November 2014, Isis launched the phase 3 CHERISH trial, in non-ambulatory SMA children between 2 and 12 years of age. It enrolled 126 patients, 42 in the sham arm, and 84 in the treatment arm, spread across 24 locations. These children were given 12-mg doses on day 1, day 29, 85 and day 274. The primary endpoint was change from baseline at 15 months in the Hammersmith Functional Motor Scale — 33 specific activities scored to assess motor function in SMA children.

The two studies were conducted under special protocol assessment with the FDA, meaning that both sides were already in agreement on the specifics. The FDA had laid out how it would like to see the trials run and what it wanted to see for approval, and Isis had built the studies in response.

It had been more than 120 years since SMA was first identified as a disease, but now things were moving quickly.

[music]

Brady Huggett: For six months, Dianne and Mathew Larson waited for Emma to turn 2 years old, so they could enroll her in the trial. Six months of anxiety, as Emma incrementally got weaker. When her birthday arrived, her gift was a trip to Columbia University Medical Center. They screened her, and she was accepted into the CHERISH trial. A hopeful moment for the family, but it also brought up some mixed feelings. Here’s Dianne.

Dianne Larson: It’s a weird position to be in, too. Because you’re hoping your child gets the medicine. You’re hoping your child gets the medicine, but what does that mean? When you think about it.

Brady Huggett: It means that somebody doesn’t.

Dianne Larson: Does not. And it’s a very crappy feeling. You know, you want your kid to get it, but you want everybody to get it. It really is, um, going through that whole process is a very emotional process.

Brady Huggett: The first injection, given in the beginning of March 2015, required Emma to stay flat on her back for six hours, a precautionary move in the trial that was later proved unnecessary. It was a struggle to keep Emma still, Dianne said. They spent the night in the hospital together just in case Emma had a reaction, passing the time by watching movies and educational programs on an iPad, and then they went home. They returned about a month later, and then about two months after that, with Emma again spending six hours on her back after the injections, but on those visits no overnight stays. Before each dose, Emma had pre-op bloodwork, and strength tests, and x-rays. It was a lot to put a child through. And then, a change came.

Dianne Larson: So, the third injection, all of the sudden — the story is crazy, but. Uh, I was in the bedroom, and Emma was in the den. You gotta remember that she didn’t really move much, like you put her somewhere and she really couldn’t go far, so you put toys around her.

Brady Huggett: Yep.

Dianne Larson: And, all of a sudden I hear, Mommy? Mommy? I’m like, Yes, Emma? I’ll be right there, right there.

Mommy? And I hear the voice getting closer and closer. And next thing you know she’s sitting at the doorstep. And I’m looking at her like, What the hell? I go, Emma, did you just crawl in here? She goes, Yeah. And I’m like, Oh my god. No freaking way.

I picked her up, put her back in the den. I said, Do that again. I said, Emma, come. And she crawled all the way back. Now you gotta understand, she couldn't even crawl two feet.

Brady Huggett: Yep.

Dianne Larson: Prior to this. And after three injections, she’s crawling. I’m like, Did we get the medicine? Like, this is like a miracle. I was in tears that day. I was like, this is insane. From your kid barely moving, to crawling from one room to the other.

Brady Huggett: Dianne, like everyone else, was blind in the trial. She didn’t know if Emma was getting the drug or not, but she knew what she saw. Dianne is part of the extended SMA community. It’s a tight-knit group — Dianne describes it as “loving” — and it has a strong social media presence. Those with babies and children in these studies were posting moments just like this one from Dianne. There was a growing sense in the community that the drug was working, at least in some of these kids. There were too many anecdotal stories for it not to be. The importance of the trial, and the need for clean data, were not overlooked, but still, anyone not in the study wanted what they were seeing online.

The trials rolled through 2015. Meanwhile, Isis prepared for the future. It started the SHINE study in October, an open-label extension for both ENDEAR and CHERISH participants, allowing them to stay on the drug after their phase 3 ended. By this time, 20 infants in the open-label phase 2 study had been on the drug for 29 months, and the 30 children in their phase 2 had been getting ISIS-SMNrx for 46 months.

Biogen was now evaluating the drug, too. It had launched a blinded, sham-controlled study called EMBRACE, to include SMA patients who did not meet the age requirements of ENDEAR or CHERISH. And in spring of 2015 Biogen launched an open-label phase 2 trial called NURTURE.

NURTURE was Doug Kerr’s idea. He’d long thought, given his experience as a neurologist, that the key to any SMA therapy was reaching patients earlier. Even before they had symptoms, if that was possible.

Doug Kerr: And I knew from my work in SMA and from treating patients with SMA that, essentially by the time you come to clinical awareness of disease, that — you know, the infant is floppy and is having trouble sucking and feeding and things like that — you’ve essentially lost function of 50-60-70% of your motor neurons. That so much of that has occurred when you were not aware of it. That, by definition, that reduces the therapeutic opportunity you have, if you wait until symptom onset.

Brady Huggett: Animal models of SMA had shown greater benefit when the drug was given early, but Doug wanted to be earlier than early. He thought there might be a chance for normal function to occur if patients were treated before they showed any symptoms at all.

Doug Kerr: It became, really, an obsession, is to figure out, how do we do this? You know, it was very challenging at first, because there was no test for SMA from a dried blood spot. Nobody did it. Nobody figured out how to do it or why to do it. And the reason was, because there was no therapy.

Brady Huggett: Doug wouldn’t let it go, however. Working with the Centers for Disease Control and Prevention, Biogen figured out how to “multiplex,” Doug said, with a dried blood spot test for the disease Severe Combined Immunodeficiency, also called SCID. Technically, detecting the presence of the exon 7 SMN1 gene was “no problem” from a similar test, and it was also easy enough to determine the severity of the disease through a blood draw. The harder part was making the test available.

Doug Kerr: So we, pretty quickly, got to the idea that we could identify these patients. We had trouble for a while getting anyone who would be willing to deploy it. Because they said, Why? What are we going to do?

Brady Huggett: Meaning, what good is this information, if we can’t treat these children?

Doug Kerr: That’s right. And my initial reaction was, two things. One, getting a child diagnosed and to a tertiary care center, where they could get appropriate occupational and physical and respiratory and nutritional support, would be very compelling. And has been shown in published literature to have a positive benefit on that child. That alone is sufficient.

But it didn’t really work. People were, kind of, unwilling to do that, to roll out this pilot testing on a dried blood spot. And so we talked about the data we were developing in the ongoing symptomatic SMA clinical trials. And said, Look, here’s what we’re seeing. And it looks real. And it would probably be better if it were administered earlier. Before the onset of symptoms.

And ultimately, several places did come on board. And that became the NURTURE trial. And this was Taiwan and New York, and several other places. And it turned out to, kind of, be really important that we were able to identify and treat them early.

Brady Huggett: The NURTURE trial was officially announced in March 2015. It was set to stay open for 10 years — to February 2025 — and follow patients for 2,891 days. It enrolled 25 babies, all less than six weeks old, all genetically confirmed to have SMA. The study had a primary endpoint of time to death or respiratory intervention. It had a long list of secondary endpoints, including metrics around weight, head and chest circumference, motor milestones, and percentage of participants that developed clinically manifested SMA.

The idea was to get the drug into these babies before they ever exhibited symptoms, hoping ISIS-SMNrx could keep the disease completely at bay. The first patient, a baby boy named Gabriel, was enrolled in the trial May 20, 2015. He was just 9 days old.

[music]
[ad]

Brady Huggett: Isis’s string of clinical and marketplace failures had caused the public to view antisense, and the company, with doubt. Isis was long used to that. But in the second half of 2014 it began to have a different sort of public relations problem.

News anchor: Breaking news tonight, we want to welcome our viewers from around the world to this breaking news coverage. An American journalist has been beheaded by ISIS terrorists. A video showing the horrific killing…

News anchor: We begin with this morning’s top story, confronting ISIS, the murderous Islamic State group in Iraq and Syria. The Pentagon is warning that ISIS…

News narration: NBC news special report. Here’s Brian Williams.

Brian Williams: And good day from New York, we’re coming on the air, sadly, to report video evidence that seems to show another American has been beheaded by the radical ISIS militants. In this case another American journalist.

Brady Huggett: The name Isis had suddenly become synonymous with a grisly brand of terrorism. It was difficult to see Isis’s stock ticker — ISIS — popping up on business television shows and websites and not think of the recent beheadings and threats against America and other Western democracies. Fund managers who held Isis stock were forced to answer questions from investors about why they had put money into an extremist terrorist group.

The coincidence for Isis the drug company was irritating, to say the least. But Stan, in typical Stan fashion, refused to back down. He had the name first, for decades now, and anyway, his company had done nothing wrong. Here he is in September 2014, on Mad Money, a circus of an investing show on CNBC, run by Jim Cramer. Over the years, Stan and Jim had developed a good working relationship: Cramer frequently plumped for Isis’s stock, which he felt was undervalued, and Stan appreciated being able to speak directly to investors. Here’s Jim.

Jim Cramer: I have to ask you something that is not, that is apol—, that is frankly, something that I don’t want to ask you. Because I think you’re a serious — you are a serious scientist and your company is serious. The name. OK, so I mention to people that I, I have Isis on tonight, Isis Pharmaceuticals, and we know the unfortunate connection with an outfit that the president now calls ISIL. But what do you tell people? Do you tell people, Listen, this is an unfortunate coincidence? You just, you can’t laugh off things and you’re a serious guy. So I just, I just, I’m actually asking for help about how to talk about the company when I mention the name.

Stan Crooke: [inhales] Uh, it drives me crazy. Um, and, but we’re not a retail company. Our investors should be sophisticated, and we’ve been Isis for 25 years, and I don’t feel like I want to capitulate to these terrorists by changing my name. They can change their name.

Brady Huggett: But of course Isis, the terrorist group, did not go away. It continued its beheadings in the months ahead, and then committed a series of coordinated attacks in Paris on November 13, 2015, that shook the world.

News anchor: At least four restaurants and bars were hit in just a matter of minutes. The epicenter of the attack, though, would be the Bataclan, a concert venue.

Brady Huggett: Gunmen stormed the packed music venue. At the end of the attacks across Paris, 130 people had been killed, and hundreds more wounded. By then, for Isis Pharmaceuticals, it was just too much. The terrorist group would go down on the wrong side of history, and take the name Isis with it. About a week before the Christmas holiday in 2015, Stan Crooke’s company changed its name to Ionis Pharmaceuticals, and their stock ticker to IONS, ions. Stan went back on Mad Money and told Cramer the name change “rids us of a distraction,” which the company needed to do, because Ionis had a lot going on. It planned to finish enrollment in three phase 3 trials in 2016, the most noteworthy being the ongoing SMA studies.

Yet, except for the name change, from the outside Ionis looked the same as it always had as 2015 ended. A company, now approaching three decades of existence, still pursuing a technology that it had had zero tangible success with. Yes, it had earned approval for two drugs, but neither of them had done anything for patients or the bottom line. Ionis brought in ~$284 million in revenue in 2015, its highest total ever, but it also posted a net loss that year of ~$88 million, and its accumulated net loss, for the company’s entire history, was about $1.1 billion. Biotech companies are notorious for burning through money and requiring a long runway for success, but Ionis was well beyond the mean.

Inside its walls, though, things indeed did look different. Ionis had more than 1,300 patents worldwide, and besides the SMA drug, it had 25 other clinical programs ongoing. Ionis had now created version 2.5 of its antisense chemistry, a constrained ethyl oligonucleotide, containing gapmer technology, which increased potency by 10, and it had moved four of those drugs into development. Ionis had also developed a technology it called “LICA,” which stood for Ligand-Conjugated Antisense. In essence, this involved attaching to the antisense molecule a ligand capable of binding to certain cell-surface receptors, giving the molecule a higher level of specificity. The ligand was N-acetyl galactosamine, and it binds the asialoglycoprotein receptor on hepatocytes. Ionis had employed the LICA technology to 8 drugs in its pipeline by this time, all aimed at the liver.

So the R&D machine was humming, as it always was. But if success in drug development is measured by helping patients, Ionis was still a company without success.

Now, as 2016 began, Ionis had a golden chance in front of it: validate its decades of work by helping a group of patients in dire need of a treatment. For months the trials moved along. Patients got their lumbar injections, or they got their sham needle prick in the small of their backs. These trial participants were seen by the physical therapists who gauged their health, their strength and their motor skills.

Then, on the first day of August in 2016, Ionis and Biogen put out a press release concerning the ENDEAR trial in babies. They had reached the interim analysis, and the results were unequivocal. The trial met the pre-specified endpoint based on achievement in motor milestones, compared to the control group. The drug had been given a generic name, nusinersen, and full results of the trial, later published, showed that 51% of infants who got nusinersen had a motor-milestone response, while 0% did in the sham arm. The likelihood for event-free and overall survival were higher in the drug arm of the trial. Also, it was clear that infants with shorter disease duration at screening benefited more than the sicker ones, as Doug Kerr had suspected.

It was exhilarating news. Ionis’s stock leaped 36% on the day, to close at just over $38 dollars a share. The surge was mostly due to the positive results, but it also had to do with all the news that came with it. Biogen had exercised its option to develop and sell nusinersen globally, paying Ionis $75 million. Also, the ENDEAR trial was stopped, and all patients rolled into the SHINE open-label study. The ethical question had reached its final answer: it was no longer fair to keep these sick babies on the sham procedure when the drug was so clearly working.

The data were so strong that a phase 2 study, called EMBRACE, also stopped the sham arm, and moved the infantile-onset SMA patients to the drug. But NURTURE, the trial for pre-symptomatic babies, continued onward, as did CHERISH, the phase 3 trial in children.

Investors were bullish, though some still worried over side effects or a yet-unseen safety signal. Biogen was hopeful but cautious. Stan, however, was sure an approval would follow, and he had been for a while.

Stan Crooke: As I say, I was convinced we had a magical drug, you know, long before the interim analysis. I mean, because I was watching these babies live. [laughs]

Brady Huggett: Yeah.

Stan Crooke: I felt that this was the most obvious success that I had ever seen.

Biogen, now the official sponsor for the drug, worked furiously to submit a package to the FDA. The regulatory authority had agreed to a “rolling submission,” meaning the process could begin and stay open, with Biogen handing over additional data whenever it had a new analysis. The FDA had also granted a “priority review” voucher for the drug, based on it being directed at a rare pediatric disease, and this would expedite the process of examining the application. The companies completed the FDA submission just before the end of September, and by the end of October, both the FDA and the European Medicines Agency had accepted their respective submissions. And the companies had landed on a brand name for the drug: Spinraza.

In early November, the CHERISH trial reported its interim results. This was Emma’s study, and the children in it were consistent with Type 2 sufferers. The results were also unquestionably positive. In the 84-patient treatment arm, children averaged a 4.0 improvement on the Hammersmith Functional Motor Scale Expanded test, while the 42 patients in the sham arm declined by a mean of 1.9 points. Spinraza had not only arrested the disease’s progression, but also some children demonstrated improvement. The drug seemed safe, too. No children dropped out of the study. As with ENDEAR, the CHERISH trial was stopped on the good results, and all participants were given the opportunity to transition to the SHINE open-label study, where they continued to receive Spinraza.

Biogen supplied the CHERISH data to the FDA, which included it in their assessment of Spinraza. The regulator said it hoped to rule on the drug before May 23, 2017.

The good news kept coming. In early December, Biogen fed the FDA new information from the earlier phase 2 study in babies, showing that 11 of 20 infants in the trial had survived to 36 months. Historically, only 1.5% of Type 1 SMA patients live to 2 years.

And now, the FDA had more than enough information in front of it. It cleared Spinraza in all types of SMA patients on December 23, 2016, the day before Christmas eve. In its communication, the FDA was careful to note that some children did not respond in the trial. It noted that some babies died. It also noted that the earlier a patient could access the drug, the better. But, it concluded, “there is no doubt” that the efficacy of Spinraza for SMA has been demonstrated.

Advocacy group Cure SMA chief scientific officer Jill Jarecki called December 23 “a landmark day,” and other groups like SMA Foundation and the Muscular Dystrophy Association put out their own statements on the approval. Online, however, there was a kind of catharsis. On Facebook, some tied the approval to the coming holiday, calling it “the best Christmas blessing ever,” or a “Christmas miracle.” Others thanked God, either directly or for allowing the scientists to come up with Spinraza. Many were aware that the drug had come too late for thousands upon thousands of children and grandchildren, and one woman wrote that “each child, and each one that passed, contributed to this moment.” Some asked when Spinraza would be available in their country, or worried over its cost. But mostly responses pointed to a vast, collective release. “I cried when I heard the news,” a woman wrote. Dianne Larson cried, too.

The FDA, Ionis and Biogen put out their own releases, but the approval had come quicker than most had expected, and there was little coverage among the general media. Forbes ran an article noting “one of the year’s most important drug approvals,” and The Wall Street Journal initially ran a small item, pulling a quote from the FDA’s press release. The New York Times published a piece the following week, calling SMA a “savage disease” and quoting a physician who described Spinraza as a “miracle,” but the majority of the article focused on drug costs. There was little else, unless you count The San Diego Tribune, which regularly covered Ionis, as it was one of San Diego’s flagship biotechs. The paper ran an article detailing what SMA was, and the great need for a therapy, and the potential market for Spinraza. It included a quote from Stan Crooke, who was only too happy to repeat what he’d been saying all along. “What [the approval] says is once again that antisense works,” Stan told the paper.

The same day as approval, Ionis issued a statement to the broader SMA community. It was signed by the “Entire Team at Ionis Pharmaceuticals,” and started by saying the company felt “privileged” to have brought Spinraza to market.

“We very much appreciate the contributions of the entire SMA community, the amazing advocacy organizations Cure SMA and SMA Foundation, and countless others who have contributed to SMA research,” the statement read. It went on to thank all families who participated in the trials, and near the end, it noted that “you, the community, the parents, and the families, are the true heroes in the creation of Spinraza and it has been our honor to have made this journey with you.”

The drug also meant something to the neurologists, these doctors who had told parents, over and over, for decades, that their child had a terrible disease and medicine had nothing for them. Those days were finished. Here’s Darryl De Vivo.

Darryl De Vivo: I want to tell you, that is one of the high points in my whole professional life. Which is a long time, I’ve been at it for 60 years or so. And you know, there is nothing like it. It’s just fabulous. Because I can remember vividly sitting with parents, in the office usually, when they come in with their 3-month old, or something, whose clearly got weakness. And making a diagnosis of SMA and saying, Gee whiz, this is terrible. We’ve got a huge problem here and I wish we had something to offer. But other than some symptomatic efforts, you know, we really can’t effectively improve your child’s condition.

It’s a miserable discussion. I’ve had many of them. I always left as sad as the parents did, in talking with them. And now I’m overjoyed to say, I’m never going to have to have that discussion again.

Brady Huggett: That had been the scene that played out for Dianne and Matthew, and Emma. They had been told there was nothing to do, and that while no one was sure how long Emma would survive, it was almost certain Dianne and Matthew would outlive their child. That had once been their grim future. And now it had been replaced.

Dianne Larson: It was going to be a lot of care. You know, she was just, basically, I would be feeding, clothing, bathing her. You know, I just — it’s a lot of despair. It really is, I can’t describe it any other way. Like, there’s no hope.

Brady Huggett: Yeah.

Dianne Larson: When you have no hope, that’s really bad. Like, that’s really — yeah, when there’s no hope, it’s complete, it’s just despair, there’s no other word to describe it.

And then, as she got stronger, after the first year, then it was like it really hit me. It was like, Oh, we can manage this. We can manage, because there’s hope. She’s not getting any worse. Like, even if she just stayed as she was — when she got better, I’m like, We can do this.

Brady Huggett: Emma is 8 years old now, cute as a button. She gets around with a walker. She’s smart and well behaved. I never have to discipline her, Dianne told me. She’s a good kid. She has a good heart. Every four months, Emma still gets her “magic medicine,” as Dianne calls it. And every once in a while, Dianne will tell her, You were part of something big.

[theme music]

Brady Huggett: Thanks to Stan Crooke, now and always. Thanks to Richard Finkel, for his clinical expertise and memories. Thanks to Dianne, Matthew and Emma Larson, for opening up their lives. If you listen closely, you can hear Emma chattering on in the background of some of Dianne’s interviews. Thanks to Kathie Bishop and Doug Kerr, for their insight into the Spinraza clinical trials. Thank you to Darryl De Vivo. News clips around the terrorist group ISIS, in order, were taken from CNN, CBS, NBC and the Canadian Broadcasting Company.

Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous seven chapters. Chapter 9 will be out in a week. Until then.

Chapter 9: the last of his kind

Brady Huggett: Chapter 9: the last of his kind

Announcers: Best biotechnology product category. The winner is Biogen and Ionis, for Spinraza. Accepting the award, Michel Vounatsos, chief executive officer, Biogen, and Stan Crooke, chairman and chief executive officer, Ionis Pharmaceuticals.

Brady Huggett: Spinraza won the Prix Galien award for best biotechnology product in 2017. The ceremony is a black tie event, held in New York City, and it’s billed as the Nobel Prize for biopharmaceutical drug development. That raucous cheer at the announcement of the winner is from the Ionis team. “Our table was in the back next to the camera,” Frank Bennett told me. The group exploded when Spinraza was called.

Ionis’s antisense drug was chosen from 14 other nominees. Being interviewed at the ceremony after winning, Biogen CEO Michel Vounatsos called the Biogen-Ionis collaboration “a true partnership between two companies,” and he commented on the years of effort it had taken to develop Spinraza. Stan Crooke noted the drug had made a “fundamental advance” against a disease that is “fatal and catastrophic.” But Stan is always ready to talk about antisense, and he also pointed out that Spinraza came from “a new technology that we have pioneered.”

Frank Bennett found that night, and mingling with the high society crowd, to be “surreal.” The stage, the announcement of winners, the legions of tuxedos. He wasn’t used to that sort of glitz and glamour. But that was nothing compared to the Breakthrough Prize ceremony.

That event was founded by tech entrepreneur royalty: Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki. The Breakthrough Prizes honor advances in the life sciences, in physics and mathematics, with winners getting $3 million in prize money. The ceremony itself is meant to mirror the Oscars, not the Nobel. There is a red carpet, a heavy media presence, and actual celebrities mixed in with the scientists.The whole event is streamed live online, and is a serious attempt to honor science and to make it look cool — a noble thought.

Spinraza was nominated in the 2019 prize cycle, though the ceremony was held in November 2018 in a NASA hangar in Mountain View, California. The host was Pierce Brosnan. The actor Rachel McAdams was there, so was Lupita Nyong’o. The director Ron Howard was seated at Frank and Adrian Krainer’s table, as well as a “supermodel” that Frank couldn’t identify.

The presenters for Spinraza’s award were Orlando Bloom and Anne Wojcicki. On a large screen, a pre-recorded video played interviews of Frank and Adrian talking about SMA and their work. Then segments from Dianne and Matt Larson, and Emma, telling their story, and how Spinraza had helped. The video ended, and the Larsons themselves came on stage, live and in the flesh. Dianne in a gorgeous black dress, one shoulder bare, Mathew in a tuxedo, his hair crisp, and freshly cut. Emma in a wheelchair wearing a pink dress, her hair pulled back with barrettes. The crowd rose into a standing ovation that lasted for nearly 30 seconds, until Dianne started to speak. She talked about what the drug had meant to them, and thanked Adrian and Frank for “the time spent away from your family to save ours.”

“Everybody was in tears,” Frank told me.

Then they called the scientists up, and the crowd rose to their feet again.

Anne Wojcicki: For the development of an effective antisense therapy for children with the degenerative disease spinal muscular atrophy…

Orlando Bloom:...the Breakthrough Prize in the life sciences is awarded to Frank Bennett and Adrian Krainer.

Brady Huggett: Afterward, the two men slipped off the stage into a press room, with the cameras and reporters. Frank felt “like a deer in the headlights,” he told me, but Orlando Bloom was with them, affable, friendly, at ease with the press attention. He was “the coolest guy,” Frank said, and Bloom honestly seemed to care about their work. He took a selfie with Adrian and Frank, Ann Wojcicki smiling wide in the background. He put it on his Instagram feed, hashtagged the scientists as “#realheros.” It got more than 40,000 likes.

So if the greater world had not fully registered what Ionis and Biogen had done against this disease, the science community absolutely did. But as Richard Finkel, neurologist and clinician on the Spinraza trials, told me, there was more juice to be squeezed from this orange.

From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

[theme music]

Brady Huggett: Spinraza was approved in the European Union in June 2017. In March 2020, a study was published in Lancet Neurology analyzing 139 SMA patients, aged 16 to 65, from 10 treatment centers in Germany. The results examined patients over 6 to 14 months and showed clinically meaningful improvements in motor function, with the percentage of improved patients increasing the longer they were on the drug.

Biogen, now fully in control of any further clinical development, launched a trial called DEVOTE in April 2020. The idea was to explore higher doses of Spinraza, in all patient types, to gauge a possible efficacy increase. The trial is set to run at 50 sites around the world. Biogen also kept monitoring the SHINE open-label extension trial, which, by 2020, had enrolled 292 patients from five earlier Spinraza studies. Each day, each patient metric formed a new datapoint, providing additional information on how the drug was working.

Doug Kerr’s NURTURE trial reported an updated interim analysis in June 2020. After 4.8 years of treatment with Spinraza, 100% of the 25 children treated pre-symptomatically were alive, none of them needing permanent ventilation. Ninety-six percent of these patients were able to walk with assistance. The natural history of this disease shows that the majority of Type 1 SMA kids, if untreated, die before their second birthday, but the average age of the children in this trial by then was 3.8 years. This kind of survival was “unprecedented,” Biogen said.

And there were some children in which not a symptom of the illness could be spotted at all. Including Gabriel Peters, the very first child enrolled in the NURTURE trial.

CBS, male anchor: Results from a drug trial is giving hope to people with a rare genetic disease called spinal muscular atrophy.

Female anchor: Doctors have found that giving the treatment very early, when patients are infants, seems to be the key to helping them develop like typical children. Hillary Lane introduces us to a boy who was the first baby in the study.

[sound of children] Hilary Lane: Four-year-old Gabriel Peters loves playing outside with his brothers. It’s something his parents never thought they’d see.

Robert Peters: We didn’t think he’d have the opportunity to run around and play with his brothers like he does.

Laurie Peters: And wrestle like he does.

Robert Peters: Yeah, it’s just amazing to see it.

Hilary Lane: Gabriel was diagnosed in utero with spinal muscular atrophy, or SMA...

Brady Huggett: By almost any measure, Gabriel is developing normally, as an otherwise healthy child would. He is a patient at Columbia, under Darryl De Vivo, who has been watching Gabriel since his first injection.

Darryl De Vivo: He has two older brothers, and an older sister, a first born child of the family. She has SMA and is in a wheelchair.

Brady Huggett: Uh-huh.

Darryl De Vivo: So, the young boy, Gabriel, was seen by me at 7 days of age, when he was perfectly normal. And at 9 days of age we gave him his first intrathecal injection of nusinersen. And he’s — I talked, I did Zoom meeting with the parents and Gabe last week actually — he’s perfectly normal. He’s running around the house, he wrestles with his older brothers, and usually wins.

Brady Huggett: [laughs]

Darryl De Vivo: And so, he gets intrathecal nusinersen every four months. Three times a year. And he’s just developing like a normal child, he’s like the other two normal children.

Brady Huggett: Even for patients doing as well as Gabriel, Spinraza is not a cure. Without regular infusions, the slow physical regression that is the hallmark of SMA would begin again. But when given before symptoms, and regularly, so far Spinraza has the potential to at least look like a cure.

Yet Spinraza is also helpful for older patients. Kyle Derkowski was born in Schenectady, NY, in 1987. His father was a firefighter, his mother a nurse, and he has a brother two years older than he is. By now this is a familiar story. For the first year of his life, everything was normal. But his parents thought he was developing slower than his brother had, and they took him to their pediatrician. The doctor found nothing outwardly wrong and advised them to just be patient. Kyle was eventually able to stand and move around by holding on to furniture, but he never took a step on his own, and by the time he was one and a half, his parents were worried enough to bring him to a neurologist, in Albany, about 20 miles away. After a muscle biopsy, the neurologist there concluded it was SMA, but he was not particularly familiar with the disease, and he incorrectly labeled Kyle as Type 1. This neurologist told the Derkowskis that their son would likely die before he turned 2, and that there was nothing therapeutically to be done.

The Derkowskis both took leaves of absence from their jobs, and family members and friends came to visit, as the imagined short window of Kyle’s life closed. But when his second birthday drew closer and he did not seem near death, his parents wanted another opinion. They went to Newington, Connecticut, to a children’s hospital there with a muscular dystrophy clinic. A neurologist examined Kyle.

Kyle Derkowski: He could tell right away that I wasn’t the most severe form, just by looking at me. And he said that I was a Type 2, actually I think he even said I was a strong Type 2. He called me, like, a Type 2 and a half, which obviously gave my parents a lot more hope than the worst case scenario.

Brady Huggett: Yeah, yeah.

Kyle Derkowski: He said I’m definitely going to live past the age of two. I’ll make it into adulthood. And I think, even that day, there happened to be a guy there, his name is Armand. He was, like, an accountant. Just a middle-aged guy, same type as me. So he actually talked to my parents.

Brady Huggett: Armand stood as an immediate example. Here was an adult man, with a job, out living in the world. That, too, gave the Derkowskis hope. Suddenly the question was no longer, When will our child die? But rather, What shape will his life take? And what can the scope of it be?

One of the first things the Derkowskis did was go to an SMA annual conference in Chicago. The gatherings were smaller then, run by Families of SMA (now called CureSMA). That organization was founded by Audrey Lewis, whose adopted son Garrett was a Type 2. Garrett was four years older than Kyle, and served as a role model. Whatever Garrett could do, Kyle hoped he’d be able to do, too. On the whole, the conference was “revelatory,” for his parents, Kyle said, helping them see how they’d be able to adjust and live within the constraints that SMA places on families.

Kyle would never walk. He spent his childhood in a wheelchair, and Medicaid paid for physical therapy once or twice a week to combat the muscle contracture that comes with all that sitting and lack of use. Still, even with the physical therapy, “it was a battle you knew you were going to lose,” he told me. Nothing could stop or reverse the disease.

He remembers when the SMA gene was discovered. “That was a big deal,” he said. He remembers when a mouse model of SMA was created — another “huge step.” These things gave Kyle valuable hope, because he knew that someone, somewhere, was working on a drug. But one day he overheard a family friend, who was employed in pharmaceuticals, telling his father that generally the path to drug approval was hard and could take as long as “30 years.”

Kyle Derkowski: At the time I was probably like 13 or 14. So that was, like, devastating news. Because I was always really hopeful. In fact I remember, someone told us once — and she was, like, in the know, so we trusted her — but she said, like, I’m sure this will be over by the year 2000.

We’re like, Oh great. You know, as a kid, I was like, OK, year 2000, I’ll be in eighth grade. If I’m walking by then, I could still reasonably make the varsity football team a couple years later. I mean, I was pretty hopeful as a kid. And the hope kind of waned as time went on.

Brady Huggett: There was no alternative, of course, but to keep moving forward, and Kyle soon learned what he needed to do in order to keep himself mentally healthy.

Kyle Derkowski: I just remember at a certain point I realized, I can, like, sit here and sob and cry and despair and feel really bad for myself. But when I’m done, I’m no less handicapped than when I started, so what good is it doing me? And from that point on, I was kind of like, I’m not going to waste my time anymore. Because I just kind of realized that happiness was a choice that I could make. And I started to make it, rather than feel bad. Because there’s, I don’t know, there’s no point. Why would I go through life feeling crappy if I didn’t have to? I could just be happy instead.

Brady Huggett: Kyle earned his undergraduate degree at The College of St. Rose, in Albany, commuting there and studying communications and computer science. His best friend Dan went away for college at Franciscan University of Steubenville, Ohio, and there he met a woman named Laura. The summer of 2006, Laura made a road trip to Schenectady to visit Dan, and she also met Kyle. Kyle and Laura hit it off, and maybe, right then in that moment, he decided to play the long game. They emailed, texted, stayed in touch for years, miles apart. When Laura graduated she moved to the Washington DC area. With school over, their communication increased, and deepened, until it turned into a form of long-distance dating. Kyle was in graduate school by then, commuting to Rensselaer Polytechnic Institute, in Troy, New York. When he graduated, with a master’s degree in information technology, he looked for a job in the DC area and moved down to be closer to Laura. Now they were seriously dating, and a few years later in December 2013, Kyle proposed.

Kyle Derkowski: I actually took her to — it was her birthday — I took her to the Lincoln Memorial.

Brady Huggett: Oh yeah.

Kyle Derkowski: At night. And it was December, but it wasn’t that cold out, it was a nice day. And I told her I wanted to take her to see the Christmas lights, or something, in DC. So we get down there, and we get to the top of the Lincoln Memorial, and I had her friends staged down at the bottom of the steps. And, um, they had a big, light-up sign with Christmas lights that said, Marry Me.

Brady Huggett: It took Laura a second to figure things out. She saw the sign and turned to Kyle. “That’s so cute,” she said. “I wonder who it’s for?”

They were married in December 2014 in Laura’s hometown in Pennsylvania. A few months before, though, Kyle took Laura to a Virginia-based CureSMA meeting. He had not attended many as an adult. He’d never really wanted to be a cheerleader for the disabled, or spend time raising awareness of the disease. He’d already led a life of being noticed. No one quietly blends into the crowd when they are in a wheelchair, he told me, particularly a wheelchair as specialized as his. It’s a “spectacle,” he said. It was not uncommon for Kyle, growing up, to feel like the center of attention just by entering the room. He didn’t want that any longer. Kyle wanted to just be an “average guy,” he told me.

But now it was important that Laura have a better understanding of the SMA community, and their life ahead. At the meeting, he was a center of attention again, but in a new way.

Kyle Derkowski: And that was great, because at that point I was an adult, and all the kids were looking at me. Especially because I was engaged, and I think that is not so common, for disabled people. A lot of people were asking me about that. And just, I don’t know, people literally came up to me and said, You give me hope.

Brady Huggett: There was interest in Laura, too. People wanted to know how they met, how they managed their day-to-day life. Laura was already used to this. She’d been getting questions for years about her life with Kyle, from curious friends who wanted to know why she’d made the choices she did. In some ways their curiosity all boiled down to the same thing: What makes you choose a disabled person to spend your life with? At first it had it exasperated Laura to have to explain that Kyle is an amazing person, witty and smart, well educated with a good career. It exasperated her to explain that Kyle’s body is not the sum of him. The questions at the CureSMA meeting felt different, though. Her friends and family had wanted insight into Laura’s life. The folks at the SMA community wanted insight into their own lives, about what might be possible for them.

The attention on Kyle reminded him how important it had been for him to have role models as a boy. And he realized that he could be a model for others. Kyle and Laura began to participate more in the CureSMA community — they are now both Virginia chapter officers — and when Kyle spoke publicly about SMA, whether it was for a local news segment or for a CureSMA profile, he dropped in select information from his life. That he has a job, for instance. He has a mortgage. That he is married. That his wife is “amazing” and “beautiful.” Each detail is a flag Kyle raises for a younger SMA person to see. They are beacons, almost. Look at me, they say. My life is full. I am out living in the world, I am contributing to society. And you can do this, too.

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Brady Huggett: Kyle had always wanted to participate in a clinical trial, but the ones he came across were for the most severe form of SMA, or younger patients. But once Spinraza was approved, “right away” he knew he wanted to be on it.

His first dose was in August 2018 at Georgetown Medical School, when Kyle was 30. He’d had spine fusion surgery when he was 12 to correct scoliosis, so the Spinraza injection had to be done into his cervical spine, rather than lumbar. The whole process took two and a half hours. When he got home, he spent the rest of the day in bed as a precaution, and drank some caffeine, because he’d heard that helps. His insurance covered the drug, and Biogen picked up the co-pays.

A few months in, he began to notice changes.

Kyle Derkowski: The SMA community has a pretty strong online presence, because we’re all spread out, so there’s a lot of people who report what they’re feeling and their results in Facebook groups and other forums. I don’t know, I had expectations about what would happen, and, um, I’d read a bunch of stuff, but in my case I really didn’t feel anything, any difference for probably a good three or four months.

Brady Huggett: Huh.

Kyle Derkowski: I think there were, like, three or four loading doses within the span of two months. And then probably like the first maintenance dose, I could actually start to feel a difference. And I think part of that was because I was really, really guarded in my own expectations.

Brady Huggett: Emotionally, you mean?

Kyle Derkowski: Yeah, I knew if I was optimistic about it, I would start finding things. Like, oh, I can do this, or I feel different now. But I didn’t want it to be, like a placebo effect. I was really cautious in admitting to myself if I was feeling any kind of effect.

Brady Huggett: So what did you feel? Did you feel like, OK, it’s easier to move around? Or, it’s easier to — I don’t know.

Kyle Derkowski: To me it’s the functionality that I noticed. So, going around an on-ramp to a highway that’s really, like a sharp turn. I’ll notice, like, wait a second, I can actually hold my own head up now in the car, where I couldn’t before. Or, I’ll notice that I can lift up a heavier cup of water, it has a little more water in it than I can normally pick up. Stuff like that.

This is the one that was kind of like, the most profound to me. I know it’s kind of weird. I was eating a hardshell taco. In my childhood, I could always pick up a taco, no problem. But for like the past couple years, I had to cut it up and eat it with a fork. Just because it was a little too heavy to lift at that point.

Brady Huggett: Yeah.

Kyle Derkowski: At one point, I think I’d been on Spinraza for like six months. I had a taco and it was, like, no problem handling it. I was like, OK.

Brady Huggett: The SMA field has shifted greatly since Spinraza was approved in late 2016. There has been a push by CureSMA, and others, to get newborn screening for the disease. It was added to a list of disorders that the Secretary of the Department of Health and Human Services recommends for states to include in their newborn screening programs. That happened in 2018, and by April of this year, 36 states had added SMA to their screening, covering an estimated 71% of newborn babies in the US. That’s according to data from CureSMA.

This has vastly increased the identification of these patients. The other aspect is new treatment options. Spinraza kicked open the door, and now others are coming through it. In May 2019, the FDA approved a gene therapy product, called Zolgensma, for SMA patients less than 2 years of age. The drug is an adeno-associated virus vector-based gene therapy, with the vector designed to carry a functional copy of human SMN gene into motor neuron cells. It is given by intravenous infusion. The drug was developed by AveXis, and sponsored by Novartis, which has plans to expand the approval for the broader SMA population, if possible.

In August 2020, the FDA approved Evrysdi, an oral, small-molecule drug, for SMA sufferers older than two months. The approval went to the biotech Genentech, which is owned by Roche, but the drug was developed by PTC Therapeutics. Evrysdi is a survival motor neuron 2-directed RNA splicing modifier.

In January of this year, Biogen said it had launched a trial called RESPOND, a phase 4 study that is evaluating the effects of Spinraza in infants and children who have unmet medical needs after receiving treatment with Zolgensma. The trial is taking place at 20 sites worldwide and aims to enroll up to 60 children.

These advancements are leading to a world in which the SMA community will be stratified. Here is the neurologist Richard Finkel.

Richard Finkel: So what’s going to happen in the coming few years, in the very near future, is that the majority of patients who have SMA will be identified within the first week or two of life, from this newborn screening method. From that blood spot that’s obtained. Those parents will be faced with the choice of, which of two or probably three drugs to select for treatment.

Brady Huggett: Uh-hm.

Richard Finkel: Or perhaps there will be some parents who will still say, You know, I’m not sure I’m comfortable with any treatment. And they want to do more comfort measures.

Brady Huggett: Yeah.

Richard Finkel: But certainly the vast, vast majority, when presented the data that these babies, by and large, are growing up and normal at 3, 4 and 5 years — and that’s been my observation in the five that I’ve treated, so I’m very much supportive of this effort. So there’s going to be that whole group of patients who will be emerging over the next few years.

And then there’s the group of patients who have already been diagnosed with SMA and are living with the disease. So you’re going to have on one hand this pre-symptomatic group, and on the other hand you’re going to have the symptomatic group. And some of the patients are now 20 and 30 years living with SMA. And others will have just recently been diagnosed. So the challenge to the clinician is going to be even more substantial, uh, because again you’ll be dealing with these two different groups of patients. And they're going to be treated differently.

Brady Hugget: Yeah.

Richard Finkel: They’re going to be given the same treatment options, but the approach to treatment may be different.

Brady Huggett: Yet if patients like Kyle were born too early, in a sense, for the best that these drugs can offer, they still can have a profound effect on their outlook. Here’s Kyle.

Kyle Derkowski: I can’t expect as much of a change as someone who’s just born and asymptomatic — or presymptomatic I guess. For me it’s still a miracle, it’s still life changing because, No. 1, I firmly believe that it’s helping me not decline. So that was always a fear, like, growing up. What can I do today that I won’t be able to do tomorrow? You know, when I was a kid, I could reach on top of my head and comb my hair, and stuff like that. I could unbutton my shirt, or whatever. At some point I realized, Welp, can’t do that anymore. So there’s always been a fear in the back of my mind: what am I doing right now that I won’t be physically able to do in a year or five years?

Brady Huggett: Yep.

Kyle Derkowski: And I feel the total opposite now. I feel like, What can I do in five years that I can’t do today? Which is just a huge difference. Yeah, so not only do I feel like I’m not declining, I feel like I’m gaining strength.

Brady Huggett: Does it, sort of, change the way you feel about the future, I guess?

Kyle Derkowski: Totally. Yeah. Again, my expectations are still modest, and I’m guarded about it. Because I’m not going to walk again, I know that. Or, walk ever, I guess. But, maybe I can do things that I used to be able to do that I can’t do now. Because every little thing I can do leads to a little more independence.

Brady Huggett: With these new treatment options, the FDA held in August 2020 a Critical Path Innovation Meeting to discuss the “shifting burden” of SMA in the patient population. The point was to discuss what life is like for people with SMA now that there are treatment options, and to consider what still can be done to address unmet needs. Kyle spoke at the meeting — virtually, because of the covid19 pandemic. He talked about his childhood, and how being disabled affected him. He talked about how he slowly downsized his view of the future as he aged, as he lost strength or abilities. Yet Spinraza has allowed him to “reorient my mindset,” he told them. “For the first time in my life, I imagined what abilities I might gain in the future instead of what I would lose,” he said. And he told them that after decades of slow decline, “when I look back over the past two years, for the first time in my life I am stronger now than I was then.”

The mortality rates for those living with SMA Type 2 was information Kyle never cared to know as he got older. He didn’t like to think about his life with an expiration date already stamped on it. Still, he did not need to look far for examples. He had Armand, for one, the man his family had seen on that first visit to the MDA clinic in Connecticut when Kyle was not yet 2. Kyle and his family ran into him again years later, when Kyle was still a teenager.

Kyle Derkowski: I saw him at a trade show. And, he was doing great, he had just retired, he was actually married, too. But at the same time, like, he had a can of soda with a straw in it, that he was kind of holding in his lap. And my dad was there with me. And he asked my dad to lift up the can to his mouth so he could, like, drink the last bit of soda.

And stuff like that I would see and I was like, gosh. I could lift soda at that point, no problem. And I’m like, am I gonna —

Brady Huggett: Is that going to be me?

Kyle Derkowski: Is that going to be me in a few years, or however long? That’s a very real fear that I had.

Brady Huggett: That fear has gone away with Spinraza. Kyle acknowledges that his future, his lifespan, is unknown now. That is a good thing. History does not contain people like him: an adult SMA sufferer who has a therapy to stop the progression of the disease. It’s never happened before. And with increased prenatal or newborn screening, even people with the most severe form of SMA should grow up looking completely different from Kyle. And he finds it exciting.

Kyle Derkowski: I kind of grew up in the atmosphere where not a lot was known, but there was a lot of hope. And now I get to, like, be an adult during this time when the hope is coming to fruition. And a lot of really exciting things are happening. So, I don’t know, I feel lucky, I think it’s a cool time to be alive. Where the disease that I have is basically on the brink of being cured. So, it makes me feel a little like an endangered species. Maybe, like, I don’t know, maybe people in the future won’t have my experiences, that I’ve had in life. And it’s kind of weird to think about that.

Brady Huggett: Laura works part time at a crisis pregnancy center, and Kyle is a software developer for the government. They live in a new development outside DC and are considering children — they already know that Laura is not a carrier for SMA. When Kyle considers the future of SMA, he thinks about polio, and these old photos seen in textbooks of people in wheelchairs. His generation sees those photos and thinks, That was an old timey sickness, and we don’t need to worry about that anymore. He hopes one day some grandchild or great grandchild of his will see a picture of him in his wheelchair and ask what was wrong. That was spinal muscular atrophy, someone will say. It’s not something we worry about anymore. This is what Kyle means when he says he feels like an endangered species. Kyle Derkowski might be the last of his kind.

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Brady Huggett: None of this is lost on those associated with developing Spinraza. Here’s Stan.

Stan Crooke: You know, that’s a piece of magic. I mean, that’s a once in a century event, to have a drug like that. If you look historically at any illness where you have a severe illness and half the patients are dying in six months. All progress in drugs is incremental. And it usually comes at a terrible tox price. Just think about the history of cancer treatment.

Brady Huggett: Uh-huh.

Stan Crooke: And that’s a history I lived, right? Here, in a single step, you have a drug that we now know if we treat before symptoms, most of these babies develop like normal children. And we’ve got now patients that have been on the drug seven years. There are really no meaningful side effects that occur, and that was all in one step.

You have to go back and think — the only place I can see where that actually happened before was like penicillin.

Brady Huggett: Uh-huh.

Stan Crooke: Where you have a very different proposition, right? That’s not a chronic disease, it’s just an acute infection. But to go from a fatal, awful, terrible disease in a single step to, you know, in effect, cure — and even if you got patients late you could make them all better, and they get better the longer you treat, so far, the better they get. And no meaningful side effects, it’s just not believable.

Brady Huggett: For Adrian Krainer, when he thinks about Spinraza, he first thinks of the patients his work has been able to help, including the children he now knows personally, like Emma Larson. He thinks, gratefully, about Ionis having done the hard chemistry work of getting the antisense molecule to function in the body. But he also thinks about the life of a researcher, and how big breakthroughs are often a combination of years of labor, and serendipity.

Adrian Krainer: I think I’d be foolish not to recognize that we were very lucky. I feel like we did all the right experiments in the right order, everything was very systematic. And, so, in some ways we were designing — you know, there is mechanism-based, there’s a whole logic — but I do know that if we hadn’t picked this chemistry and we picked a similar chemistry with a subtle difference, it wouldn't have worked. It would have worked — it would have looked like it worked — and when it got to the CNS, and it’s bad. And probably, if that’s what we had at the time, we would have had to drop it.

And so there’s the luck that the timing was such that we had access to this chemistry that does work well in the CNS. And that is very empirical. You know, until you have a chemistry that works, you don’t know if you can get a chemistry that works. There's no doubt there was luck, but, you know, people say luck favors the prepared mind, so. [laughs]

Brady Huggett: For Frank Bennett, the approval of Spinraza not only has put an exclamation point in a long career wrangling with antisense, but it’s given him something to keep chasing.

Frank Bennett: The SMA project — I should go back and really emphasize how really wonderful a partner Adrian Krainer was in this process. You know, without Adrian — I think it’s converse. Without each other I’m not sure we’d have a drug. Adrian was a tremendous collaborator, uh, partner, in moving that drug forward.

But it’s like — uh, maybe a bad sports analogy but — winning the Super Bowl. You know, where you’ve worked your whole life, worked really hard and you finally won the Super Bowl. Everything else feels like a letdown after that one moment. It’s kind of addicting, where you want to do that again and again. And you have to recognize that you may not be that fortunate in the future. But it really was the most gratifying thing I’ve ever done in my life, and the most special. And it wasn’t so much the accolades, as really seeing the impact on the children.

Brady Huggett: Kathie Bishop is now the senior vice president, head of rare disease and external innovation at Acadia Pharmaceuticals. During the years that she attended CureSMA meetings, giving talks about the clinical trials, and what they were like, she often got letters and holiday cards from parents, thanking her for the work she was doing. It wasn’t always nice, though. Sometimes she was attacked, online or in emails and letters, because Ionis and Biogen refused to supply the drug on compassionate use grounds to the general population. That sort of thing would be unfair to the parents who had taken the courageous step of enrolling their children into the placebo-controlled trials, but it speaks to the desperate, emotional place that the parents of SMA children inhabit. I asked Kathie about the need for parents to have hope when dealing with a terminal diagnosis for their child.

Kathie Bishop: And that’s what I always thought about, was hope. SMA, especially the infant form, is a terrible disease. So, the parents, you have a child that seems normal, you go home, everything’s going along well. You have a new baby, so, adjusting to that. Then you find out, at say about three months of age, they start not functioning as well as other babies, so you start to notice differences. LIke you said, you go in, you get this terrible diagnosis, and before Spinraza, or any of the other drugs, it was just, OK, they’ll probably end up on a ventilator but there’s nothing you can do. And the average age of survival is 18 months. So it’s a really, really terrible situation.

Um, in talking to parents, especially early on, there was just so much hope.

Brady Huggett: That hope goes a long way for parents, and children. After we’d finished one of our interviews, Kathie sent me a follow-up email. “What you said about hope really strikes a chord with me,” she wrote, “as I felt all along that was the driving force behind Spinraza.”

“I actually have carried this quote around in my wallet since I left the Salk Institute in 2001,” she wrote, “and thought of it often when working on Spinraza.”

The quote is inscribed on the walkway to the courtyard at the Salk Institute, and it comes from Jonas Salk himself. It reads: Hope lies in dreams, in imagination and in the courage of those who dare to make dreams into reality.

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Brady Hugget: Thanks to Stan Crooke, now and always. Thanks to Darryl De Vivo and Richard Finkel, for their clinical expertise. Thanks to Kathie Bishop and Frank Bennett and Adrian Krainer. Thank you to Kyle and Laura Derkowski, for sharing their experience with SMA and Spinraza, and the details of their life. The news clip on Gabriel Peters is from CBS station WCAX.

Sound mix and original theme by Brian Flood. All art created by Erin Dewalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous eight chapters. Chapter 10, the final chapter, will be out in a week. Until then.

Chapter 10: Dr. Crooke

Brady Huggett: Chapter 10: Dr. Crooke

In December 2017, Biogen and Ionis entered another collaboration — their fifth — this one focused on finding new antisense oligonucleotides to treat spinal muscular atrophy. It was a forward-looking agreement, an attempt to hold onto their leadership position in the space as new drugs neared approval, and it was also an admission that Spinraza, as magical as it was, might be improved upon. The deal brought Ionis $25 million up front, with milestones for achievements and royalties on any approved drug.

But the sixth deal between the companies, in April 2018, truly opened eyes.

Squawkbox anchor: Big news in biotech. Biogen announcing it will pay Ionis a billion dollars to form a partnership to fight brain disorders. The stock is up today. Meg Tirrell covers biotech for us, we’re also joined by Ionis CEO Dr. Stanley Crooke. Dr. Crooke, great to have you with us.

Stan Crooke: Thanks very much for having me. It’s great to be here.

Anchor: So the billion dollars breaks down up front to $375 million payment and $675 million...

Brady Huggett: The two companies had formed a long, 10-year collaboration to broadly develop antisense drugs against neurological diseases. The $1 billion price tag, when broken down, called for Biogen to pay Ionis $375 million in cash for the right to keep accessing its antisense technology, and another $625 million to buy more than 11 million shares of Ionis stock. That made Biogen a sizable shareholder in Ionis, and had investors wondering if the deal had almost gone in a different direction entirely.

Squawkbox anchor: As we’ve said, you’ve had a partnership with Biogen before. In the discussions to this, because now Biogen owns about 10% of Ionis, just underneath 10% or so, was there talk of a potential full takeout? I mean. I mean, I think that’s what investors are wondering. Was that ever under consideration?

Stan Crooke: Well, I think that’s — yes, certainly that is a consideration. But I think that Bigoen felt very strongly that it’s much more likely that we will continue to be as productive as we have been by being independent. And we certainly are committed to remaining independent. We think that’s the best way to bring value to patients and shareholders.

Anchor: But you guys had discussed it?

Stan: Yes.

Brady Huggett: Indeed, before the sixth Biogen deal was announced, the companies had an amiable, casual meeting of the minds to discuss a buyout. Here’s Stan.

Stan Crooke: Uh, I got a call from Stelios, you know, basically asking if he could come, with Michel, to my home in Sedona to chat with me. And Stelios and Michel came, and so, we talked. And certainly, the possibility of acquisition was very much alive. You don’t have that, you’re never that explicit in these conversations, because once you are, that’s an announceable event. So, that’s an interpretation of mine.

Anyway, in the end, the conversation went well, but we ran into a time when it appeared the deal was not going to happen. These things happen — you know, in these big deals, it can get off the rail at any time.

Brady Huggett: Yeah.

Stan Crooke: And finally, when I had written it off, I got the call from Stelios. He said, We want a deal. Here are terms that will not change.

Brady Huggett: [laughs]

Stan Crooke: And the numbers got my attention, and so I said, OK! [laughs] And we did the deal.

Brady Huggett: Stan did not want to be bought. He felt Ionis was better off, scientifically, as a stand-alone company. And as it turns out, Biogen felt similarly. Here’s Stelios Papadopoulos, chairman of Biogen’s board.

Stelios Papadopoulos: Basically, what we did is, Michel Vounatsos, the CEO of Biogen, and I, we flew to Arizona, and we met with Stan Crooke and Lynne Parshall, for several hours. Really talking about the philosophy of what we wanted to accomplish jointly, what we wanted to do. So, like casually, the issue of, should we buy them, should we not? And our conclusion was, typically, when you buy such a science-intensive company, you know, invariably, the good people move on. And we thought this group was special. And it should have been allowed to remain intact and independent.

Uh, the second point was, the ASO technology platform of Ionis is broadly applicable, not just for neurology. So we would either have to waste away all the other applications — in cardiology and oncology, whatever other therapeutic indications you can imagine — or go into an out-licensing mode, trying to find partners for cardiology, for this, for that. And that didn’t seem to be practicable.

Brady Huggett: Ionis had become what many successful biotechs become: an acquisition target. It had a now proven, valuable area of expertise, and a revenue stream. But in the end, that wasn’t enough to kill the good thing the two companies had going. Biogen valued Ionis more as a partner, and Ionis was left alone.

From Nature Biotechnology, I’m Brady Huggett, and this is Hope Lies in Dreams.

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Brady Huggett: Biogen set the price for Spinraza at $125,000 per dose in the US, which means that, after the initial loading period, the drug would cost $375,000 annually per patient. That amount immediately set off a renewed discussion on the cost of innovation in the drug development world, and just what the US healthcare system can bear. Meanwhile, with the pent-up demand for the drug in the SMA community, sales quickly added to Biogen’s bottom line. In that tiny window, after approval and before the end of 2016, Spinraza brought Biogen $4.6 million. And in 2017 sales took off, climbing to ~$884 million, and ramped up from there. Spinraza revenue for Biogen was $1.7 billion in 2018, and more than $2 billion in both 2019 and 2020.

Ionis got a percentage of each sale, and by the end of 2020, Ionis had earned in total $1.3 billion in revenues from the collaboration around Spinraza, of which more than $930 million came from drug royalties. The drug had been approved in 50 countries, with reimbursement established for 40 of them. Spinraza became the thing that pushed Ionis over the top. In 2017, the company announced a narrowing net loss, of just more than $17 million, but in 2018 it posted a net income of $273 million, the first time in its 30-year history that it reported a year in the black. That was followed by another year of profitability in 2019.

Through 2020, through all the years as Isis, and then Ionis, the company had earned $5 billion in revenue. The company had brought in money one way or another: service deals, research collaborations or drug sales, including from Spinraza. It had raised another $2 billion by selling its equities and securities. It had also borrowed long-term debt equaling $1.5 billion. But it had blown through all of that by fueling its R&D machine, and at the end 2020, it still had an accumulated net deficit of $1.2 billion.

And, by last year, it was again in the red. It saw increased spending in 2020 for its pipeline, which had more than 40 ongoing programs, and it incurred about $90 million in costs associated with ingesting its wholly owned subsidiary, Akcea. That moved the company back to a net loss for the year.

The Akcea subsidiary was formed in December 2014 to develop and commercialize Ionis’s drugs for metabolic diseases caused by lipid disorders. The company was based in Cambridge, Massachusetts, and the idea was that Ionis would hand over drugs for Akcea to take through phase 3 and approval, and then market them.

This went along with Stan Crooke’s desire to keep the needs and ambitions of marketers far away from the scientific core he so cherished at Ionis. The first drug to follow this route was Waylivra. It was aimed at Familial Chylomicronemia Syndrome, or FCS. It’s a genetic disease, rare, affecting 3,000 to 5,000 people annually around the world. It can cause a buildup of fat in organs, and pancreatitis, and there were no effective therapies for it. The phase 3 package Akcea handed to the FDA included data from two trials, both of which showed more than a 70% mean reduction in triglycerides, and also a reduction of pancreatitis attacks. But the drug caused reduced platelet counts in some patients, and though an FDA advisory committee voted 12-8 in favor of the drug, the regulator eventually declined to approve it, in August 2018.

Stan Crooke: We had side effects that, you know, people were worried about.

Brady Huggett: Yeah.

Stan Crooke: And anything to do with platelets causes everybody to be particularly anxious. And so, they didn’t approve it; it was approved in Europe. And then we, almost simultaneously, had the platelet issue with Tegsedi.

Brady Huggett: Akcea submitted Tegsedi for US approval in November 2017, to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis, which is caused by transthyretin protein misfolding and accumulating as amyloid in tissue. The drug is a 20-base oligonucleotide that binds to transthyretin messenger RNA in the liver.

The disease is also rare, and as it progresses it is life threatening. The phase 3 program showed benefit against placebo in quality-of-life measurements, and on neuropathy impairment.

But patients in the trial also had cases of thrombocytopenia, and safety signals associated with renal function. The FDA approved Tegsedi in October 2018, but it included a black box warning on the label, pointing to the platelet levels and kidney function, and the drug must be prescribed through a Risk Evaluation and Mitigation Strategy program (called REMS). The drug faces competition on the market from Alnylam’s Onpattro, which targets the same disease through a RNA interference mechanism of action, rather than antisense, and that drug was approved first, in August 2018.

Together, these two Ionis drugs were more like Kynamro, which worked in the body but was plagued by safety issues, than Spinraza, which revolutionized the disease space. Waylivra and Tegsedi were further validation that antisense could be an effective disease modifier if side effects were controlled, but the drugs didn’t sell, with revenues being “very modest,” Stan told me.

So if Akcea was an experiment, it didn’t seem to be working out. In 2019 the top management positions were purged there, and then in 2020, Ionis bought the remaining shares of Akcea it didn’t already own, and brought the unit fully in house.

The move was billed as “another step forward in Ionis’s evolution,” in a press release, but the comment was supplied by Brett Monia, not Stan Crooke.

[music]

Brady Huggett: In December 2018, Ionis announced that Stan would be stepping down as CEO, effective January 2020. He would remain as executive chairman of the board, but his replacement as CEO was to be Brett Monia. It was a kind of continuation that had begun at Baylor, with Harris Busch taking Stan under his wing and serving as a father figure, and then Stan doing much the same for Brett at Ionis for three decades.

The impending change marked 2019 as a year of transition for Ionis, which seemed fitting, as it was also the 30-year anniversary of the company’s founding. On a Saturday night in September 2019, Ionis held a company-wide party at the Omni La Costa Resort in Carlsbad. Originally built in the 1960s as an equestrian ranch, the resort is an impressive, sprawling estate. The golf course there has hosted the Tournament of Champions, and, for tennis, the Davis Cup has been held there, too. It was a warm night — early autumn amid the soft, rolling hills of coastal California. Ever since Isis changed its name to Ionis, the company employees have been referred to as Ions, and on this night they gathered in the Costa Del Sol ballroom. Tables everywhere, good food, open bars at the peripheries of the space. Ionis was celebrating a measure of success after Spinraza and the huge Biogen deal, and also it was patting itself on the back for pushing the science of RNA for decades, and for surviving as long as it had.

In the ballroom, the company had erected 5 displays, intermittently spaced, each one with a timeline depicting an “era” of the company’s history. Beyond the current Ions, there were also retired employees, or people who had worked at Ionis for years before leaving on good terms. The mood was festive, a constant din of warm conversation in the huge ballroom, the sound of people enjoying each other, catching up. Around 7:30 pm, Stan took the stage, three big screens lit up behind him.

Announcer: Ladies and gentlemen, please welcome Stan Crooke, the founder, CEO and chairman of the board to the stage.

[applause]

Stan Crooke: [applause dwindles] That’s all?

[laughter, applause grows again]

Stan Crooke: That’s enough. [laughter] Well, you know the old motto of, take care of the ego and it takes care of you, it works great. Just ask for what you want and you get it.

Brady Huggett: Stan had been addressing the company for decades. He’d run countless webinars and investor meetings. Spoken at scientific conferences all over this world. He’s at ease talking in front of others, he’s funny, making jokes when the opportunity arises. And that was the case on this night, too. He began by pointing out that pharmaceuticals have been around for some 120 years, and the core of the industry for most of that period was small-molecule drug discovery. Then came monoclonal antibodies. Then, he said, came antisense, with 5 or 6 companies formed right at the beginning. One by one they all failed or turned away. Except Ionis. With little help from academia, he said, “all the significant advances in the technology came from the people in this room: you.”

The future, Stan said, was nothing more than “an extrapolation” from these prior three decades of accomplishment.

Stan Crooke: When I think back to 30 years ago, to our first strategic plan, it’s just astonishing to me that what’s going to come, is so straightforward for us. So today, you are improving the lives of thousands of patients. Tomorrow, it’s millions. It’s millions of people who will live longer, live better. And they’ll do it because of the people in this room. That is an accomplishment. Right? [applause]

Brady Huggett: Then, he began a slow backward march through time.

We’re here to celebrate the journey, he said. We had a challenging path, and the obstacles we faced were considered by essentially everybody to be “impossible.” As the antisense field emptied out over the years, “we persevered,” he said. Then he pointed to the Dust Bowl. The farmers who did not flee the drought-stricken land in those years, these folks who stubbornly stayed in place and hoped for a better tomorrow, were sometimes called “next year people.” Well, to the antisense observers, Stan said, “we were next year people for two decades.” But inside the company, he said, “we had our shoulders to the wheel.” And all the hard work, and the great scientific culture that had been instilled at Ionis, and the collective drive to succeed, had been a kind of crucible for employees.

Stan Crooke: And when I look out into the audience here, I see people who have grown. And that probably is the thing that makes me proudest, of you and our journey. And it’s very fulfilling to me to think that many, maybe most of you, will look back on your time at Ionis and say, That was the period of my life when I grew the most. When the demands were intense, and the support was there, and I grew the most. So congratulations on our journey. It’s been a wonderful trip. [applause]

Brady Huggett: And the reason the company persevered, the reason so many sacrifices had been made by the people in that room, was the belief in the power of medicine, Stan said.

Stan Crooke: As I look around, I see lots of heroes. People who committed, made sacrifices, stayed the course for the right reason, in the right way, and did the right things. And the reason: sick people depend on us. Sick people depend on us. What more do you need? That’s what we get to do for a living. The leverage of one good drug is so incredible, that it’s just hard to get a sense of the value that we have created, and the value you will create, as you go forward.

Brady Huggett: After his speech, the night's program moved to individual recognition. Ionis handed out lifetime achievement awards to Frank Bennett, Brett Monia, and Lynne Parshall. Also, to Dave Ecker — who had returned from Abbott, and was now safely back in the fold at Ionis.

The company would hand out more awards in 2020, to Joseph Wender, Richard Geary, Scott Henry, and Rosanne, for whom they would also name a new conference center.

But on this night, in his talk, full Stan was on display. He was self-deprecating yet aggrandizing all at once. He was businesslike at times, and was, as he always wants to be, firmly in control of the proceedings. Yet he also peppered his comments with moments of heartfelt sentimentality as well as honesty, telling the crowd he knew he wasn’t always “the easiest guy to live with.” When he made jokes, the crowd was right there with him. But when he spoke of the challenges

the company had faced and the great needs of patients the entire ballroom fell into rapt silence, radiating toward the stage a kind of adoration for a retiring patriarch.

Stan Crooke is a man of deep emotions, and contradictions. He has bursts of anger, followed by sincere contrition. He likes to laugh hard, and blow off steam, yet he is a tireless worker. He is a devoted father. He is fiercely loyal to close friends, yet he can hold a grudge until the end of time.

And for all the support he knows employees need, he is not particularly touchy-feely — perhaps this is no surprise, considering that he can’t recall anyone giving him a hug as a child. So in the later years at Isis and then Ionis, Stan had an unofficial policy of allowing hugs only to people who had been with the company for 20 years or more. That kept the group small. Then, as the company grew and aged, he moved the number to 25 years. At the anniversary party, he acknowledged that his hugs had historically been focused on “the top line,” but on this celebratory night, at the end of the presentations, he threw the door wide open.

Stan Crooke: Now, um, I’m open for hugs, and, thank you so much for being here tonight. [applause]

[music]
[ad]

Brady Huggett: In December of 2020, Ionis announced the final step in the transition of power. Stan Crooke would fully retire from Ionis and step away from the board in June 2021. On June 1 of this year, Stan sent a company-wide email, with the subject line, Farewell. He noted that it seemed “like yesterday that I closed on our initial financing of $5.2 million, started Ionis in a garage, and had our first board meeting in a cramped, hot corner of our offices.” Yet, he wrote, in truth it had been a long journey “into the unknown,” and along the way the company “blazed a path that many companies are now following.”

He drew the email to a close by saying “the Ionis we created together and all of you are in my heart,” and he signed it, Fondly, Stan.

I’d asked him, way back in 2015, if Ionis — a company indelibly linked to his name — could survive without him at the helm. He answered almost instantly. “Yes,” he said, and if not, then “I haven’t succeeded” as a leader.

Time will tell. But Brett Monia, the current CEO, has been associated with the company since its inception, and he helped to instill the science-first culture that got Ionis to where it is. He is not an unknown entity, and overall, the core of Ionis remains. Few industry observers seem worried that Ionis will weaken under a new chief executive.

Retirement Stan looks a lot like the old Stan. He and Rosanne officially founded in January 2020 a nonprofit organization called n-Lorem, which hopes to provide RNA-targeted therapeutics, for free, for life, to patients with ultra-rare genetic diseases. It is focused on antisense technology — which is hardly a surprise — and it aims to provide therapies to patient populations as small as 1. The company was financially started by Stan and Rosanne, who have put in $3.2 million of their own money, and now has sponsorship from Ionis and Biogen. It also accepts donations. In its first year, n-Lorem received 50 applications from patients, and it is “moving forward” on 20 of those applications. That includes one for a boy named Connor, who has a rare mutation in the SCN2A gene. This causes him severe seizures, development delays, and problems with movement. There are no effective treatments available, and n-Lorem hopes to fashion an antisense therapeutic specific to this mutation, and provide it, for free, to Connor and his family.

In truth, though, this is not how Stan planned to spend the second half of his 70s. Certainly he’d wanted to give up the things at Ionis that “bored me,” he said — aspects mostly related to business — but he still wanted to do the science that intrigued him. What he’d envisioned was a “long glide path,” that included some work, but more time to write, or, frankly, just relax. Instead, he got n-Lorem.

Stan Crooke: But in the end, it’s a moral question. [laughs] If I could do this, how could I

not? I mean, how could I leave these patients suffering and dying, if I had a chance to help them?

Brady Huggett: The concept of n-Lorem marks the return of Stan Crooke, the doctor, seeing patients and working to solve an illness one-on-one. A metaphorical throwback to the days when he still saw patients, reading their charts and interacting face to face. At n-Lorem, there are no sales goals, no annual reports to deliver to the public markets. That’s a relief. But somehow the “intimate pressure” of dealing with a single patient, whose name and face you know, “is worse,” Stan told me.

Stan is 76 years old now, and as far as he is concerned, this is how he’ll spend the rest of his professional life. He’ll run n-Lorem until he can step away, and turn it over to someone else.

When one looks at the long, tangled history of antisense, at the billions of dollars needed, and spent, by Ionis in order to get a single breakthrough drug like Spinraza, the path can seem incredible. And it is. But also, this is simply what it takes to bring a new drug modality to patients. Antibodies arrived on a similar path. The first antibody drug, muromonab-CD3, was approved by the FDA in 1986, after a decade of work. The FDA would not approve another for 8 years, and the field grew slowly from there. Now antibodies are an established, valuable component in fighting a wide range of diseases, and in April this year, the FDA approved its 100th antibody therapeutic, GlaxosmithKline’s Jemperli, aimed at PD1, and cleared for endometrial cancer.

A crucial difference is that for decades there were many biotechs focused on antibodies as the field matured, whereas with antisense the field dwindled until there was just one company to carry the torch through the dark years. And only one CEO. That is a heavy burden.

In retrospect, Stan Crooke was the perfect person to carry that load. He has an exhaustive work ethic, and his pugnacious side means he refuses to quit. He brings an unwavering focus to the task at hand. His circuitous background has benefited him: medical school and academic research in pharmacology, but also pharmacy school and all the years and experience inside big pharma. And while he has not practiced medicine in decades, he never forgot what it felt like to be a physician, to have a patient’s life in his hands. The great responsibility of that.

It is possible that only this sort of person could have gotten antisense to where it is today. That needs to be considered. And many have.

Here’s Stelios, who has known Stan from the very first days of Isis.

Stelios Papadopoulos: How did Ionis manage to persevere? You know, one of the unspoken things about this — I don’t think you and I have spoken about this — is, you need capital to persevere. How do you convince investors to put up money while you’re still undergoing serial failures? Or disappointments? And that’s a very subtle thing to think about. I think it was the strength of character of Stan that could convince so often people that there was value there. And he was right. And they were right. Except that every now and then, what looks like value doesn’t translate into commercial value.

Brady Huggett: Yeah.

Stelios Papadopoulos: And it finally happened with Spinraza, so now he doesn’t have to prove anything to anybody. ASOs work. Bingo. There’s Spinraza. They worked before, but now they work in a commercially meaningful application. End of discussion.

Brady Huggett: Here is Kleanthis Xanthopoulos, who ran the RNA therapeutics company Regulus for 8 years, after Ionis and Alnylam put it together with their combined intellectual property, and funding. He has spent years knee-deep in the RNA field, and knows Stan well.

Kleanthis Xanthopoulos: Stan has very firm opinions, um, very, very focused on advancing science on a fundamental level. He has this perseverance that is a unique attribute to all successful entrepreneurs and scientists. He has that demand of immense loyalty.

Brady Huggett: Uh-huh.

Kleanthis Xanthopoulos: And falling in line with his vision. He is not a consensus seeker, neither would he debate forever and solicit multiple ideas. But it is precisely those attributes that have been ultimately so critical to advancing the overall field.

Frankly, if it wasn’t for Ionis, I believe there wouldn’t have been an RNA therapeutics field. Because there are so many things that, um, Ionis has been able to understand, about the pharmacology, the ADME properties, the toxicology, the manufacturing of RNA therapeutics.

Stan is, as I said, I give him a tremendous amount of credit, because no RNA therapeutic would have been possible today, no RNA therapeutic company — whether it’s siRNA, antisense, aptimer, messenger RNA, I would say, even — if it wasn’t for all the understanding of the things that Isis/Ionis has done over the last 35 years or so.

Brady Huggett: And all that work of holding Ionis together, and pushing the chemical modifications of antisense, are bearing fruit today, with the giant blossoming of the RNA therapy field. Luke Evnin is a partner at MPM Capital. He earned a PhD in biochemistry from the University of California at San Francisco, and afterward he joined Accel Partners as an associate. Accel was an early investor in a tiny antisense startup called Isis Pharmaceuticals. Evnin stayed with Accel until the middle of 1997, and had a view from “the second-row bleachers,” he said, as Isis was being built. Even now, he thinks, Ionis does not get enough recognition.

Luke Evnin: You know, I just think, I don’t think Isis and Stan get the credit for being the pioneers of the field that they kinda deserve. That’s sort of my general point. And I still feel that way. I mean, it’s not self-serving in the least — it was certainly not my deal. I was at Accel Partners at the time, but I had nothing — I didn’t make the decision and I was just an observer. So, um, I think the investors who stepped up and backed him, and Stan himself, deserve a ton of credit. I mean, I think it was — the fact that he kept it going through all these — I mean, I think if Isis had gone away, I’m not sure where the field would be today.

Brady Hugget: Yeah.

Luke Evnin: Because there would have been no one else working on it, to be honest. I mean, who else was going to do all that incredibly hard work? You probably had to fail on all those things, in order to get to where we are today. But, who was going to do it? [laughs]

I’m not — I’m sure money got wasted, but you probably did have to run these experiments at least once, fail, realize, oh shit that’s not going to work, I gotta go do something else. In order to realize what you needed to do.

Brady Huggett: So when you talk about the credit, it’s No. 1, that Stan was in love with RNA. Right? That’s part of it. But the second is, just the tenacity of the company to not stop.

Luke Evnin: Yeah! I mean, come on. That’s a long desert to cross.

Brady Huggett: Stan did not build Ionis alone, of course, did not singly make all the chemical modifications that brought antisense to bear. He had a gifted, loyal core that bought into the concept of antisense maybe as much as he did. He was surrounded by a great team. Dan Kisner, who was chief operating officer in the ’90s, told me that Lynne Parshall is “one of the smartest people I ever met.” Frank Bennett, he said, “is made of gold.” Then there’s Brett Monia, who met Stan back at UPenn, followed him west and never left his side. Rosanne, who learned from Stan in the lab, fell in love with him, and who helped build both the science and the culture at the company. There’s Dave Ecker, who left and returned. Either because of Stan’s example of loyalty, or the communal love of science, or the lure of the challenge, or maybe even something else, most of that core is still there. Here’s Dave.

Dave Ecker: I’m thinking about it — almost everybody was a first generation in college. I’m pretty sure Brett was. Frank was. I was, certainly Stan was. You know, it may be — it’s not like we knew one another’s backgrounds and bonded because, you know, we all came from very little. It may be that coming from very little makes you a certain kind of person that finds one another, I don’t know. I never really thought about it.

Brady Huggett: Yeah.

Dave Ecker: I mean, if you look around, so many of the original, the people who joined within the first six months or a year, are still around, in leadership positions in the company. So there’s a cultural bond. You know, never give up. As long as there’s a scientific foundation for proceeding, culturally, I don’t think any one of us would have ever thought, This is too hard, I’m going to go do something easier. It just wasn’t in the playbook.

[music]

Brady Huggett: Children of addicts, or who grew up in unstable homes, sometimes become addicts themselves. A product of their genetics and environment. That is not the case with Stan Crooke. He never got much of a taste for alcohol, and doesn’t even drink coffee — his lone vice has always seemed to be the soda Tab, which he drinks even to this day, thanks to a personal stockpile.

Other times, these children grow up and seek order in their lives. And this is the path that is more ascribable to Stan. And he knows it.

Stan Crooke: And I’ve never wanted to lose touch with reality, ever. My whole life is about control. Gaining control. Being in control. People don’t get to do to me. I get to, make my own way. But I am proud that I have lived up to what I said I’d do. That, if I had control, I’d do everything I knew how to do to be fair. That I would, not take advantage of people. And, you know, fairness is in the eye of the beholder, but I know I’ve tried.

And the difference is, I have control. Of my life, and I don’t have to worry about, you know, do I have money to pay for food, or all the care that Evan and Nancy need. So all that went away, not because I fixed myself, but I fixed the environment. I gained control. And I’m no good, unless I have control.

Brady Huggett: Stan had ambition, and aspirations, and he knew he wanted to do the things that smart people do: earn a law degree, build a rocket. But it wasn’t until he met true scientific rigor, that he found his purpose and it all came together. At Baylor, in Harris Busch’s lab, watching the post-docs from all over the world live and breathe their research, a fire was lit in Stan Crooke that has never gone out.

Stan Crooke: And I told you, over and over again, that it was all luck.

Brady Huggett: Yeah.

Stan Crooke: That I did everything I could do to destroy my life as a young person. And it was because I was angry. And it’s taken me a lifetime to gain the control I have now, which is not good enough.

And, and it was the discovery of demands, the discovery of science, and the discovery of medicine. And, you know, that is what I was born to do. And the notion that the best way to leverage your knowledge was to make a drug. And I knew how, I don’t know, from birth how to make a drug, I think.

And so, that fluke of picking Baylor — I mean, hardly I picked them. Harris gave me a chance that I didn’t deserve. And I fell in love with the notion that I could help patients. I loved taking care of patients. It’s what I do. I take care of people. That’s what I’ve always done.

Brady Huggett: Among Stan’s many achievements, as a teacher, a researcher, CEO and drug developer, is the Massry Prize. He won that in 2019, and it puts him in good company — a third of Massry recipients have also won the Nobel Prize. He was named in 2019 on Forbes’ list of most innovative leaders. In 2017 he was inducted into the Medicinal Chemistry Hall of Fame, and that same year he received the E.B. Hershberg Award from the American Chemical Society. He also was given the Lifetime Achievement Award by the Oligonucleotide Therapeutics Society, and the SCRIP Lifetime Achievement award. He has published more than 550 academic papers, and edited more than 20 books on oligonucleotides or drug development.

That is a long way from a tar paper shack on the grounds of the Republic Creosoting Factory in Indianapolis. It is a long way from that shotgun house at 363 Terrace Avenue, it is a long way from Arsenal Technical High School. When Stan looks back on his life, it is with a sense of bafflement.

Stan Crooke: And I told you, the first time I saw you, that my life astonishes me every day. And, of course I can take a little bit of credit for working and taking advantage of the opportunities I was given that I didn’t deserve. But it’s not false modesty. I don’t deserve much credit for what’s happened to me.

Brady Huggett: So. Looking back at your life, are you still angry, Stan?

Stan Crooke: Less. Far less. You know, my temper, my quickness, my unwillingness to be patient when people dither on, is still my worst character. And it’s why I make some people really not like me, and I’ve tried and I regret it, but I keep doing it. You know, I’m not going to fix myself much more.

Brady Huggett: Stan’s favorite author, if forced to pick, would be William Faulkner. And if forced to pick a favorite work of Faulkner’s, it would be the novella-length story The Bear.

The story is experimental in both structure and language, and Stan does like it for that reason. It explores humankind’s position in the natural world, and how foolish we are to think we can own the land. Stan finds that interesting, too. But most importantly, Faulkner shines a light on America’s painful racial past and the injustices of slavery. The Bear is about “a man wrestling with fairness, and unfairness,” Stan told me. All great American literature, he said, “in one way or another, is about patterns of unfairness, and individuals standing up and saying, It’s wrong. And that really means a lot to me.”

Yet The Bear is also a story of a young man coming of age and turning his back on an ugly family history. And that thread also resonates with Stan Crooke’s life. He does not refute how his early years shaped him, nor does he necessarily express regret for them, but it is a life he has willfully ignored since 1976.

Stan Crooke: And, as I say, I haven’t talked to my brother in 50 years, and as I told you, my sister called once, but, um, uh, I ref — I didn’t, I didn't accede to her efforts to get us back together. And I’ve heard from some of the grandchildren. But, again, I refused to, uh, participate.

Brady Huggett: Why?

Stan Crooke: We don’t have anything in common. And, I don’t — I do not want to revisit any of that past. There’s only — I never had anything in common with my family anyway, really. And I certainly don’t have anything in common with my sister or brother really. I took care of them for a while, and I loved them. But, that was, you know, truly a lifetime ago. And the idea of reconnecting — the only reason for me to reconnect is to brag. You know, show off. That’s why I stayed in touch, you know, when I was in pharmacy school. I was showing off. But I don’t need that. And any other — going back, all it does is just bring back memories that I don’t want to remember. You know, I tell funny stories, but that’s not, that wasn’t my life.

Brady Huggett: Yeah. But I just, I’m going to ask one thing and then I’ll stop. But you just said you loved them. So you don’t have any, you don’t have any desire to, I don’t know.

Stan Crooke: No. It’s one of my worst characteristics. When I get to a place, I sever, and never reconnect and never go back and have no feelings. And that’s happened a few times. And, so, no. But I did love them. And, you know, I did babysit them, a lot. And, and, and, um. And yet, I refuse to even consider a rapprochement.

I grew up, really, with my two cousins, Richard and Shirley. And —

Brady Huggett: You’re not in touch with them?

Stan Crooke: No, uh-uh. Um, it’s just — that’s who I am. It’s not a thing I’m, a

characteristic I’m proud of. But if I’m telling the truth, that’s the truth. And it doesn’t feel good to tell you.

Brady Huggett: “Everyone views their life through a lens of self justification.” Stan told me that. So maybe the only way you get to the core essence of who a person is, is by speaking with those who know that person best. Here’s Dave Ecker, who has known Stan for more than three decades.

Dave Ecker: There's a bunch of things about Stan that are the same as when I first met him in the mid-80s. But he’s gotten wiser, he’s gotten more patient, he’s gotten less abrupt. I mean, he’s extraordinarily smart, obviously, and tolerating the time it takes for other people to catch up to him is something he didn’t do well in the beginning, and he does a lot better now. And he’s recognized certain things that matter, maybe more.

Brady Huggett: For, as impatient as he can be, he’s also quite funny at times, and empathetic. He’s got a lot of compassion.

Dave Ecker: Yeah, well so I gotta admit, when I first met him, I didn't like him. And I don’t know whether he liked me or not, but we clashed in the beginning. There came a point when I realized where his heart is. His heart's, kind of, always, kind of been in what I call the right place. Once you learn where his heart is, it’s easy to overlook rough edges.

Brady Huggett: Lynne Parshall, by handling the financial side of Ionis, rose up in the company until she was viewed as a kind of second pillar, next to Stan. And it earned her a lot of attention in the broader biotech industry. The sector was in full growth mode in the ’90s and early 2000s, talent was short, and Lynne could have helped a lot of companies. She never left. Partially that’s because she fell in love with antisense, too, like the rest of the believers. But also it’s because of her relationship with Stan.

Lynne Parshall: I love the company. I felt committed to its future. Stan was an amazing boss, mentor, partner. Um, I believed that we sort of embarked on this mission of creating, you know, the third rung of the pharmaceutical industry, which I’m sure he’s used that with you. But it was a passion. And, I got lots of phone calls all the time, for other jobs, including CEO jobs, which might have been interesting. But none of them for a company that I could feel as excited about working for, as working for Ionis.

And as the company continued to mature, it just got more and more and more exciting. And so I, you know, made it pretty clear to people who, you know, headhunters I knew who would call me all the time: just don’t bother. Unless you find something that is so amazing, but it’s unlikely that it’s going to be. So, I was just very committed.

Brady Huggett: You know, just having talked to Stan about his background, he’s really loyal. And I think, um, once you’re in that circle, he’s loyal to you and then you end up feeling loyal to him, back.

Lynne Parshall: Absolutely. Um, Stan and I were a partnership. And I, you know, it was very difficult for me to retire before he did. Because it was kind of breaking up the partnership.

Brady Huggett: Well, you’re still, obviously, in touch. Right?

Lynne Parshall: I didn't break it up very successfully, that is true. [laughs]

Brady Huggett: [laughs] So, you like Stan?

Lynne Parshall: Yes. Stan is one of my best friends, and mentors, and, yes I — yes.

Brady Huggett: Yet the person who knows Stan best is Evan Crooke. Stan cared for Evan when he was young, when his son was still struggling with his learning disability. They supported each other during and after Nancy’s long illness and her passing. Stan was there for Evan’s marriage, and the birth of his child. For more than 50 years they have been bonded by blood. So it is Evan who gets the last word.

Evan Crooke: And he spent his life taking care of people. Right? Starting with, working at 8 years old, on a paper route, and your money having to go to your mom. And then going to, falling in love with my mom and having to take care of her, her getting sick. Then, focus on therapeutics and drugs and development of the most complex stuff in the world, which, by the way, does what? Takes care of people who are sick. Takes care of human beings. And then take care of the people who built that technology and the company. So it’s really one thread that goes throughout everything: a desire to take care of other human beings.

Brady Huggett: Yeah, but that’s — you’re in there, too.

Evan Crooke: Yeah, absolutely. My point is that, when he says the slogan, you know, Ionis’s slogan, which is Sick People Depend on Us. Really what that is, in my opinion, it’s way deeper than that. It’s I, Dr. Crooke, want to take care of all of you. It goes way deeper than that.

And so, it’s not just a slogan on the wall. I know that. No one else walking through that place understands it as well as I do. I understand it. I see it. I know him very well. I know exactly where that came from.

And so yes, from a sound bite, it sounds great, and it works well, and it’s meant. It’s genuine, it’s not a cliche, it’s not bullshit. But the subtext of that, which is the deep stuff, is his entire life: a giving person trying to take care of others. That's really what it is.

[silence]

[theme music]

Brady Huggett: Thank you, now and always, to Stan Crooke. Thanks to Dave Ecker, Lynne Parshall, Kleanthis Xanthopolous and Stelios Papodopoulos for their thoughts on Ionis and Stan Crooke. Thanks to Luke Evnin for his memory of early Isis. Thanks to Evan Crooke for his time and insight. And to the many, many other people at Ionis and in this industry whom I interviewed during this project.

The audio clip is from CNBC’s Squawkbox. Sound mix and original theme by Brian Flood. All art by Erin DeWalt. Hope Lies in Dreams was written and produced by me, Brady Huggett. Go to the homepage of Nature Biotechnology to find the landing page for this podcast, which includes a list of sources, historical photos and a transcript of this, and the previous nine chapters. This is the end of Hope Lies in Dreams. Thank you for listening.