No drug for COVID: ‘the most successful failure in my life’

In March, Laura Walker left the biopharmaceutical company she had co-founded three years earlier to join Moderna as the head of its infectious disease biotherapeutics team in Cambridge, Massachusetts.

Walker was chief scientific officer at Invivyd in Waltham, Massachusetts, which launched as Adagio Therapeutics at the start of the COVID-19 pandemic to develop an antibody drug for the disease. The company was spun off from Adimab in Lebanon, New Hampshire, where Walker had worked since 2012. Adagio raised more than US$450 million in funding during its first two years and carried out several clinical trials before disappointment struck when the SARS-CoV-2 virus evolved and the firm’s antibody candidate was no longer effective.

Walker tells Nature why she moved to industry after her PhD in immunology and microbiology, and the challenges of developing a drug during a global pandemic.

Why did you decide to leave academic science for industry?

My dad was a neuroscientist at Brown University in Providence, Rhode Island, so my exposure to science began at an unusually early age. Towards the end of my PhD at the Scripps Research Institute in La Jolla, California, I was contemplating my future but wasn’t convinced that a life in academia was compatible with the life that I wanted to live, which included having kids. Strikingly, there was an absence of female professors in my department. My dad passed away while I was in graduate school, and although I can’t prove it, I think one of the contributing factors to his death was the high-stress lifestyle. Given all of that, I decided to try industry. In 2012, after getting my PhD, I joined the biotechnology company Adimab. It was one of the better decisions I think I’ve made.

What do you see as the losses and gains of leaving academia for industry?

For me, the biggest pro of industry is the opportunity to develop molecules that can be advanced into the clinic. This is a long road, and most drugs fail, but as a scientist there is something very exciting about collecting definitive human data and then letting that data drive the path forwards. Another major pro is the opportunity to work as part of a team, which isn’t always possible in academia.

I don’t feel like I’m missing out on anything because I work at a company that is highly research oriented. That said, I think academia might be a better option for scientists who are interested in more basic science or the freedom to explore. Typically, companies are very focused on specific areas of research.

How did Adagio Therapeutics come about?

When SARS-CoV-2 emerged at the end of 2019, Adimab started identifying very potent neutralizing antibodies. We took a couple of months to engineer improved antibodies, but by then big pharma companies had already partnered up with other antibody developers and biotech firms, so the then-chief-executive Tillman Gerngross said, “Let’s spin this off ourselves”. I ended up joining as chief scientific officer and working at both Adimab and Adagio for two years, which was a little rough.

The biggest challenge was simultaneously building a functional organization and developing a drug at record speed, during a pandemic. While that was happening, I had a two-year-old and a four-year-old at home. The company was also virtual, which was a challenge because you don’t have those closer relationships from talking in the lunch room.

Scientifically, it was even more of a roller coaster. After the emergence of the variant Omicron BA.1, neutralization data for our antibody showed a 100-fold loss in potency. I cried on the floor of my office. Fast forward a month, and clinical data showed it was efficacious against Omicron. There was so much excitement. Then down came the roller coaster again. The subsequent, dominant BA.2 variant completely knocked out our activity. We had spent two years killing ourselves for a drug that would never see the light of day.

But when I look back, it was the most successful failure in my life, because what the team had accomplished — building a company to bring this drug through three, clinical trials in less than two years — was extraordinary.

What advice would you give to others dealing with setbacks?

Zoom out and remember that your scientific career is a long journey, so any individual setback is really just a blip. As long as you’ve learnt something, then it isn’t really a setback because you’ll be smarter the next time around. And over time, if you keep learning from your mistakes and moving forward as a better scientist and person, then you’ll almost certainly be successful in the long term.

How did it feel to leave a company that you co-founded?

I was very conflicted about leaving because I had worked so hard to help build the company. But I had also learnt that being a chief scientific officer wasn’t all that I had imagined it to be, and that I was spending a lot of my time on non-scientific activities, which isn’t where I wanted to be.

Sometimes in life, you’re presented with an offer that you can’t refuse. I had the opportunity to use messenger RNA technology to develop biotherapeutics and specifically antibodies. To me, it’s the obvious next step for the technology. Moderna has published a proof of concept¹ showing that mRNA technology can deliver antibodies safely to humans and hit concentrations that, at least for COVID-19, we know are protective.

I see a lot of opportunity on the delivery side. You can imagine targeting lipid nanoparticles (containing mRNA) to specific tissues, and of course there’s the speed of mRNA technology, which was demonstrated with the COVID-19 vaccine. It would be a total game-changer for how monoclonal antibodies are used, and I guess I’m here to see if I can make that happen.

So far, how are you adjusting to working in a much bigger company?

Bigger companies are notorious for being very slow. Moderna, surprisingly, seems to be completely the opposite. Unlike a smaller company, we have the resources here to get things done very quickly. As Adagio’s chief scientific officer, I spent a lot of time doing administrative duties and talking to investors. I now get to spend almost all of my day thinking and talking about science, and that’s when I’m most happy.

Compared with a small biotech firm, there’s a lot of different departments and programmes, and that can feel overwhelming. I joke that it’s like The Matrix in here. But the company is very focused on the mRNA lipid nanoparticle technology, which connects all the departments together, so you can collaborate even if someone else is doing very different things. That’s been interesting, because I haven’t had the opportunity to work in that way previously.

The antibody drugs developed for COVID-19 eventually lost potency owing to the antigenic drift of the SARS-CoV-2 virus. How can you overcome this for other infectious diseases?

Not all viruses have high antigenic variability, but for SARS-CoV-2, influenza and HIV, I think it will remain a challenge, and those types of antibodies are pretty high risk in the near term, given the rate of viral evolution. The safest strategy for COVID-19 and other variable viruses is to use combinations of antibodies. It would be even better to use combinations of multispecific antibodies that recognize antigenic regions that are under minimal immune pressure, because those are the regions that are least likely to mutate.

With its speed of manufacturing and the ability to deliver many antibodies, including bispecifics which can bind to two types of antigen, mRNA technology could provide real advantages. Those might be particularly relevant in the context of antigenically variable seasonal respiratory viruses. You can imagine a regulatory model in which you update your antibody sequence every year when you know what strain or variant is likely to be dominant.

What advice would you give to graduate students who are thinking of moving into industry?

A lot of people ask me whether or not they should transition after their PhD or do a postdoc. If you’ve done a PhD in a relevant discipline, it would make sense to jump immediately after your PhD rather than spending years in a postdoc. I’d recommend a postdoc for people who are on the fence about leaving academia. Spend some more time trying to work out what makes the most sense for your career. Because once you’re in industry, I think there can be a barrier to going back.