Lymphoma market turf war imminent, pending Bexxar approval

from Nature Biotechnology

Ken Garber

Ann Arbor, MI

The field of cancer radioimmunotherapy received a big boost in December when a US Food and Drug Administration (FDA; Rockville, MD) advisory committee certified Corixa's (Seattle, WA) Bexxar as effective against relapsed non-Hodgkin's lymphoma. The FDA is now expected to formally approve Bexxar for marketing before a May 2 deadline. Now it appears that Corixa and IDEC Pharmaceuticals (San Diego, CA), already embroiled in patent litigation over IDEC's competing antibody Zevalin (Nat. Biotechnol. 19, 1005, 2001), will battle for dominance of the new but still uncertain market for cancer radioimmunotherapeutics.

The December 17 action of the FDA's Oncologic Drugs Advisory Committee ended a long period of frustration for Corixa and, earlier, Coulter Pharmaceuticals (S. San Francisco, CA). (Corixa acquired Coulter, and with it Bexxar, in December 2000.) Bexxar, a mouse monoclonal antibody attached to iodine-131, was first tested in patients in 1990, and has consistently shown impressive results in clinical trials. But Coulter, and then Corixa, suffered a series of regulatory setbacks after Coulter submitted its biologic license application in June 1999 (Nat. Biotechnol. 17, 940, 1999) primarily because data submitted was deemed insufficient to prove safety and clinical benefit. The delays allowed IDEC Pharmaceuticals' Zevalin, a similar antibody radiolabled with yttrium, to reach market first, in March 2001.

There is a lot at stake for both companies. Lymphoma, the fifth most common cancer, is hardly a niche market: 300,000 people in the United States alone have the disease, about 40% of whom suffer from the largely incurable "low-grade" form. IDEC's Rituxan, a nonradiolabeled or "cold" monoclonal antibody introduced in 1998, surpassed $1 billion in sales in 2002 and its use is expanding quickly. But Rituxan does not cure low-grade lymphoma, and both Zevalin and Bexxar have been shown to work when Rituxan fails.

Rituxan, Zevalin, and Bexxar all target the same CD20 antigen on B cells. In clinical trials, more patients responded to the new radiolabeled agents, with about 20% of heavily pretreated, chemotherapy-resistant patients surviving three years or more after a single Bexxar treatment. Bexxar is "the most active agent that I have seen in patients with multiply relapsed or refractory low-grade B cell non-Hodgkin's lymphoma," says prominent lymphoma specialist James Armitage, dean of the University of Nebraska (Omaha) medical school, at the December meeting. While toxicity in the form of myelosuppression, secondary leukemia, and myelodysplastic syndrome—a fatal destruction of the bone marrow—are serious concerns, so far Bexxar and Zevalin have proven safe for the vast majority of patients. "These drugs can make a major contribution to the treatment of patients with non-Hodgkin's lymphoma," says Bruce Cheson, head of hematology at the Lombardi Cancer Center (Washington, DC).

However, so far, that hasn't happened with Zevalin. Sales have been disappointing, totaling only $5 million in the third quarter of 2001 and a projected $9 million in the fourth quarter, according to SG Cowen (New York) biotech analyst Phil Nadeau. These numbers are a far cry from the $70 million that Salomon Smith Barney (New York) analyst Elise Wang originally forecast for Zevalin in 2002.

One reason is that Medicare, the US government insurance program for seniors that the private insurance industry uses as a bellwether, did not begin to reimburse hospitals for Zevalin treatment until October 2002.

Other problems may prove more intractable. Administering Zevalin and Bexxar requires the collaboration of a nuclear medicine physician in addition to a medical oncologist, so smaller medical centers can't yet provide these drugs. "This is not something you can do in your office," Cheson points out. Patients must have minimal cancer in the bone marrow to avoid the drug's wiping out their immune systems, so many patients don't qualify. Given these obstacles, Nadeau predicts that Zevalin sales will only attain $170 million by 2006, with Bexxar sales reaching $100 million. To surpass these modest numbers, "they'd have to be moved up in the treatment paradigm so they're not given to quite as sick patients," Nadeau says.

In spite of these limitations, radioimmunotherapy's backers say it has great long-term potential, based on its proven effectiveness. "There could be a hill to climb before [any] particular institution gets its feet wet with this," says Bexxar co-inventor Mark Kaminski, a hematologist at the University of Michigan (Ann Arbor). "But I think once they do, and they get good results, I think it'll be difficult not to do this therapy."

Despite the many dramatic responses seen in clinical trials, most Zevalin and Bexxar patients still relapse and die. "Since neither of them appears to cure a significant proportion of patients, we should learn how to increase their activity, reduce their toxicity, and spend more time on improving these two drugs," says Cheson. Some possibilities: repeat use, higher doses along with stem-cell transplants, and combination use with chemotherapy. Corixa CEO Steve Gillis, in a conference call, said the company eventually hopes to expand Bexxar use to the so-called "aggressive" lymphomas—a much bigger challenge, since these cancers are often curable using chemotherapy. Clinical trials are also underway to test Bexxar and Zevalin in combination with chemotherapy as front-line treatment. Paul Latta, an analyst at McAdams Wright Ragen (Seattle), thinks the eventual market for lymphoma radioimmunotherapy, if all disease indications are achieved, could reach $1 billion a year.

In the short term, SG Cowen's Nadeau gives the sales edge to Zevalin because of its head start and because it's slightly easier to give to patients, since it emits no potentially harmful gamma radiation. Also, dosing does not have to be calculated based on the drug's biodistribution. On the other hand, such precise dosimetry (Zevalin dosing depends just on body weight) will be attractive to some oncologists. Ultimately "it's going to depend on personal biases," says Cheson. "They're both very active, very important drugs [and] the toxicities do not appear to be...meaningfully different." It's possible, because of the longer path length of Zevalin's beta emissions, that Zevalin will prove more effective against larger tumors while Bexxar will be a better choice for smaller tumors, although no evidence yet exists for any clinical difference. "The marketplace will determine what happens in the end," says Cheson.

Competing products might be an additional factor: several other anti-lymphoma antibodies are in the pipeline. Immunomedics (Morris Plains, NJ), in collaboration with Amgen (Thousand Oaks, CA), for instance, has an anti-CD22 antibody in phase III trials for lymphoma, with Immunomedics' yttrium-labeled version in phase I/II. IDEC is finishing a phase I lymphoma trial of its anti-CD80 antibody, while Human Genome Sciences (Rockville, MD) is about to begin clinical trials of its iodine- and yttrium-labeled antibody against the LymphoRad receptor. And Genmab (Copenhagen, Denmark) has a second-generation anti-CD20 Mab in advanced preclinical development. Lymphoma is relatively easy to target with antibodies because it's highly vascular, allowing easy antibody penetration, and because B cells have antigens that allow fairly specific tumor targeting. IDEC and Corixa must seize their opportunity while they can.