Drugmakers Join To Study A Viral Threat

Big pharma drug development collaborations, such as Pfizer and Glaxo­Smith­Kline’s ViiV Healthcare HIV/AIDS joint venture, have become fairly commonplace. The Alzheimer’s disease pact among Pfizer, Johnson & Johnson, and Elan and the diabetes partnership between AstraZeneca and Bristol-Myers Squibb (BMS) are two other examples of two or three big drug companies joining forces against a huge therapeutic target.

In contrast, a unique consortium of five major drug companies is aiming at an extremely small target: progressive multi­focal leukoencephalopathy (PML), a rare and often fatal viral brain infection associated with immunodeficiency that has primarily affected HIV/AIDS patients.

The PML Consortium—composed of Biogen Idec, BMS, Elan, Pfizer, and Roche—is unique in that it is not, at least currently, involved in drug development. Nor was its formation compelled by an interest in treating the disease itself, which occurs in an estimated 3 to 5% of patients with HIV/AIDS. Instead, the group was formed to pool patient information and fund academic research into the basic biology of the disease.

The companies involved are marketing or developing immunosuppressive drugs, both monoclonal antibodies and small molecules, for which PML has emerged as a real or potential side effect. The group is motivated to solve the complex puzzle of PML in order to keep providing drugs for a variety of large therapeutic areas including multiple sclerosis (MS), arthritis, and Crohn’s disease. Oncology and organ-transplant drugs are also at risk.

And the puzzle is a stumper, says Sophie Banzet, head of safety for central nervous system therapies for Roche and chair of the consortium. PML is caused by an apparently benign virus, called John Cunningham virus, present in 50% of all adults, she says. In rare cases of immunodeficiency, the virus mutates and begins a demyelinating neurodegenerative process. It is not known where the virus resides in the body before mutation, Banzet says. And not much attention has been paid to it, given that the disease affects “one or two out of 100,000 people, depending on the underlying disease,” Banzet says. “It’s worse than an orphan disease.”

Roche and Genentech began paying attention to PML, however, after they voluntarily pulled Raptiva, a psoriasis therapy, from the U.S. market in 2009 on the basis of its association with increased risk for PML. This followed the withdrawal of Elan and Biogen Idec’s Tysabri for the same reason in 2004. In both cases, the number of patients diagnosed with PML in trials was small—three in the case of Tysabri and four in the case of Raptiva—and the Food & Drug Administration allowed Tysabri back on the market in 2006. Roche and Genentech have not reintroduced Raptiva.

Roche, Elan, and other companies concerned about PML as a side effect of their drugs were in a difficult position, Banzet says. No reliable diagnostic tool existed for physicians, most of whom are unaware of PML, to determine which patients might be affected. A recently developed blood test indicates only whether a patient carries the virus (C&EN, Feb. 13, page 26). And the drug companies had information on just a small number of patients. None of the companies was equipped to develop any kind of diagnostic guideline on its own.

“Some companies decided that in order to mitigate the risk, there is value in putting together data and resources and expertise,” Banzet says. Five companies eventually formed the consortium “to try to put together everything we can to understand the disease, to predict the disease. Basically, it is around sharing resources.” The group is established as a legal entity in which competitors share data in a noncommercial venture. “This, to me, is unique,” she says.

Nicki Vasquez, vice president of program and portfolio management at Elan, says the consortium started out as a dialogue among corporate safety and research groups. “We said, ‘We have this serious opportunistic infection that can be linked with immuno­modulatory drugs. We are all looking at this problem. How can we get together and make some headway?’ ”

The focus, Vasquez says, is on developing a means of controlling PML as a side effect of a range of immunotherapies. “The issue for patients as well as drug companies is that PML raises the specter of derailing a therapeutic that might otherwise be effective,” she says. “If we stop the development of a particular drug because it might result in PML as an adverse event, we may be hurting patients by blocking access to a potentially beneficial drug.”

It was unlikely that industry would band together to cure PML rather than prevent it as a side effect for drugs, Vasquez acknowledges. “Companies aren’t going to be particularly motivated to find cures for PML per se,” she says, “even with the increased frequency with immunomodulatory drugs. It is not on the radar of antiviral companies because it really is extremely rare.”

The group, which formed in 2009, “hit its stride” last year, Vasquez says, awarding grants to laboratories at Harvard University, the University of Kentucky, Pennsylvania State University, and Penn State College of Medicine. A call for proposals for a second round of funding courts researchers internationally, she says, with the same offer as in the first round—two-year, $300,000 grants. The PML Consortium has a scientific advisory board made up of academic researchers, and the consortium liaises with regulatory authorities, according to Vasquez. The European Medicines Agency has a representative who attends consortium meetings.

In addition to pooling data, the consortium members share best practices for acquisition, shipping, storage, and sharing of biological samples. The group plans to host a conference in 2013.

David B. Clifford, a neurologist in clinical neuropharmacology at Washington University in St. Louis, chairs the PML Consortium’s scientific advisory board. “I have worked in the development of AIDS therapies for years,” he says, “and I have seen nothing like this group in that field. I guess it was surprising to me that companies would band together to share research efforts and data about patients who took their drugs.” He emphasizes that the challenge of PML is also unique. The biological mechanism of the virus, for which there is no animal model, is a mystery.

“There are all these monoclonal anti-inflammatory drugs that are very exciting possibilities to move therapy forward for MS, arthritis, inflammatory bowel syndrome—drugs for big, big markets,” Clifford says. “And FDA is sweating every one of these things for the risk of PML. It has become a common industry problem.”

Although the PML Consortium has no commercial objective, “in the future we would like to support the development of drugs to treat PML,” Vasquez says. “But this is not a commercial collaboration in the sense of what you see with drug companies where they band together to pool resources for commercial purposes. Our intent is not commercial. Because PML is so rare, we see this as the only real way to get our heads around it and really advance the field.”

For now, the consortium is a group effort to navigate uncharted biology around the John Cunningham virus. That should keep it busy, notes Clifford, who is skeptical that any commercial drug company would bear down on developing a therapy for the disease itself. “This is not something that will result in a blockbuster drug,” he says.