FDA Advisory Panel Recommends Approval of Tysabri

The FDA in February allowed Biogen Idec to resume using natalizumab (Tysabri) in clinical trials for patients with relapsing-remitting multiple sclerosis (MS). If the FDA follows the recommendation of its Peripheral and Central Nervous System Drugs Advisory Committee, the agency also will allow Biogen, and its partner Elan Corporation, to make the drug available for patients with relapsing MS, regardless of whether they are participants in clinical trials.Biogen and Elan voluntarily removed natalizumab from the market on February 28 last year, just months after the FDA granted approval to market the drug in October 2004. The companies took the action after 2 cases of progressive multifocal leukoencephalopathy (PML), one of them fatal, were confirmed in patients treated with natalizumab. A later fatal case of PML surfaced among a group of patients receiving the drug for the treatment of Crohn disease.Pressure to bring natalizumab back has come from patients who believe that the drug has helped them enormously and from neurologists impressed with the superior improvements in relapse rates and disease progression. After the PML case reports, Biogen set in motion a safety review to see whether these were isolated reports.On March 6 and 7, the FDA advisory committee met to evaluate the safety concerns and decide whether it would recommend returning natalizumab to the market. Even before the meetings, FDA staff wrote in briefing documents: "Primarily because of the risk of PML, which is not well quantified, it is unclear for which patients the risk-benefit profile would be acceptable."After 2 days of hearings, on March 8, the 12-member panel unanimously voted in favor of approving natalizumab as a treatment for MS. The panel had a split decision, however, in its recommendation for a first-line indication: 5 of the 12 members advised against granting that recommendation. The FDA's final decision about re-entry into the market and details of post-marketing surveillance were expected by June. It would be unusual for the agency not to follow the spirit of the panel's recommendations.Biogen and Elan have offered to manage a patient registry of the first 5000 patients taking the drug, who would be followed up for the next 2 years. "This would be a very good risk management strategy," said Bruce Cree, MD, PhD, assistant professor of neurology and clinical research at the University of California, San Francisco. "If within the next 2 years we find that the chance [of PML] is 0 to 1 in 1000, this will be very good news, but if we find that the drug increases the risk for PML, that will be another story."QUESTIONS TO ADDRESSYet some neurologists expressed skepticism about how the registry would be organized and monitored. Would participation in the registry be a mandatory requirement or voluntary? Who would run it? How would independence be maintained?Industry-not a public regulator-seems most likely to establish and maintain the registry. Leslie Weiner, MD, professor of neurology and molecular microbiology, and chair of neurology, University of Southern California's Keck School of Medicine, voiced concerns about how the registry would be managed. "No matter who funds the registry, the company can't control it. The registry should be managed by an independent committee and not paid consultants."Lloyd H. Kasper, MD, professor of neurology, microbiology, and immunology, Dartmouth Hitchcock Medical Center in Lebanon, NH, called the 2-year follow-up "insufficient." "It takes a long time to pick up some adverse effects," he explained. "It is potentially a very good drug that could make a substantial difference, but at this point, I think that there are a lot of critical issues to be addressed before the drug is administered in a haphazard way." Besides PML, Kasper raised concerns about the emergence of opportunistic infections such as pneumonia, hepatitis, and toxoplasmosis, which are commonly seen in patients with AIDS.Another issue on which Kasper said he could only speculate is the risk for a rebound effect when patients stop taking the drug and while T-cells continue to be activated. Although no evidence of a rebound effect has been identified with natalizumab, such a risk has been seen with other drugs. Kasper explained that the risk for development of solid tumors would not be depicted accurately using only 2-year data."I would have liked to see a broader population of patients followed over a more prolonged period of time," commented Pat Coyle, MD, acting director of neurology, and director of the Multiple Sclerosis Comprehensive Care Center, State University of New York at Stony Brook. "It's not as if we have no other treatment." Coyle said that she is not likely to use natalizumab in treatment-naive patients until longer-term safety data become available. "I just can't get over the PML, and it's not like you have an untreatable disease."Some neurologists cautioned that the true risk for PML is unknown. "It would be nice to know what the risk of PML is, but 1 in 1000 in 2 years is only a guess," said Hillel Panitch, MD, professor of neurology and clinical trials, University of Vermont College of Medicine. Weiner also questioned whether the 1 in 1000 statistic is accurate. "It could be more; it could be less," he said. "What I would like to see are numbers in the hundreds of thousands."SUPERB CLINICAL OUTCOMESEven though neurologists have different opinions about the benefit-risk ratio and the long-term patient outcomes, many have been quick to state that natalizumab has been associated with better outcomes than any other conventionally used drug for treatment of MS. "The 68% reduction in relapse [rate] is very impressive," remarked Coyle. She called the data from the phase 3 monotherapy trial "extremely strong," but the study data on combination-therapy are not particularly compelling.Publication of clinical trials and safety evaluation data in the March 2 New England Journal of Medicine1-3 less than a week before the FDA panel met undoubtedly shored up Biogen's and Elan's case. A spate of commentaries also analyzed the controversy surrounding natalizumab.4-6The phase 3 clinical trial1 led by Chris Polman, MD, Free University of Amsterdam, randomly assigned 942 patients to receive an intravenous infusion of either the active drug at a dose of 300 mg (n = 627) or placebo (n = 315) every 4 weeks. Both groups were treated for more than 2 years. Among patients treated with the active drug, the rate of clinical relapse was diminished by 68% and the number of new or enhancing MRI lesions was reduced by 83%. This was a striking improvement over other drugs for treatment of MS, which have been shown to only reduce relapses by one third. Disease progression also was much slower in patients treated with natalizumab; disease progressed in 17% of patients receiving natalizumab versus 29% of patients receiving placebo.In the 2-year combination therapy trial,2 patients who had experienced at least 1 relapse were randomly assigned to receive interferon beta-1a (Avonex, Biogen) monotherapy or interferon beta-1a plus natalizumab. The annualized rate of relapse was 34% among patients on dual treatment, compared with 75% among patients receiving interferon beta-1a alone.The data in the articles were not really new, according to many neurologists. Publishing the results was more for the public record. "It's not as if the data weren't already known," observed Panitch, because the information had been presented at meetings.Whether Tysabri will catch on as the "next big drug" for multiple sclerosis remains unclear. "Let's not forget that it's a very effective drug in patients with greater than 9 lesions, relapsing-remitting multiple sclerosis, patients who are not over age 40, who are very ambulatory, and it works better in women than in men," said Daniel Wynn, MD, director of clinical research and co-director of Consultants in Neurology in Multiple Sclerosis, Northbrook, IL. "As neurologists caring for patients with MS, we need to have a realistic understanding and tremendous empathy for our patients and not scare them. The majority of patients do very well."As for using the drug as a first-line therapy, neurologists said they were unlikely to do so until more evidence is presented. Cree viewed it this way: "How we do in the first 2 years will largely determine how we will use it."Laura Newman, MA, is a freelance science writer in New York City.REFERENCES1. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899-910.2. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911-923.3. Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924-933.4. Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med. 2006;354:965-967.5. Chaudhuri A. Lessons for clinical trials from natalizumab in multiple sclerosis. BMJ. 2006;332:416-419.6. Langer-Gould A, Steinman L. What went wrong in the natalizumab trials? Lancet. 2006;367:708-710.