ROCKVILLE, Md., Jan. 14 -- The FDA today approved natalizumab (Tysabri), the star-crossed multiple sclerosis agent, for refractory moderate-to-severe Crohn's disease showing evidence of inflammation.
The agency's action followed an advisory committee's recommendation for approval subject to "strict post-marketing surveillance."
Natalizumab was approved for relapsing MS in November 2004. But in February 2005 it was withdrawn by its maker, Biogen Idec, and distributor, Elan, after three patients in clinical trials developed progressive multifocal leukoencephalopathy, a rare viral infection of the brain. Two of the cases were fatal. At the same time, the FDA stopped clinical trials of the drug.
The drug was returned to the market in June 2006 under a strict risk management program. There were no cases of multifocal leukoencephalopathy reported in the Crohn's trials.
The approval requires that everyone involved in using natalizumab in Crohn's disease -- patients, prescribing physicians, pharmacies, and infusion centers -- participate in a special educational program called TOUCH. MS patients must also participate in their own TOUCH program.
For Crohn's, the program involves strict monitoring guidelines, including an extensive education program on natalizumab's risks.
The drug's prescribing information includes a boxed warning about the risk of progressive multifocal leukoencephalopathy. Natalizumab is a humanized monoclonal antibody that targets alpha-4 integrin, an adhesion molecule involved in inflammatory processes.
Other adverse effects in clinical trials include headache, fatigue, infusion reactions, urinary tract infections, joint and limb pain, rash, respiratory tract infections, and nausea.
The drug's manufacturers, Elan Corp. and Biogen Idec, have also reported cases of clinically significant liver injury in the post-marketing setting.
Concerns about progressive multifocal leukoencephalopathy have so far kept the drug off the European market for Crohn's. In July and again in November of last year, medical advisory panels in the European Union recommended against approval for Crohn's.
The companies said the European Commission is still considering their application. They expect a decision by the end of March.
Conventional therapies for Crohn's disease include corticosteroids and tumor necrosis factor inhibitors such as infliximab (Remicade) and adalimumab (Humira).
The FDA's approval was based primarily on two clinical studies, ENCORE and ENACT-2.
In the former, 12 weeks of natalizumab led to responses in 60% of patients, compared with 44% of placebo-treated patients. Forty-eight percent of natalizumab patients sustained responses through week 12, compared with 32% of placebo-treated patients (P<0.005 for both), according to Elan and Biogen Idec.
ENACT-2 showed that an additional year of natalizumab led to sustained response and remission among patients with an initial response to the drug after three months. There were sustained responses during ENACT-2 for 61% of patients treated with natalizumab at every visit through an additional six months of therapy, compared with 29% for placebo.
Among patients on steroids and in whom a clinical response was achieved, approximately two-thirds were able to discontinue steroids within 10 weeks of beginning to taper steroids, the companies said.
At the advisory committee hearing, FDA staff analysts questioned the efficacy of the drug, noting that clinical trial data suggested that natalizumab added no benefit beyond currently available Crohn's treatments.
Nonetheless, advisory panel chair David Sachar, M.D., of Mount Sinai in New York, was unambiguous in his support of natalizumab, pointing out that fewer than 30% of Crohn's disease patients achieve adequate control with available drugs.
Moreover, Dr. Sachar said, testimony from Crohn's patients and treating physicians along with quantitative quality-of-life data and objective risk assessment data provided evidence of benefits "that I think transcend simple P values."