The up-and-down story of Tysabri (natalizumab) as a treatment for Crohn's disease took another downturn when a European group for the second time recommended rejecting marketing authorization requested by Elan Corp. plc, of Dublin, Ireland, and Biogen Idec, of Cambridge, Mass.
The Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), again said no to the marketing authorization for natalizumab as a treatment for Crohn's disease. That decision came on the companies' appeal following a previous negative opinion adopted by the CHMP earlier in 2007.
The second negative opinion now sends the issue to the European Commission, which determines marketing authorizations in the European Union. The commission usually follows CHMP recommendation, and the companies said they expect to hear from the EC during the first quarter of 2008.
In August, the FDA's Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 12-3 in favor of Tysabri's use in Crohn's disease patients who have failed or cannot tolerate existing therapies. The chief issue before the panel was whether Tysabri, a recombinant anti-alpha4 integrin monoclonal antibody, had an appropriate risk/benefit profile for the CD population.
The chief issue before the panel was whether Tysabri, a recombinant anti-alpha4 integrin monoclonal antibody, had an appropriate risk/benefit profile for the CD population.
The drug was pulled from the market in February 2005, only a few months after gaining approval for multiple sclerosis, and ongoing trials in MS and CD were halted after two patients contracted progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection. Further analysis and review by the agency led to the drug's return to the market, with limited use in MS patients.
As part of its recommendation, the FDA joint advisory panel suggested that the companies conduct additional analyses to determine the CD population most inclined to benefit from Tysabri treatment and look at longer-term safety data. Panel members also stated the need for strict postmarketing surveillance.
Biogen's and Elan's marketing application for Tysabri in CD was based on data from two Phase III induction studies and one maintenance study.
Though the first Phase III study failed to show a statistically significant difference in clinical response rates, defined as CDAI (Crohn's Disease Activity Index) reduction of 70 or more from baseline, a subsequent subset analysis demonstrated that patients with elevated CRP had a higher clinical response rate compared to placebo.
The second study, which specifically enrolled patients with elevated CRP, yielded positive results, showing response rates of 48 percent compared to 32 percent for patients in the placebo arm.