COPENHAGEN — Maintenance therapy with natalizumab in patients with Crohn's disease led to improved quality of life compared with placebo, and normalized quality of life measures in a study with 339 patients.
“We're trying to normalize” patients with Crohn's disease, Brian G. Feagan, M.D., said at the 13th United European Gastroenterology Week. Maintenance therapy with natalizumab produced quality of life scores that were similar to scores measured in normal populations.
Dr. Feagan presented findings from a secondary analysis of data collected in the pivotal, phase III trial for natalizumab in patients with active Crohn's disease—the Efficacy of Natalizumab as Active Crohn's Therapy (ENACT) trial. This study had an induction phase, ENACT-1, with 905 patients randomized to natalizumab or placebo, and a maintenance phase, ENACT-2, that included the 339 patients who had a response to the drug in ENACT-1.
The studies were sponsored by Elan Pharmaceuticals and Biogen Idec, the two companies that jointly market natalizumab (Tysabri). Dr. Feagan has served as a consultant to Elan Pharmaceuticals.
The results from ENACT-1 failed to show an advantage for natalizumab over placebo for producing clinical responses, but the ENACT-2 data showed that continued treatment with 300 mg natalizumab once every 4 weeks led to a 61% rate of sustained responses during 36 weeks of follow-up, significantly higher than the 28% rate of sustained responses in the placebo group. These primary end point results were reported in November (N. Engl. J. Med. 2005;353:1912–25).
Natalizumab was approved by the Food and Drug Administration in late 2004 for treating multiple sclerosis, and then was withdrawn from the U.S. market in February 2005 following reports that associated its use with cases of multifocal leukoencephalopathy.
In September, the companies submitted a supplemental application to the FDA in a move to resume selling the drug for treating multiple sclerosis.
Natalizumab is a humanized, IgG monoclonal antibody that binds α4 integrin and thereby blocks the adhesion of leukocytes to the gut and the migration of these cells into the gut.
The quality of life analysis led by Dr. Feagan used data collected on the inflammatory bowel disease questionnaire (IBDQ) and the Short Form-36 (SF-36).
Starting with the first maintenance dose, patients receiving natalizumab had significantly higher IBDQ scores than did those treated with placebo. After 1 year of treatment, patients who took natalizumab had an average score of 181, compared with an average score of 157 in the placebo group, a statistically significant difference, said Dr. Feagan, a professor of medicine at the University of Western Ontario, London.
After 1 year, patients on maintenance therapy with natalizumab also showed significantly better scores than did placebo patients for all of the physical and mental component scores of the SF-36, including bodily pain, social function, and mental health.
In addition, the analysis showed no significant differences between individual component scores for patients in the active-treatment arm and scores from an age-adjusted sample of normal Americans, except for the categories of vitality and general health.
In contrast, the scores of patients in the placebo arm were consistently and significantly lower than scores of the normal, general population, Dr. Feagan said.
Safety Issues Call for Selective Use
Despite natalizumab's safety issues, the drug remains a viable option for treating selected patients with Crohn's disease, Dr. Feagan said at the meeting.
After the drug was withdrawn from the market, the two companies that comarket it as Tysabri offered an extensive safety evaluation to the more than 3,500 patients who had participated in the drug's trials. This offer was accepted by about 90% of all patients in the multiple sclerosis, rheumatoid arthritis, and Crohn's disease trials—a total of more than 3,000 patients—said a spokeswoman for Biogen Idec, one of the two companies jointly developing and marketing natalizumab.
The investigation turned up no additional cases of multifocal leukoencephalopathy beyond the three patients that had been reported previously, noted Biogen Idec and Elan Pharmaceuticals in written statements.
“That's good news,” Dr. Feagan said. “What it comes down to is, will we, as physicians, accept this rare but serious and often fatal complication? I think we will pick our spots, and focus on patients who fail other treatments, at least until there are more safety data. Do I think that the drug will come back for Crohn's disease? Yes I do,” he said.
In an editorial that accompanied the published report of the primary efficacy and safety data for natalizumab in 905 patients with Crohn's disease, Daniel K. Podolsky, M.D., wrote that natalizumab treatment may interfere with immune control of the endemic JC virus, and that this may be the trigger for progressive, multifocal leukoencephalopathy (N. Engl. J. Med. 2005;353:1965–8).