Adalimumab and Natalizumab Induce Remission in Some Crohn's Disease Patients

Karla Harby

May 20, 2004

May 20, 2004 (New Orleans) — Two fully human monoclonal antibodies have been found to induce remission in some patients with active Crohn's disease in two separate, randomized, double-blind, placebo-controlled trials described here during Digestive Disease Week.

One agent, adalimumab, is already approved for the treatment of rheumatoid arthritis by the U.S. Food and Drug Administration. The data reported here for the other agent, natalizumab, were results from a phase III trial.

In the adalimumab study, investigators randomly assigned 300 patients with a Crohn's disease activity index (CDAI) of 220 to 450 to receive subcutaneous injections of either placebo or adalimumab. The injections were administered according to one of four different regimens (n = 75 in each subgroup). The regimens were 160 mg at the study outset, decreasing to 80 mg at two weeks; 80 mg at outset, decreasing to 40 mg at two weeks; 40 mg at outset, decreasing to 20 mg at two weeks; or placebo at outset, and placebo at two weeks. The researchers assessed the results after four weeks, with the primary end point being induction of clinical remission (CDAI < 150).

For the lowest dose group, 40 mg followed by 20 mg, the proportion of patients who experienced clinical remission (18%) was not statistically different from the results for those in the placebo group (12%). For the next highest dose group, 80 mg followed by 40 mg, 24% of patients experienced remission, but this too was not statistically significant. In the highest dose group, 160 mg followed by 80 mg, 36% of patients experienced remission, which was significantly different from placebo (P < .05). When the investigators combined the findings for the highest and next-highest dose group (n = 150), they concluded that 30% of patients experienced remission of their disease (P = .004).

"Adalimumab is well-tolerated," said lead investigator Steven B. Hanauer, MD, from the University of Chicago Pritzker School of Medicine in Illinois. "We saw injection-site reactions in 8% to 15% of patients at the highest dose," and no other adverse effects. Patients can also self-administer this agent, he said.

In the natalizumab study, researchers sought to determine whether response and remission induced by natalizumab could be maintained for six months. After receiving three infusions of natalizumab, 339 adults whose Crohn's disease had responded to the new agent were then randomized again to receive either natalizumab at 300 mg (n = 168) or placebo (n = 171) in up to 12 monthly infusions.

The researchers found that after six months, 103 (61%) of 168 subjects continued to experience a 70-point or greater reduction in their baseline CDAI score compared with 49 (29%) of 170 for those receiving placebo (P < .001). Of those patients who had experienced remission during the induction phase — defined as a CDAI score of less than 150 — 57 (44%) of 130 patients experienced maintenance of their remission compared with 31 (26%) of 120 of those in the placebo group (P = .003).

The researchers also found that 37 of the 67 subjects who were also receiving steroids during the induction phase, and who were randomized to natalizumab, were able to stop taking steroids after re-randomization. This was statistically different from the placebo group, in which 19 of 76 patients were able to stop receiving steroids (P < .001). The researchers did not observe notable adverse effects among the various groups.

James D. Lewis, MD, from the Inflammatory Bowel Disease (IBD) Program at the University of Pennsylvania in Philadelphia, declined to make comparisons among any agents under investigation, or to speculate which will turn out to be the most clinically useful. "This is exciting, it's the culmination of years and years of research, and it is changing the way we think about inflammation," he said. "But it is way too early to say which one will have the biggest impact."

In an interview he told Medscape that adalimumab was a logical choice to investigate. "Much of the therapeutic armamentarium we have in IBD mimics what has been done in rheumatoid arthritis," he said. "Sulfasalazine and steroids continue to be used in rheumatoid arthritis." The partly murine chimera infliximab, which is widely used in Crohn's, is effective, he said, but the hope is that newer monoclonals that are fully human will cause fewer antibody reactions. "The long-term safety of these new agents still has to be determined," he added.

The adalimumab study was funded by Abbott Laboratories, which markets the drug under the trade name Humira. Dr. Hanauer has served as a consultant to Abbott. The natalizumab study was funded by Biogen Idec, Inc., which distributes the drug under the trade name Antegren.

DDW 2004: Abstracts 900030 and 900085. Presented May 19, 2004.

Reviewed by Gary D. Vogin, MD

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