FDA advisory committee considers Humira as potential treatment for ulcerative colitis

The FDA’s Gastrointestinal Drugs Advisory Committee met today to discuss the approval of Abbott Laboratories’ Humira as a treatment for ulcerative colitis.

The drug currently is approved to treat Crohn’s disease and other inflammatory conditions. Abbott proposed an expanded indication for Humira (adalimumab) to include treatment for moderate-to-severe ulcerative colitis in adult patients who have been unresponsive to standard therapy, and presented results of two randomized, placebo-controlled trials as evidence of Humira’s efficacy. The proposed dosage, to be administered subcutaneously, includes four 40-mg injections on the first day or two 40-mg doses on the first and second day, followed by 80 mg after 2 weeks and a biweekly 40-mg maintenance dose, which can be escalated to a weekly 40-mg dose if patients become nonresponsive.

One presented study indicated a remission rate of 18.5% in treated patients compared with 9.2% among those receiving placebo after 8 weeks (P=.031), while the second study indicated remission rates of 16.5% among treated patients and 9.3% among placebo patients after 8 weeks (P=.019), 17.3% and 8.5%, respectively, after 52 weeks (P=.004), and 8.5% and 4.1%, respectively at both 8 and 52 weeks (P=.047).

When asked whether the proposed dosage had been sufficiently established as optimal, 14 committee members voted no; three voted yes. Most acknowledged that the dose demonstrated some clinical effectiveness, but that the data suggested that a higher dose might be more beneficial, and that additional dose-ranging studies should be considered.

The majority of the committee agreed and voted that the remission rates indicated a clinically meaningful benefit to treatment after 8 weeks (15-1, with one abstention), after 52 weeks (15-1, with one abstention) and at both 8 and 52 weeks (10-6, with one abstention). While many members noted that the differences in rates between treated and placebo patients were relatively small, several also suggested that the limited number of existing treatments for UC was an important consideration.

“Although the magnitude of effect is certainly modest,” committee member Michael D. Rice, MD, inpatient medical director, Gastroenterology/Hepatology, University of Michigan Medical Center in Ann Arbor, Mich., said, “having the option of another steroid-sparing agent, and recognizing the irreversibility of colectomy and that many of our patients have exhausted their options, I believe makes this clinically meaningful.”

Members who voted no or abstained cited a lack of sufficient data on durability of response and safety. Of particular concern was the loss of a large portion of patients to follow-up after 8 weeks, and the long-term possibility of malignancy and other serious adverse events.

When asked whether the benefits of the treatment outweighed the risks, 15 members voted yes and 2 voted no. Most members again suggested that additional studies should be performed to establish the optimal dose and the most responsive population, and to better outline the effect of the treatment in patients with previous anti-TNF therapy. Most members voted that additional study, however, was not necessary prior to approval of the new indication (14-2, with one abstention).

“This is an indication [with] 700,000 patients; this is not an orphan indication,” member Thomas Fleming, PhD, professor of biostatistics at University of Washington, Seattle, who voted for additional pre-approval study, said. “We have a responsibility not to just provide a choice, but an informed choice. My sense is there are important additional insights needed in terms of efficacy and dose, and dose in key populations.”