SILVER SPRING, MD. – The majority of a Food and Drug Administration panel on Aug. 28 agreed that data on adalimumab from two studies of patients with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatments, support its approval for this indication.
The FDA’s Gastrointestinal Drugs Advisory Committee voted 15-2 that, based on these studies, the expected benefits of adalimumab, a subcutaneously administered tumor necrosis factor blocker, outweighed its potential risks as a treatment for such patients. While most of the panel agreed that the recommended dose had been shown to be clinically effective, they agreed that the optimal dose for treating ulcerative colitis (UC) had not yet been determined and that postapproval studies addressing optimal dosing, subpopulations of patients who may benefit most from treatment, and long-term safety are needed.
Those voting in favor of approval cited the need for more treatments and the availability of a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects. And although the differences in remission rates between placebo and treatment at 8 weeks and at 1 year were less than 10% – one of the main issues raised by FDA reviewers – most of the panel members agreed that these differences still represented a clinically meaningful benefit. Infliximab (Remicade), an intravenous TNF blocker, is approved for treating UC.
One of the panelists voting in favor of approval, Dr. Andelka LoSavio of the department of gastroenterology and nutrition, Loyola University, Maywood, Ill., said that once adalimumab became available for patients with UC, its use would provide more insight into which subpopulations of patients with UC can benefit most, which was the case with Crohn’s disease and adalimumab. She and other panel members supported the company’s recommendation that if a patient does not respond after 8 weeks of treatment, that treatment be stopped.
The two statisticians on the panel voted no on the risk-benefit question for reasons that included inadequate long-term data, missing data, and uncertainties about the dose.
Since adalimumab – marketed as Humira by Abbott Laboratories – was first approved in 2002 for treating adults with moderately to severely active rheumatoid arthritis, it has been approved for treating moderately to severely active Crohn’s disease, as well as psoriasis, ankylosing spondylitis, and juvenile idiopathic arthritis indications. Based on the same data submitted to the FDA, adalimumab was approved in April 2012 in the European Union for treating adults with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy, according to Abbott.
The recommended dosing schedule for UC is a single 160 mg starting dose, followed by 80 mg on day 15, and then 40 mg every other week starting at day 29, continuing treatment only in people who have responded within the first 8 weeks of treatment.
Abbott filed for approval in January 2011, but the FDA raised questions about whether the appropriate dose had been studied and the strength of the results in the two pivotal trials, including whether the differences in clinical remission rates between placebo and treatment were clinically meaningful.
The two double-blind placebo-controlled phase III studies compared adalimumab to placebo in 1,094 treatment-refractory patients with moderately to severely active UC. In one 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% among those on placebo, a 9.3% difference that was statistically significant.
In the second study, which followed patients for 1 year and included patients who had been treated with infliximab (40%), the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference that was statistically significant. At 52 weeks, the remission rate was 17.3% among those on adalimumab, vs. 8.5% among those on placebo, an 8.8% difference that also was statistically significant. No new safety signals for adalimumab were identified in the trials. If approved, the company plans to start a postmarketing registry of patients with UC treated with adalimumab.
If approved for UC, adalimumab will be the only self-administered biologic therapy available for patients with UC, the company pointed out.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.