The FDA’s Gastrointestinal Drugs Advisory Committee voted Thursday unanimously in favor of including an optional high-dose regimen for tofacitinib (Xeljanz) for induction and maintenance in specific ulcerative colitis patient subpopulations.
The committee was not asked specifically to vote on the more general question of whether tofacitinib should be approved for ulcerative colitis, an indication that drugmaker Pfizer is seeking. But the 15-0 vote on dosing didn’t suggest opposition to the idea.
Tofacitinib is currently approved for use in rheumatoid arthritis and psoriatic arthritis, in a dosing regimen of 5 mg twice daily. For ulcerative colitis, briefing documents from FDA’s technical staff stated that there is a high unmet need for patients with this lifelong disease who do not respond adequately to the available approved treatment and have persistent moderate to severe disease.
“The availability of an additional agent with a different mechanism of action would provide needed mechanistic diversity for a disease involving the adaptive immune system characterized by multifaceted pathogenesis and shortened drug survival (especially with lack of durable efficacy of current [tumor necrosis factor] blockers),” according to the briefing information.
Pfizer’s two phase III clinical trials included both induction and maintenance phases, with 8 weeks of induction using a 10-mg twice daily dose and 44 additional weeks of maintenance with 5 mg or 10 mg twice daily doses. The two studies included 1,139 patients.
Based on the results of those studies, Pfizer requested a higher dose for for adults with moderately to severely active disease who have had an inadequate response, lost response, or were unable to tolerate tumor necrosis factor blocker therapy. For this patient subpopulation, the company has requested that the labeling include an induction regimen of 10 mg twice daily for 8 weeks, followed by an optional 10 mg twice daily for maintenance.
The committee’s unanimous vote in favor of the high dose came despite some concerns among members about infections and particularly about the possibility of herpes zoster developing with the higher dose. They noted that this is a “desperate population,” and that the benefits seemed greater than the risks.
The proposed dosing also included an option for patients who do not respond adequately with 8 weeks of 10 mg twice daily induction to have an additional 8 weeks of the higher dose, because in the clinical trials, 50% of those who failed to respond by 8 weeks did so after the additional higher dose induction period.
The panel also voted 15 to 0 in favor of that option, again stressing the need for flexibility and reliance on clinical judgment and education of both physicians and patients about the potential risks. Other strategies for mitigating risks could include efforts to encourage the use of the new shingles vaccine, they noted.
But when asked whether Pfizer should conduct a postmarketing study to compare the different maintenance doses, the panel split with seven members voting yes and eight saying no.
The FDA is not bound to follow its advisory committees’ recommendations but it frequently does.