Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis
William J Sandborn1, Brian G Feagan1, Geert D'Haens1
1From the University of California San Diego, La Jolla (W.J.S.); Western University, London, ON, Canada (B.G.F.); the Inflammatory Bowel Disease Center, Academic Medical Center, Amsterdam (G.D.); the Center for Crohn's Disease and Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta (D.C.W.); the Division of Gastroenterology, University Hospital Medical Center Bežanijska Kosa, Belgrade, Serbia (I.J.); the Feinberg School of Medicine, Chicago (S.B.H.); APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland (S.G.); Bristol Myers Squibb, Princeton, NJ (A.P., S.Y.H., J.H.L., L.C., D.C., K.U.); the Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (J.-F.C.); Yale School of Medicine, New Haven, and the Veterans Affairs Connecticut Healthcare System, West Haven - both in Connecticut (L.L.); and IRCCS Humanitas Research Hospital and University Vita-Salute San Raffaele, Milan (S.D.).
Background:
Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease.
Methods:
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed.
Results:
In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod.
Conclusions:
Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).
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