Abstract
BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD. METHODS: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes. RESULTS: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE). CONCLUSION: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy. CLINICAL TRIAL REGISTRATION NUMBERS: NCT03440372, NCT03440385, NCT03464097, NCT03467958.