Ozanimod as a novel oral small molecule therapy for the treatment of Crohn's disease: The YELLOWSTONE clinical trial program.

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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Brian G. Feagan has consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, enGene, Ferring Pharma, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GSK, Ironwood, Janssen, Johnson & Johnson, Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB, and is a director at Robarts Clinical Trials. Stefan Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. Anita Afzali has served as a consultant for AbbVie, Takeda, Janssen, Pfizer, Bristol Myers Squibb, Eli Lilly, Gilead, TLL Pharmaceuticals, Arena Pharmaceuticals, and DiaSorin, and has received speaker fees from AbbVie, Takeda, Janssen, Pfizer, and Bristol Myers Squibb. Florian Rieder has consulted for Adnovate, AgomAb, Allergan, AbbVie, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CDISC, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, GuidePoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Janssen, Koutif, Mestag Therapeutics, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, Redx Pharma, Roche, Samsung, Surmodics, Surrozen, Takeda, TechLab, Theravance, Thetis, UCB, Ysios Capital, and 89bio. Jeffrey Hyams served on advisory boards for Janssen, Pfizer, and Boehringer Ingelheim and as a consultant to Takeda, Bristol Myers Squibb, Thetis, and Eli Lilly. Kanthi Kollengode, Jared Pearlman, Vladimir Son, and Cecilia Marta are employees of Bristol Myers Squibb. Douglas C. Wolf has received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB. Geert G. D'Haens has consulted for AbbVie, Cellceutix, Celgene, Endo, Ferring, Gilead, Janssen Ortho Biotech, Eli Lilly, American Regent, Merck, Morphic, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for UCB, Janssen Ortho Biotech; editor (honorarium) Gastroenterology and Hepatology (Gastro-Hep Communications), Springer Science and Business Media; received book royalties from SLACK, Inc., and Professional Communications, Inc.
(Copyright © 2022. Published by Elsevier Inc.)