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

**Background:** Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5 receptors. It is approved for moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis. The pathogenesis of inflammatory bowel disease involves lymphocyte trafficking to gut tissues; ozanimod reduces lymphocyte egress from lymphoid tissues by internalizing S1P1 receptors. A phase 2 trial in CD (STEPSTONE) showed reductions in Simple Endoscopic Score for Crohn's Disease (SES-CD), Global Histologic Disease Activity Score (GHAS), and Robarts Histopathology Index (RHI) at Week 12, along with CDAI reductions. The YELLOWSTONE program was designed to confirm these findings in a phase 3 setting.

**Methods:** The YELLOWSTONE program comprises two identical, randomized, double-blind, placebo-controlled induction studies (NCT03440372 and NCT03440385), a maintenance study (NCT03464097), and an open-label extension (OLE; NCT03467958). Patients are randomized 2:1 to ozanimod 0.92 mg or placebo for 12 weeks of induction, stratified by prior biologic use and baseline corticosteroid use. Recruitment caps prior biologic exposure at approximately 50%. Responders to ozanimod are rerandomized 1:1 to ozanimod or placebo for 52 weeks of maintenance. Patients not eligible for maintenance, those who relapse, or those completing maintenance or ≥1 year of STEPSTONE may enter the OLE for up to 234 weeks. Estimated enrollment is 600 per induction study, 485 in maintenance, and 1200 in the OLE. The program is active in >40 countries at >400 sites; induction studies were approximately 70% enrolled as of October 2022. Efficacy endpoints include clinical remission (CDAI), endoscopic response (≥50% reduction in SES-CD), endoscopic remission (SES-CD ≤4), histologic improvement (GHAS and RHI), and corticosteroid-free remission. Colonoscopies are centrally read with a multiple-reader adjudication process. Safety monitoring includes assessment of adverse events of special interest (bradycardia, macular edema, malignancy, serious infections, hepatic effects). An independent data monitoring committee reviews accumulating data.

**Key Results:** No efficacy or safety results are yet available. Induction studies are expected to complete in Q2 2023, the maintenance study in Q2 2024, and the OLE in Q2 2026.

**Clinical Implications:** The YELLOWSTONE program is designed to address several unmet needs in CD treatment: the need for oral therapies with novel mechanisms, durable efficacy, and favorable safety profiles. The use of centrally read endoscopic and histologic endpoints may reduce placebo response rates and provide more objective evidence of disease modification. Histologic data from 5 intestinal segments using both GHAS and RHI may help validate clinically relevant histologic thresholds in CD. The CDAI is retained as a symptom-based endpoint, reflecting patient priorities. If positive, ozanimod could offer a first-line oral option for patients with moderately to severely active CD, an alternative for those who have failed multiple biologics, and a corticosteroid-sparing therapy. The OLE will provide >5 years of long-term safety and efficacy data specifically in the CD population.