Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study

Background: Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease. Methods: STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015–002025–19, and is completed. Findings: 69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was −2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9–34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change −130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6–51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0–68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was −66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was −5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) −10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]). Interpretation: Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated. Funding: Celgene Corporation.