Efficacy and Safety of Ozanimod in the Blinded Extension (120 weeks) of RADIANCE, a Phase 2 Trial in Relapsing Multiple Sclerosis

Friday, May 26, 2017: 3:08 PM
R06 (New Orleans Convention Center)
Giancarlo Comi, MD , Vita-Salute San Raffaele University, Milan, Italy
Douglas L Arnold, MD , Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Amit Bar-Or, MD , Montreal Neurological Institute and Hospital McGill University, Montreal, QC, Canada
Krzysztof W Selmaj, MD, PhD , Department of Neurology, Medical Academy of Lodz, Lodz, Poland
Lawrence Steinman, MD , Stanford University School of Medicine, Stanford, CA
Eva K Havrdova, MD, PhD , Department of Neurology and Center for Clinical Neuroscience, First Medical Faculty, Charles University, Prague, Czech Republic
Bruce AC Cree, MD, PhD , Neurology, University of California, San Francisco, CA
Hans-Peter Hartung, MD , Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany
Ludwig Kappos, MD , University of Basel, Basel, Switzerland
Brett E Skolnick, PhD , Receptos Services LLC, San Diego, CA
Jeffrey A Cohen, MD , Mellen Center U-10 Cleveland Clinic, Cleveland, OH
Jacqueline Marut, BA , NA, Lyndhurst, NJ

Background: Ozanimod is an oral, selective sphingosine 1-phosphate (S1P) receptor-1 (S1P1R) and -5 (S1P5R) modulator in development for relapsing multiple sclerosis (RMS). The increased receptor selectivity of ozanimod and additional pharmaceutical properties may result in a more favorable safety profile vs. other non-selective and selective S1P receptor modulators.

Objectives: To further describe the safety and efficacy of once-daily ozanimod (0.5 and 1.0 mg) at 120 weeks.

Methods: In the completed RADIANCE Part A phase 2 trial (NCT01628393), patients with RMS were randomized (1:1:1) to once-daily ozanimod 0.5 mg or 1.0 mg or to placebo for 24 weeks (Cohen et al. Lancet Neurol. 2016; 15: 373). At week 24, patients could enter a 96-week, blinded extension phase. Patients randomized to ozanimod continued their assigned dose (0.5 mg, n=85; 1.0 mg, n=81); patients administered placebo were re-randomized (1:1) to ozanimod 0.5 mg (n=41) or 1.0 mg (n=42). Ozanimod was dose-escalated over 7 days to attenuate first-dose effects.

Results: 89% (0.5 mg) and 90% (1.0 mg) of patients completed 120 weeks. At week 120, 89–91% of patients were free of gadolinium-enhancing lesions. Unadjusted annualized relapse rates were 0.31 (0.5 mg) and 0.18 (1.0 mg). 79% (0.5 mg) and 76% (1.0 mg) of patients experienced ≥1 treatment-emergent AE (TEAE), most commonly increased alanine aminotransferases, nasopharyngitis, and upper respiratory tract infection. 12 (0.5 mg) and 9 (1.0 mg) patients reported a serious TEAE. Mild blunting of the normal diurnal heart rate was observed. The largest mean decrease in heart rate relative to pre-dose was 3.5 bpm at hour 6 on day 1, with no associated symptoms. No type II or 2:1 atrioventricular block was reported. At week 120, ALT levels were ≥3x ULN in 6% (0.5 mg) and 7% (1.0 mg) of patients. 2% (0.5 mg) and <1% (1.0 mg) of patients discontinued ozanimod due to increased liver transaminases. Between baseline and week 120, 3 patients (1.0 mg) had absolute lymphocyte count (ALC) <200 cells/µL; none was associated with severe or serious infection. There were no notable cases of pulmonary TEAEs and no cases of macular edema, malignancy-related TEAEs, or serious opportunistic infections.

Conclusions: Both ozanimod doses demonstrated durable efficacy, with a favorable safety profile in patients continuing ozanimod for 120 weeks or switching from placebo to ozanimod for 96 weeks. These data support the ongoing RADIANCE (NCT02047734) and SUNBEAM (NCT02294058) phase 3 studies.