Reinitiation of Ozanimod After Dose Interruption: Assessment of Effect on Heart Rate

Introduction: Ozanimod (OZA) is a selective sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis. Treatment with OZA and other S1P receptor modulators has been associated with bradycardia likely due to the pharmacologic effect of S1P1 receptors on heart rate (HR). Thus, dose titration with OZA is implemented to mitigate this risk. Methods: This randomized, double-blind, placebo (PBO)–controlled, adaptive phase 1 study evaluated the effects of OZA reinitiation (0.92 mg) on HR after different washout intervals relative to dose escalation in healthy adults. Participants were randomized to receive once-daily OZA (dose titration: Days 1–4, 0.23 mg; Days 5–7, 0.46 mg; then 0.92 mg) or PBO for 28 days in Period 1, followed by a washout of 3, 7, or 14 days, and then treatment reinitiation with a single dose of OZA 0.92 mg or PBO in Period 2. Changes at Period 2 Day 1 from Period 1 Day 1 (CFP1) in the HRNadir from 0–12 h postdose were compared between OZA/OZA and PBO/PBO groups after each washout interval and were analyzed using an ANCOVA model with fixed effects for treatment, Period 1 Day 1 HRNadir (0–12 hours), sex, and treatment × Period 1 Day 1 HRNadir (0–12 hours); least squares (LS) mean differences between OZA/OZA and PBO/PBO with 90% CI were calculated. Safety was also assessed. Results: Of 64 participants, 15, 16, and 15 received OZA/OZA and completed the 3-, 7, and 14-day washout intervals, respectively; 18 participants received PBO/PBO (6 in each washout group, combined for all washout interval comparisons). LS mean CFP1 Day 1 HRNadir changes were generally similar between OZA/OZA and PBO/PBO groups at each washout interval: 3 days = 3.51 vs 1.73 beats per minute (bpm), 7 days = 0.85 vs 1.87 bpm, and 14 days = 0.27 vs 1.81 bpm, respectively. The CFP1 Day 1 HRNadir LS mean differences between OZA/OZA and PBO/PBO (90% CI) at each washout interval were 3 days = 1.78 bpm (–1.76 to 5.32), 7 days = –1.02 bpm (–3.88 to 1.85), and 14 days = –1.54 bpm (–4.20 to 1.11). There were no severe or serious adverse events during any period or washout interval. Conclusion: Overall, reinitiation of OZA at the maintenance dose of 0.92 mg once daily after dose interruption of 3, 7, or 14 consecutive days was not associated with meaningful changes in HR. OZA can be safely reinitiated at the 0.92 mg dose without repeating dose titration within 14 days of drug discontinuation.