By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The Food and Drug Administration has approved the third sphingosine-1-phosphate (S1P) receptor modulator, following fingolimod and siponimod, to treat relapsing multiple sclerosis (MS). Ozanimod selectively binds to S1P subtypes 1 and 5 (S1PR1/S1PR5). Ozanimod will be marketed as Zeposia.

Indications

Ozanimod should be prescribed to treat relapsing MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.1

Dosage

Ozanimod is taken orally and is initiated with a titration schedule: 0.23 mg once daily (days 1-4), 0.44 mg once daily (days 5-7), and 0.92 mg once daily (day 8 and thereafter).1 Before drug initiation, conduct a complete blood count; electrocardiogram (ECG); liver function tests; ophthalmic assessment; antibodies to varicella zoster virus; and current or prior treatment with immunosuppressives, antineoplastics, and drugs that slow heart rate or atrioventricular (AV) conduction. Ozanimod is available as 0.23 mg, 0.44 mg, and 0.92 mg capsules.

Potential Advantages

Ozanimod is a selective S1P modulator similar to siponimod. Fingolimod is nonselective, with binding to receptor subtypes 1, 3, 4, and 5 (S1PR1, S1PR3, S1PR4, and S1PR5). S1PR3 is associated with AV conduction slowing.2 Ozanimod has a longer elimination than siponimod (mean 21 hrs vs. 4 hrs), permitting once-daily dosing.1,3

Potential Disadvantages

Ozanimod is contraindicated in patients who have experienced a cardiovascular or cerebrovascular event (e.g., myocardial infarction, unstable angina, stroke, transient ischemic attack, class III or IV heart failure) or severe, untreated sleep apnea.1 Ozanimod may increase the risk of infection caused by significant reduction in blood lymphocyte count. In addition, a slower heart rate and AV conduction delays, macular edema, reduction in pulmonary function, and elevation of liver transaminases may occur. Progressive multifocal leukoencephalopathy, a rare but serious viral brain infection, has been reported with S1P receptors modulators and other MS drugs.1 Due to potential fetal risk, women of child-bearing age should use effective contraception during treatment and for three months after stopping treatment. Concomitant use with strong CYP2C8 inhibitors, strong CYP2C8 inducers, breast cancer resistance protein inhibitors, and monoamine oxidase inhibitors is either not recommended or should be avoided.2

Comments

The efficacy of ozanimod was evaluated in two randomized, double-blind, active comparator-controlled clinical trials.1,4,5 Study participants were mainly white females with a relapsing form of MS. At baseline, the mean age was 35.5 years, mean time to onset of symptoms was 6.6 to 6.9 years, there had been a mean of 1.3 relapses in the prior year, there were a mean of 1.8 Gadolinium-enhancing (i.e., active) lesions, and the median Expanded Disability Status Scale (EDSS) score was 2.5 (the severity ranged from 0-10). Subjects were randomized to ozanimod (0.92 mg once daily) or interferon beta-1a (30 mcg intramuscularly once weekly).1 The primary endpoint was the annualized relapse rate (ARR) over 12 months in study 1 and 24 months in study 2. Additional outcomes included new and or enlarged magnetic resonance imaging (MRI)-detected lesions and the time to confirmed disability progression (one point increase from baseline EDSS score).

Ozanimod showed a relative reduction in ARR compared to interferon (48% in study 1, 38% in study 2). A relative reduction (48% and 42%, respectively) also was observed in new or enlarging lesions. However, there was no difference in three-month or six-month confirmed disability regression. The primary difference in adverse reactions between ozanimod and interferon beta-1a was hepatic transaminase elevation (10% vs. 5%).1 There are no comparative studies between ozanimod and fingolimod. A post hoc analysis of a matched cohort from data from ozanimod or fingolimod vs. interferon beta-1a provided an indirect comparison between ozanimod and fingolimod.6 The findings suggest similar efficacy (i.e., ARR reduction) but fewer adverse reactions with ozanimod (e.g., slower heart rate, ECG findings, change in blood pressure).

Clinical Implications

MS is a chronic, immune-mediated, inflammatory, demyelinating disease of the central nervous system. Most patients are diagnosed with relapsing-remitting disease. MS is incurable, but the relapsing-remitting form is considered treatable. There are now 19 approved drugs for MS with the goal of reducing the number of relapses, delaying the progression of disability, and limiting new disease activity (e.g., MRI-detected lesions). Individual differences in characteristics of the disease, variability in response to treatment (effectiveness and tolerability), and disease breakthrough welcome new treatment options. Ozanimod is the second selective S1P receptor modulator to be approved with the convenience of once-daily dosing. The release of ozanimod may be delayed because of the COVID-19 pandemic. Cost information is unavailable.

REFERENCES

  1. Celgene Corporation. Zeposia Prescribing Information, March 2020.
  2. Novartis. Mayzent Prescribing Information, March 2019.
  3. Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics 2017;14:859-873.
  4. Cohen JA, Comi G, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): A multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol 2019;18:1021-1033.
  5. Comi G, Kappos L, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): A multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol 2019;18:1009-1020.
  6. Swallow E, Patterson-Lomba O, Yin L, et al. Comparative safety and efficacy of ozanimod versus fingolimod for relapsing multiple sclerosis. J Comp Eff Res 2020;9:275-285.