Multiple Sclerosis (MS)


Zeposia (ozanimod) is an approved, once-daily oral treatment for adult patients with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).1

The US Food and Drug Administration (FDA) approved Zeposia in March 2020.2 The European Commission approved it for use in adult patients with RRMS in May 2020.3

Zeposia is given as a 0.92 mg dose once a day after a 1-week treatment initiation period; patients receive 0.23 mg for the first 4 days and 0.46 mg for days 5 through 7.1 The treatment was developed by Celgene, which was subsequently acquired by Bristol-Myers Squibb in 2019.4 Zeposia is also being investigated for use in ulcerative colitis and Crohn’s disease.3

Mechanism of Action

Overactivity of the immune system leads to targeting of the myelin sheath in the central nervous system (CNS) of patients with MS. The infiltration of T-cells and B-cell autoantibodies into the CNS leads to demyelination, breakdown of the blood-brain barrier (BBB), inflammation of other CNS tissues, and ultimately the death of neurons.5

Zeposia belongs to a class of molecules called sphingosine-1-phosphate (S1P) receptor modulators and is similar to other treatments, such as siponimod (Mayzent®), fingolimod (Gilenya®), and ponesimod (Ponvory®). The exact mechanism of action in MS of these molecules is not fully known, however, they are believed to stop the migration of lymphocytes out of peripheral lymphoid tissue and into the bloodstream, thereby limiting their ability to arrive at inflamed tissues to modulate immunity.5

Get detailed prescribing information on the Zeposia monograph page on MPR.

Zeposia selectively targets the S1P receptors 1 (S1P1) and 5 (S1P5) with little activity on receptors 2 through 4.5 Binding of the S1P 1 receptors by Zeposia causes internalization and degradation of the receptors, leading to lymphocytic desensitization against S1P ligands that usually signal the cells to leave the lymphoid tissue. Murine experimental autoimmune encephalomyelitis (EAE) models have suggested that Zeposia may also have additional neuroprotective effects through its targeting of S1P1 and S1P5 receptors.6

Warnings, Precautions, and Adverse Reactions

Zeposia may increase a patient’s risk of developing severe infections, such as herpes zoster, cryptococcal meningitis, and progressive multifocal leukoencephalopathy, due to its immunosuppressive effects.1 Other serious effects of Zeposia can also include bradyarrhythmia, atrioventricular conduction delays, liver damage, increased blood pressure, a reduction in respiratory function, and macular edema.1

There is insufficient data to support the use of Zeposia in pediatric, geriatric, pregnant, or breastfeeding patients. Animal studies have shown adverse effects of Zeposia on embryofetal development leading to malformations and death, therefore women of childbearing age should use contraception during treatment and for 3 months after ending treatment.

Prior to the start of treatment, patients should undergo complete blood count (CBC), testing to establish baseline levels of transaminase and bilirubin, an electrocardiogram (ECG) to check for conduction abnormalities which could be exacerbated, and testing for varicella-zoster virus (VZV) antibodies if the patient does not have a history of VZV infection or vaccination.

The most common adverse reactions, with an incidence of at least 2% during clinical trials, include upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, hypertension, and upper abdominal pain.1

Efficacy in Trials and Trial Results

Zeposia has been tested in a number of completed clinical trials. The 2 main studies that contributed to its approval were named RADIANCE and SUNBEAM.

RADIANCE was actually made up of 2 parts. The first part (NCT01628393) was a multicenter randomized phase 2/3 trial that investigated 2 dosages (0.5 mg or 1 mg) of Zeposia compared to a placebo in patients with relapsing MS. A total of 252 patients were randomized between the 3 groups and completed the 24-week trial. Results showed that patients treated with Zeposia had fewer gadolinium-enhancing MRI lesions compared to the placebo group, as well as a favorable safety profile.7 Three serious adverse events — optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related) — were reported in the patients taking ozanimod 0.5 mg, and were unrelated to treatment. 

The results of the first part of the RADIANCE trial led to the second part of the trial (NCT02047734), which investigated the same 2 doses of Zeposia compared to 30 µg intramuscular injections of interferon beta-1a (Avonex®) and matching placebos. A total of 1313 patients with relapsing MS, from 147 medical centers across 21 countries, were recruited and received treatments.8 

At the end of the 24-month study period, 1138 patients had completed the study. Patients treated with Zeposia had lower adjusted annualized relapse rates (ARR) than those receiving interferon beta-1a (0.17 for the 1 mg dose of Zeposia, 0.22 for the 0.5 mg dose, and 0.28 for interferon beta-1a).8 The rate ratio of Zeposia compared to interferon beta-1a was 0.62 (P <.0001) for the 1 mg dose and 0.79 (P <.0167) for the 0.5 mg dose.8 The numbers of adverse events between treatment groups were similar, with Zeposia numbers being slightly lower.

The SUNBEAM trial (NCT02294058) also investigated the 0.5 mg and 1 mg daily oral doses of Zeposia compared to 30 µg weekly intramuscular interferon beta-1a with matching controls. A total of 1346 patients with relapsing MS were recruited and randomized between the study groups where they were studied for at least 12 months.9

Findings from the study showed that adjusted ARRs were higher for patients receiving interferon beta-1a (0.35) than either dose of Zeposia (0.18 for the 1 mg group and 0.24 for the 0.5 mg group). These resulted in rate ratios of 0.52 (P <.0001) and 0.69 (P =.0013) for the higher and lower Zeposia doses, respectively, compared to interferon beta-1a.9

Patients from these 2 trials, as well as an earlier study involving the pharmacokinetics and pharmacodynamics of Zeposia in patients (NCT02797015), were allowed to roll into an open-label extension study, called DAYBREAK (NCT02576717), to continue receiving Zeposia. The results of these trials were used to file for regulatory approval of Zeposia.

Zeposia is also currently being investigated in an open-label phase 3 trial, called ENLIGHTEN (NCT04140305), to evaluate its effect on cognitive processing speed in patients with relapsing MS. The study is recruiting approximately 250 patients from sites across the US and Canada to receive daily doses of 1 mg of Zeposia for up to 3 years. Changes in the Symbol Digit Modalities Test,10 MRI scans, and several other tests will be monitored over the trial period. The trial is estimated to conclude in June 2025.

References

1. Zeposia. Package insert. Bristol Myers Squibb; 2020. Accessed June 16, 2021.

2. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Zeposia® (ozanimod), a new oral treatment for relapsing forms of multiple sclerosis. News release. Bristol Myers Squibb; March 26, 2020. 

3.Bristol Myers Squibb application for Zeposia® (ozanimod) for the treatment of ulcerative colitis accepted for filing with priority review by U.S. Food and Drug Administration. News release. Bristol Myers Squibb; February 1, 2020. 

4. Bristol-Myers Squibb completes acquisition of Celgene, creating a leading biopharma company. News release. Bristol Myers Squibb; November 20, 2019. 

5. Scott F, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778-1792. doi:10.1111/bph.13476 

6. Musella A, Gentile A, Guadalupi L, et al. Central modulation of selective sphingosine-1-phosphate receptor 1 ameliorates experimental multiple sclerosis. Cells. 2020; 9(5):1290. doi:10.3390/cells9051290 

7. Cohen J, Arnold D, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381. doi:10.1016/S1474-4422(16)00018-1

8. Cohen J, Comi G, Selmaj K, 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(11):1021-1033. doi:10.1016/S1474-4422(19)30238-8

9. Comi G, Kappos L, Selmaj K, 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(11):1009-1020. doi:10.1016/S1474-4422(19)30239-X10.

10. Benedict R, DeLuca J, Phillips G, et al. Validity of the symbol digit modalities test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23(5):721-733.  doi:10.1177/1352458517690821

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.