Efficacy and Safety of Ozanimod in the Treatment of Relapsing-Remitting MS
The sphingosine-1-phosphate receptor (S1PR) modulator ozanimod has recently been approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). We summarize the current knowledge on its mechanism of action and the results of available studies evaluating its efficacy and safety.
Mechanism of Action
Ozanimod belongs to the group of S1PR1 modulators, which are present on lymphocytes, neurons, endothelial cells, smooth muscle cells, atrial myocytes, and AV node cells. It binds with high affinity to S1PR1 and S1PR5, whereas it exhibits minimal or no activity toward S1PR2, S1PR3, and S1PR4. Its interaction with S1PR1 leads to receptor internalization and subsequent degradation, resulting in decreased migration of circulating lymphocytes into the central nervous system, where they can exert pro-inflammatory and neurodegenerative effects. This induced reduction in lymphocyte count in peripheral blood is reversible and dose-dependent, with a preference for CD4+ CCR7+, CD8+ and CCR7+ T cell subtypes, thus maintaining the ability of protective immune response.
Additionally, ozanimod easily crosses the blood-brain barrier and potentially has a beneficial effect through direct interaction with brain cells. It is believed that its modulation of S1PR in neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells supports myelin regeneration and prevents the occurrence of synaptic defects.
Ozanimod can be taken with or without food. It is metabolized to produce several circulating active metabolites, including the main metabolite CC112273 with a long half-life, which is related not only to the once-daily oral dosing regimen but also to the median time for the return of lymphocyte counts in peripheral blood to normal, approximately 30 days.
What Do Available Clinical Studies Say?
The safety of ozanimod was initially tested in two randomized double-blind phase I clinical studies, which demonstrated a dose-dependent negatively chronotropic effect (but not a prolongation of the QT interval) on the initial dose. Therefore, in subsequent studies, the dose was escalated up to day 7.
RADIANCE A was a double-blind, placebo-controlled phase II clinical study in which patients with RRMS received ozanimod at doses of 0.5 mg or 1 mg/day for 24 weeks. This study demonstrated ozanimod's efficacy in reducing new/enlarging T2 and GdE (gadolinium-enhancing) lesions on brain MRI. Both doses were well tolerated, with the most common adverse events being nasopharyngitis and headache.
Patients were subsequently enrolled in an extended 2-year study with ozanimod. The annualized relapse rate (ARR) of the disease was 0.32 in patients continuing on ozanimod at 0.5 mg/day, 0.30 in patients previously on placebo, and 0.18 in patients on ozanimod at 1 mg/day.
Phase III Studies
In the multicenter double-blind placebo-controlled phase III RADIANCE B study, a total of 1320 patients received ozanimod (at doses of 0.5 mg or 1 mg/day) or interferon (IFN) β-1a (intramuscularly at a dose of 30 µg once weekly) for 24 months. Lower ARR (0.17 and 0.22) was observed in patients receiving ozanimod at doses of 1 mg and 0.5 mg/day, respectively, compared to patients treated with IFN-β-1a (0.28) with a relative risk (RR) of 0.62 (95% confidence interval [CI] 0.51–0.77; p < 0.0001) and 0.79 (95% CI 0.65–0.96; p = 0.0167).
In patients treated with ozanimod, a reduction in new/enlarging T2 lesions (1.84 for ozanimod 1 mg/day; 2.09 for ozanimod 0.5 mg/day; 3.18 for IFN-β-1a) and GdE (0.18; 0.20; 0.37) was observed, similar to the phase II study. Ozanimod also showed a more pronounced effect in reducing brain volume loss, while the proportion of patients with disability progression after 3 and 6 months of treatment did not differ significantly between groups. Adverse events were reported in 75% of patients on ozanimod and 83% on IFN-β-1a, most being mild or moderate, with > 5% of patients reporting (naso)pharyngitis, urinary tract infections, or laboratory elevations in alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT). During the initial dose escalation, no significant cardiac adverse events (such as bradycardia or AV block) were observed.
Similar results regarding efficacy and safety were shown in the 12-month phase III SUNBEAM clinical study, which included 1346 patients. Its post hoc analysis additionally pointed to favorable outcomes related to cognitive functions.
The recently published phase III DAYBREAK clinical study included a total of 2495 patients from the RADIANCE B and SUNBEAM studies. These patients took ozanimod at a dose of 1 mg/day for an average of 19 months, with safety and efficacy results similar to those of the previously mentioned studies.
How Does Ozanimod Compare to Other S1PR Modulators?
According to the analysis of pivotal clinical studies, the first administration of ozanimod is associated with a lower incidence of adverse events (including bradycardia or AV block) compared to the non-selective S1PR modulator fingolimod. The incidence of adverse events is generally lower even after 1 and 2 years of treatment.
In a meta-analysis comparing ozanimod with other S1PR modulators, it exhibited the lowest risk of serious adverse events leading to discontinuation of treatment.
Conclusion
Ozanimod is the newest S1PR modulator indicated for the treatment of active relapsing-remitting multiple sclerosis. It was approved by the European Medicines Agency (EMA) in May 2020 and newly reimbursed in the Czech Republic since March 2023. It shows good efficacy and safety and is better tolerated due to its selectivity for S1PR1 and S1PR5 compared to older drugs in this group.
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Sources:
1. Fronza M., Lorefice L., Frau J., Cocco E. An overview of the efficacy and safety of ozanimod for the treatment of relapsing multiple sclerosis. Drug Des Devel Ther 2021; 15: 1993–2004, doi: 10.2147/DDDT.S240861.
2. 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 (4): 275–285, doi: 10.2217/cer-2019-0169.
3. Tong J., Zou Q., Chen Y. et al. Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis. Neurol Sci 2021; 42 (5): 1687–1695, doi: 10.1007/s10072-021-05049-w.
4. SPC Zeposia. Available at: www.ema.europa.eu/en/documents/product-information/zeposia-epar-product-information_cs.pdf
Find the abbreviated product information here.
Notice for commercial purposes from Bristol-Myers Squibb spol. s r.o
2084-CZ-2300024
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