Long-term Safety and Efficacy of Ozanimod in the Treatment of Relapsing Forms of MS
Ozanimod is classified as a modulator of sphingosine-1-phosphate (S1P) receptors types 1 and 5. It is approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and moderate to severe ulcerative colitis (UC) and continues to undergo intensive clinical research. The DAYBREAK open-label, single-arm study for participants with RRMS from previous trials with ozanimod was scheduled to be completed by January 2023, and its final results can therefore be expected soon. The following article presents the interim analysis results of this study 5 years after initiation.
Study Design and Goals
The DAYBREAK study included patients from previous clinical trials: This included a phase I study focused on obtaining information on the pharmacokinetics and pharmacodynamics of the drug, as well as phase II and III trials (RADIANCE and SUNBEAM), which compared the efficacy and safety of ozanimod with a placebo or active control – intramuscular interferon (IFN) β-1.
The open-label, single-arm DAYBREAK study was initiated in October 2015. Interim analysis results started in February 2021 were published in June 2022. The primary goal of the study was to gather additional safety information on ozanimod, focusing on treatment-associated adverse events (mainly infections, malignancies, macular edema, cardiovascular events, and pulmonary and liver function abnormalities). The secondary goal was to analyze efficacy.
Results
A total of 2494 patients were included in the DAYBREAK study, and the average duration of ozanimod use was 46.8 months (standard deviation [SD] 11.9). The annual relapse rate (ARR) was 0.103 (95% confidence interval [CI] 0.086−0.123). 71% of patients did not experience a relapse during the 48-month period. MRI examinations showed no progression or new lesion formation in most cases.
The incidence of serious treatment-associated adverse events (TEAEs), pulmonary disorders, and malignancies remained relatively stable. TEAEs were predominantly mild to moderate and reported in 2143 (85.9%) patients. The most common were nasopharyngitis or other upper respiratory infections and headaches. Serious adverse events occurred in 298 (11.9%) patients, resulting in discontinuation of ozanimod treatment in 75 cases.
Infections occurred in 56.7% of patients, with serious cases in 2.8% and opportunistic infections in 5.6% (most commonly herpes labialis and herpes zoster). Lymphopenia was detected in 9.8% of patients, but after 30 days, it persisted in only 1.2%, and 7 (0.3%) participants had to discontinue treatment due to it. Lymphocyte levels remained stable for the other patients during the study.
Malignancies developed in 38 patients during the original studies and the DAYBREAK study. The most common were basal cell carcinoma and breast cancer, but no specific pattern of malignancy type was identified. During the DAYBREAK study, 3 patients died from cancer (metastatic pancreatic cancer, disseminated cancer with unknown primary, and glioblastoma).
Macular edema occurred in 0.2% of study participants, and cardiovascular complications were found in 69 (2.8%) patients.
Summary and Conclusion
The DAYBREAK study provided information on long-term treatment of relapsing forms of MS. Disease activity, both clinical and radiological, remained low while using ozanimod. Patients who switched therapy from IFN β-1a or lower doses of ozanimod subsequently experienced a reduction in relapse numbers and fewer MRI-visible lesions. Treatment was sometimes associated with opportunistic infections, most commonly by herpes viruses, none of which were severe or disseminated. Some patients developed malignancies, and the results did not rule out a possible link between S1P modulators and basal cell carcinoma. Macular edema and cardiovascular complications were very rare, and pulmonary and liver complications were not clinically relevant. Lymphocyte counts dropped below normal in 95.6% of patients, but significant lymphopenia was noted in a small number of patients and was not linked to the development of opportunistic infections.
Results from the DAYBREAK study confirmed that using ozanimod at a dose of 0.92 mg daily reduces disease activity and relapse rates in MS. It is also a relatively safe medication, with manageable side effects that rarely necessitate treatment discontinuation.
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Source: Cree B. A., Selmaj K. W., Steinman L. et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler 2022 Oct; 28 (12): 1944−1962, doi: 10.1177/13524585221102584.
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