BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data. METHODS: We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data. RESULTS: At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE. CONCLUSIONS: Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results.

Bristol Myers Squibb 3401 Princeton Pike Lawrenceville New Jersey 08648 USA

Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology Perelman School of Medicine University of Pennsylvania 3400 Spruce Street 3 Dulles Building Philadelphia Pennsylvania 19104 USA

Center for Neurology Tylna 12 90 324 Łódź Poland and Collegium Medicum Department of Neurology University of Warmia and Mazury Warszawska 30 11 082 Olsztyn Poland

Department of Neurology and Center for Clinical Neuroscience 1st Medical Faculty Charles University Katerinska 30 120 00 Prague 2 Czech Republic

Department of Neurology and Neurological Sciences Beckman Center for Molecular Medicine Stanford University Medical Center 300 Pasteur Dr Stanford Stanford California 94305 USA

Department of Neurology Medical Faculty Heinrich Heine University University Hospital Dusseldorf Moorenstr 5 40225 Düsseldorf Germany; Brain and Mind Centre University of Sydney Camperdown NSW 2006 Sydney Australia; Department of Neurology Medical University Vienna Spitalgasse 23 1090 Vienna Austria

Department of Neurology Mellen Center for MS Treatment and Research Neurological Institute Cleveland Clinic 9500 Euclid Avenue Cleveland Ohio 44195 USA

Department of Neurology Neuroimmunology Centre d'Esclerosi Múltiple de Catalunya Hospital Universitario Vall d'Hebron Pg Vall d'Hebron 119 129 08035 Barcelona Spain

Department of Neurology San Raffaele Scientific Institute Vita Salute San Raffaele University via Olgettina 48 20132 Milan Italy

NeuroRx Research and Montréal Neurological Institute McGill University 3801 University Street Montreal Quebec H3A 2B4 Canada

Research Center for Clinical Neuroimmunology and Neuroscience Basel Departments of Medicine Clinical Research Biomedicine and Biomedical Engineering University Hospital and University of Basel Petersgraben 4 CH 4031 Basel Switzerland

Weill Institute for Neurosciences Department of Neurology UCSF University of California San Francisco 675 Nelson Rising Lane San Francisco California 94158 USA

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Multiple sclerosis: time for early treatment with high-efficacy drugs

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