Ofatumumab versus Teriflunomide in Multiple Sclerosis.

Heinz Wiendl, Ludwig Kappos, Martin Merschhemke, Krishnan Ramanathan, Dieter A Häring, Ratnakar Pingili, Alexandra Goodyear, Davorka Tomic, Algirdas Kakarieka, Bingbing Li, Roman Willi, Cecile Kerloeguen, Stephen L Hauser, Krzysztof Selmaj, Xavier Montalban, David Leppert, Jerome de Seze, Anne H Cross, Patricia K Coyle, Jorge Correale, Giancarlo Comi, Jeffrey A Cohen, Amit Bar-Or

Journal: The New England journal of medicine 2020;383(6):546-557

PMID: 32757523

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Abstract

BACKGROUND

Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

METHODS

In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

RESULTS

Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

CONCLUSIONS

Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

Address: From the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco (S.L.H.); the Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.B.-O.); the Department of Neurology, Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland (J.A.C.); the Institute of Experimental Neurology and Multiple Sclerosis Center IRCCS, San Raffaele Hospital, Milan (G.C.); the Department of Neurology, Fleni, Buenos Aires (J.C.); the Department of Neurology, Stony Brook University, Stony Brook, NY (P.K.C.); Washington University School of Medicine, St. Louis (A.H.C.); the University Hospital of Strasburg and Clinical Investigation Center INSERM 1434, Strasburg, France (J.S.); University Hospital Basel (D.L.), Novartis Pharma (C.K., R.W., A.K., D.T., D.A.H., K.R., M.M.), and the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel (L.K.) - all in Basel, Switzerland; the Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona (X.M.); the University of Warmia and Mazury, Olsztyn, and the Center of Neurology, Lodz - both in Poland (K.S.); the Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany (H.W.); and Novartis Pharmaceuticals, East Hanover, NJ (B.L., A.G., R.P.).

DOI: 10.1056/NEJMoa1917246

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MeSH Terms: Adult, Antibodies, Monoclonal, Humanized, B-Lymphocytes, Brain, Crotonates, Disease Progression, Double-Blind Method, Female, Humans, Hydroxybutyrates, Injections, Subcutaneous, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Multiple Sclerosis, Relapsing-Remitting, Nitriles, T-Lymphocytes, Toluidines