• Amit Bar-Or, Richard A Grove, Daren J Austin, Jerry M Tolson, Susan A VanMeter, Eric W Lewis, Frederick J Derosier, Monica C Lopez, Sarah T Kavanagh, Aaron E Miller, and Per S Sorensen.
• From the Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Neuroimmunology Unit (A.B.-O.), Montreal Neurological Institute and Hospital, McGill University and McGill University Health Center, Quebec, Canada; Neurosciences Clinical Statistics (R.A.G.), Clinical Pharmacology (R.A.G., D.J.A.), and Modeling and Simulation (D.J.A.), GlaxoSmithKline, Uxbridge, Middlesex, UK; Neurosciences Therapy Area Unit (J.M.T., S.A.V., E.W.L., F.J.D., M.C.L., S.T.K.), SAVM (F.J.D., M.C.L.), Global Clinical Safety and Pharmacovigilance (E.W.L.), and Neurosciences Clinical Statistics (SecTK), GlaxoSmithKline, Research Triangle Park, NC; Department of Neurology (A.E.M.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY; and Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Dr. Derosier is now at Clinical Development, Isis Pharmaceutical, Carlsbad, CA. amitbar@upenn.edu.
• Neurology. 2018 May 15; 90 (20): e1805-e1814.

ObjectiveTo assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).MethodsPatients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.ResultsThe cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.ConclusionImaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.Classification Of EvidenceThis study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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