Ofatumumab Reduces Disability Progression Independent of Relapse Activity in Patients with Relapsing Multiple Sclerosis
Ludwig Kappos1, Xavier Montalban2, Patricia Coyle3, Jacqueline Nicholas4, Sven Meuth5, Bingbing Li6, Krishnan Ramanathan7, Wendy Su6, Roman Willi7, Dieter A. Häring7, Stephen Hauser8
1Neurologic Clinic and Policlinic and Research Center for Clinical Neuroimmunology and Neuroscience, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 2Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain, 3Department of Neurology, Stony Brook University, Stony Brook, NY, USA, 4OhioHealth Multiple Sclerosis Center, Columbus, OH, 5Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany, 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 7Novartis Pharma AG, Basel, Switzerland, 8Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
Objective:
To test the robustness of the effect of ofatumumab on confirmed disability Progression Independent of Relapse Activity (PIRA) against variability in body weight in the overall ASCLEPIOS population and to evaluate the relevance of PIRA in newly-diagnosed, treatment-naïve patients with relapsing multiple sclerosis (RMS). 
Background:
Ofatumumab, the first fully-human anti-CD20 monoclonal antibody with a 20-mg subcutaneous monthly dosing regimen, is approved by the US FDA for the treatment of adults with RMS. Ofatumumab significantly reduced PIRA in the ASCLEPIOS I/II trials in RMS. 
Design/Methods:
In the pooled ASCLEPIOS population, the effect of ofatumumab versus teriflunomide on PIRA and its robustness to variability in body weight (by quartile; Q1: <60.1; Q2: ≥60.1–<70.8; Q3: ≥70.8–<84.4; Q4: ≥84.4) was evaluated. Risk of 3-month/6-month PIRA was defined as ≥1.0-point increase if baseline EDSS score <6 or ≥0.5-point increase if baseline EDSS score ≥6 and was analyzed using Cox-regression models. Further, the proportion of PIRA events (3m/6mPIRA) among the confirmed disability worsening events (3m/6mCDW) was quantified in 2 subsets of newly-diagnosed, treatment-naïve patients: Subset-A, without confirmed relapses on-study; Subset-B, without confirmed relapses prior to a 3m/6mPIRA.
Results:
Ofatumumab (versus teriflunomide) delayed PIRA in overall RMS population, irrespective of body weight; the risk of 6mPIRA by body weight quartiles was reduced with ofatumumab in both subsets (Subset-A: Q1–Q4: 31%–37%; Subset-B: 36%–47%). In newly-diagnosed treatment-naïve patients, >50% of the CDW events were PIRA; ofatumumab (versus teriflunomide) reduced the risk of 6mPIRA by 56% (p=0.049) in Subset-A and by 59% (p=0.023) in Subset-B, with similar results for 3mPIRA. 
Conclusions:
Ofatumumab had superior efficacy versus teriflunomide on PIRA in RMS patients, independent of body weight. In newly-diagnosed treatment-naïve RMS patients, a high proportion of CDW events were PIRA; ofatumumab markedly reduced the risk of PIRA in early RMS patients versus teriflunomide.