Primary Results of NOVA: a Randomized Controlled Study of the Efficacy of 6‑Week Dosing of Natalizumab Versus Continued 4-Week Treatment for Multiple Sclerosis
John Foley1, Gilles Defer2, Lana Zhovtis Ryerson3, Jeffrey A. Cohen4, Doug L. Arnold5, Helmut Butzkueven6, Gary Cutter7, Gavin Giovannoni8, Joep Killestein9, Heinz Wiendl10, Karen Smirnakis11, Shan Xiao11, George Kong11, Robert Kuhelj11, Nolan Campbell11
1Rocky Mountain MS Clinic, 2Department of Neurology, Centre Hospitalier Universitaire de Caen, 3Department of Neurology, NYU Langone Health, New York University, 4Cleveland Clinic, 5Montreal Neurological Institute, McGill University, and NeuroRx Research, 6Department of Neuroscience, Central Clinical School, Monash University, 7University of Alabama School of Public Health, 8Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 9Department of Neurology with Institute of Translational Neurology, University of Münster, 10Department of Neurology, MS Centre Amsterdam, VU University Medical Centre, 11Biogen
Objective:
Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.
Background:
Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsing-remitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. NOVA is the first randomized trial to assess Q6W efficacy.
Design/Methods:
NOVA is a randomized, controlled, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W. The primary endpoint was new/newly enlarging T2 (N/NET2) lesions. Secondary endpoints included relapses and 24-week confirmed disability worsening (CDW). Primary estimand used all observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.
Results:
195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. Proportions of patients with N/NET2 lesions were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. Differences were mainly due to 2 Q6W patients with high values (≥25 lesions); otherwise the distributions of N/NET2 lesions were similar with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were similar between groups.
Conclusions:
Despite a small difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinically meaningful loss of efficacy.