1John Foley, 2Gilles Defer, 3Lana Zhovtis Ryerson, 4Jeffrey A. Cohen, 5Douglas L. Arnold, 6Helmut Butzkueven, 7Gary Cutter, 8Gavin Giovannoni, 9Joep Killestein, 10Heinz Wiendl, 11Karen Smirnakis,11Shan Xiao,11George Kong,12Robert Kuhelj,11Nolan Campbell
1Rocky Mountain MS Clinic, Salt Lake City, United States; 2Department of Neurology, Centre Hospitalier Universitaire de Caen, Caen, France; 3Department of Neurology, NYU Langone Health, New York University, New York, United States; 4Cleveland Clinic, Cleveland, United States; 5Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; 6Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Canada; 7University of Alabama School of Public Health, Birmingham, United States; 8Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; 9Department of Neurology, MS Centre Amsterdam, VU University Medical Centre, Amsterdam, Netherlands; 10Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany; 11Biogen, Cambridge, MA, USA; 12Biogen, Baar, Switzerland
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. Real-world data suggest similar effectiveness, but NOVA is the first randomized trial to assess Q6W efficacy. The objective of NOVA was to evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.
Material(s) and Method(s):
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 arms. The primary endpoint was number of new/newly enlarging T2 (N/NET2) hyperintense lesions analyzed by negative binomial regression with baseline (BL) weight, prior natalizumab exposure, and region as covariates. 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.
Result(s):
195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. BL characteristics were well balanced. Proportions of patients with N/NET2 lesions among observed data 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. The difference was mainly due to 2 Q6W patients with high values: (1) 30 lesions that occurred 3 months after natalizumab discontinuation and (2) 25 lesions that occurred with asymptomatic PML observed at week 72. The sum of all other N/NET2 lesions in NOVA was 18 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 consistent with the known drug profile and similar between groups.
Conclusion(s):
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. No conclusions on PML risk can be drawn from NOVA.
*Additional authors: Karen Smirnakis (Biogen, Cambridge, USA); Shan Xiao (Biogen, Cambridge, USA); George Kong (Biogen, Cambridge, USA); Robert Kuhelj (Biogen, Baar, Switzerland); Nolan Campbell Biogen, Cambridge, USA).