Safety, pharmacokinetic, and functional effects of the Nogo-A monoclonal antibody in amyotrophic lateral sclerosis: A randomized, first-in-human clinical trial

Vincent Meininger, Pierre François Pradat, Andrea Corse, Safa Al-Sarraj, Benjamin Rix Brooks, James B. Caress, Merit Cudkowicz, Stephen J. Kolb, Dale Lange, P. Nigel Leigh, Thomas Meyer, Stefano Milleri, Karen E. Morrison, Richard W. Orrell, Gary Peters, Jeffrey D. Rothstein, Jeremy Shefner, Arseniy Lavrov, Nicola Williams, Phil OverendJeffrey Price, Stewart Bates, Jonathan Bullman, David Krull, Alienor Berges, Bams Abila, Guy Meno-Tetang, Jens Wurthner

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42 Citations (Scopus)


The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3:1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3:1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS.

Original languageEnglish
Article numbere97803
JournalPLoS ONE
Issue number5
Publication statusPublished (in print/issue) - 19 May 2014


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