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Lancet Neurol. 2017 Mar;16(3):208-216. doi: 10.1016/S1474-4422(16)30399-4. Epub 2017 Jan 28.

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

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Ramsay Generale de Sante Hopital Prive Peupliers, Paris, France.
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, QC, Canada.
Department of Neurology, Brain Centre Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
KU Leuven, Department of Neurosciences, Experimental Neurology University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
Department of Neurology, University of Ulm, Ulm, Germany.
Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
Department of Neurology, Hanyang University Medical Center, Seoul, South Korea.
Division of Medicine (Neurology), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, University of Sussex, East Sussex, UK.
Brain & Mind Centre, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia.
Barrow Neurological Institute, Phoenix, AZ, USA.
Department of Neurology, University Hospital of Nice, Nice, France.
Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, UK; Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK.
R&D Projects Clinical Platforms and Sciences, Quantitative Sciences, Clinical Statistics, GlaxoSmithKline, Uxbridge, UK.
Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, UK.
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, UK.
Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK. Electronic address:



Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.


This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with, number NCT01753076, and with, NOG112264, and is completed.


Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).


Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.



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