Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Ramsay Generale de Sante Hopital Prive Peupliers
- Montreal Neurological Institute and Hospital
- University Medical Center Utrecht
- University Hospitals Leuven
- Ulm University, Ulm, Germany
- University of Turin
- Hanyang University
- Westmead Hospital and the University of Sydney
- Barrow Neurological Institute
- Pasteur I University Hospital
- University of Southampton
- University Hospital Southampton NHS Foundation Trust
- Hannover Medical School
- University of Sussex
BACKGROUND: 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.
METHODS: 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 ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.
FINDINGS: 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).
INTERPRETATION: 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.
|Number of pages||9|
|Journal||The Lancet Neurology|
|Publication status||Published - Mar 2017|
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis/drug therapy, Antibodies, Monoclonal, Humanized/therapeutic use, Double-Blind Method, Electrocardiography, Female, Humans, Immunologic Factors/therapeutic use, International Cooperation, Male, Middle Aged, Nogo Proteins/immunology, Survival Analysis, Treatment Outcome, Young Adult