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

  • Lancet Neurol. 2017 Mar;16(3):208-216. doi: 10.1016/S1474-4422(16)30399-4.
Vincent Meininger  1 ,  Angela Genge  2 ,  Leonard H van den Berg  3 ,  Wim Robberecht  4 ,  Albert Ludolph  5 ,  Adriano Chio  6 ,  Seung H Kim  7 ,  P Nigel Leigh  8 ,  Matthew C Kiernan  9 ,  Jeremy M Shefner  10 ,  Claude Desnuelle  11 ,  Karen E Morrison  12 ,  Susanne Petri  13 ,  Diane Boswell  14 ,  Jane Temple  15 ,  Rajat Mohindra  16 ,  Matt Davies  16 ,  Jonathan Bullman  17 ,  Paul Rees  14 ,  Arseniy Lavrov  18 ,  NOG112264 Study Group
Affiliations
  • 1. Ramsay Generale de Sante Hopital Prive Peupliers, Paris, France.
  • 2. Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, QC, Canada.
  • 3. Department of Neurology, Brain Centre Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
  • 4. KU Leuven, Department of Neurosciences, Experimental Neurology University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
  • 5. Department of Neurology, University of Ulm, Ulm, Germany.
  • 6. Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
  • 7. Department of Neurology, Hanyang University Medical Center, Seoul, South Korea.
  • 8. Division of Medicine (Neurology), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, University of Sussex, East Sussex, UK.
  • 9. Brain & Mind Centre, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia.
  • 10. Barrow Neurological Institute, Phoenix, AZ, USA.
  • 11. Department of Neurology, University Hospital of Nice, Nice, France.
  • 12. Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, UK; Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK.
  • 13. Department of Neurology, Hannover Medical School, Hannover, Germany.
  • 14. Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK.
  • 15. R&D Projects Clinical Platforms and Sciences, Quantitative Sciences, Clinical Statistics, GlaxoSmithKline, Uxbridge, UK.
  • 16. Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Uxbridge, UK.
  • 17. Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, UK.
  • 18. Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK. Electronic address: [email protected].
PMID: 28139349 DOI: 10.1016/S1474-4422(16)30399-4
Abstract

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.

Funding: GlaxoSmithKline.

Products