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PLoS One. 2014 May 19;9(5):e97803. doi: 10.1371/journal.pone.0097803. eCollection 2014.

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

Author information

1
Département des Maladies du Système Nerveux, Assistance Publique - Hôpitaux de Paris, Centre de Référence Maladies Rares SLA, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre-et-Marie-Curie, Paris, France.
2
Département des Maladies du Système Nerveux, Assistance Publique - Hôpitaux de Paris, Centre de Référence Maladies Rares SLA, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre-et-Marie-Curie, Paris, France; Unité Mixte de Recherche-678, Institut National de la Santé et de la Recherche Médicale - Université Pierre-et-Marie-Curie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
3
Neuromuscular Pathology Lab, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
4
Department of Clinical Neuropathology, Kings College Hospital/Kings College London, London, United Kingdom.
5
Carolinas Neuromuscular/Amyotrophic Lateral Sclerosis-Muscular Dystrophy Association Center, Department of Neurology, Carolinas Medical Center and University of North Carolina School of Medicine-Charlotte Campus, Charlotte, North Carolina, United States of America.
6
Wake Forest School of Medicine, M Reynolds Tower, Medical Center Boulevard, Winston-Salem, North Carolina, United States of America.
7
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
8
Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
9
Department of Neurology, Weill Cornell School of Medicine, New York, New York, United States of America.
10
Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Sussex, United Kingdom.
11
Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
12
Centro Ricerche Cliniche, University Hospital G.B. Rossi, Verona, Italy.
13
School of Clinical and Experimental Medicine, University of Birmingham and Neurosciences Department, Queen Elizabeth Hospital, Birmingham, United Kingdom.
14
Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom; Department of Neurology, Royal Free London NHS Foundation Trust, London, United Kingdom.
15
GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
16
Brain Science Institute, Johns Hopkins University, Department of Neurology, Baltimore, Maryland, United States of America.
17
Department of Neurology, SUNY Upstate Medical University, Syracuse, New York, United States of America.
18
Neurosciences Therapy Area Unit, Medicines Discovery and Development, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom.
19
Clinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
20
Clinical Pharmacology, Science and Study Operations, BioPharm and Infectious Diseases, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
21
BioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
22
Clinical Pharmacology Modelling & Simulation (Neurosciences), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
23
Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
24
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom.
25
Oncology Translational Medicine, Novartis Basel, Switzerland.

Abstract

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330.

PMID:
24841795
PMCID:
PMC4026380
DOI:
10.1371/journal.pone.0097803
[Indexed for MEDLINE]
Free PMC Article

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