Meininger, V, Pradat, PF, Corse, A, Al-Sarraj, S, Rix, BB, Caress, JB, Cudkowicz, M, Kolb, SJ, Lange, D, Leigh, PN, Meyer, T, Milleri, S, Morrison, KE, Orrell, RW, Peters, G, Rothstein, JD, Shefner, J, Lavrov, A, Williams, N, Overend, P, Price, J, Bates, S, Bullman, J, Krull, D, Berges, A, Abila, B, Meno-Tetang, G and Wurthner, J (2014) Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS ONE. e97803-.

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 (3ratio1) 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 (3ratio1) 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

Item Type:	Article
Additional Information:	NIBR author: Wurthner, J institute: NIBR contributor address: Departement des Maladies du Systeme Nerveux, Assistance Publique - Hopitaux de Paris, Centre de Reference Maladies Rares SLA, Groupe Hospitalier Pitie-Salpetriere, Universite Pierre-et-Marie-Curie, Paris, FranceDepartement des Maladies du Systeme Nerveux, Assistance Publique - Hopitaux de Paris, Centre de Reference Maladies Rares SLA, Groupe Hospitalier Pitie-Salpetriere, Universite Pierre-et-Marie-Curie, Paris, France; Unite Mixte de Recherche-678, Institut National de la Sante et de la Recherche Medicale - Universite Pierre-et-Marie-Curie, Groupe Hospitalier Pitie-Salpetriere, Paris, FranceNeuromuscular Pathology Lab, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of AmericaDepartment of Clinical Neuropathology, Kings College Hospital/Kings College London, London, United KingdomCarolinas 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 AmericaWake Forest School of Medicine, M Reynolds Tower, Medical Center Boulevard, Winston-Salem, North Carolina, United States of AmericaDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of AmericaDepartment of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of AmericaDepartment of Neurology, Weill Cornell School of Medicine, New York, New York, United States of AmericaTrafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Sussex, United KingdomDepartment of Neurology, Charite - Universitatsmedizin Berlin, Berlin, GermanyCentro Ricerche Cliniche, University Hospital G.B. Rossi, Verona, ItalySchool of Clinical and Experimental Medicine, University of Birmingham and Neurosciences Department, Queen Elizabeth Hospital, Birmingham, United KingdomDepartment of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom; Department of Neurology, Royal Free London NHS Foundation Trust, London, United KingdomGlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, United KingdomBrain Science Institute, Johns Hopkins University, Department of Neurology, Baltimore, Maryland, United States of AmericaDepartment of Neurology, SUNY Upstate Medical University, Syracuse, New York, United States of AmericaNeurosciences Therapy Area Unit, Medicines Discovery and Development, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United KingdomClinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomClinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomClinical Pharmacology, Science and Study Operations, BioPharm and Infectious Diseases, GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomBioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomClinical Pharmacology Modelling & Simulation (Neurosciences), GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomSafety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of AmericaClinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United KingdomBioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United KingdomClinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United KingdomOncology Translational Medicine, Novartis Basel, Switzerland
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22628