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


BACKGROUND
ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330.
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.
Vincent
V
Meininger
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.
Pierre-François
PF
Pradat
Neuromuscular Pathology Lab, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Andrea
A
Corse
Department of Clinical Neuropathology, Kings College Hospital/Kings College London, London, United Kingdom.
Safa
S
Al-Sarraj
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.
Benjamin
B
Rix Brooks
Wake Forest School of Medicine, M Reynolds Tower, Medical Center Boulevard, Winston-Salem, North Carolina, United States of America.
James B
JB
Caress
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Merit
M
Cudkowicz
Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
Stephen J
SJ
Kolb
Department of Neurology, Weill Cornell School of Medicine, New York, New York, United States of America.
Dale
D
Lange
Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Sussex, United Kingdom.
P Nigel
PN
Leigh
Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Thomas
T
Meyer
Centro Ricerche Cliniche, University Hospital G.B. Rossi, Verona, Italy.
Stefano
S
Milleri
School of Clinical and Experimental Medicine, University of Birmingham and Neurosciences Department, Queen Elizabeth Hospital, Birmingham, United Kingdom.
Karen E
KE
Morrison
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.
Richard W
RW
Orrell
GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Gary
G
Peters
Brain Science Institute, Johns Hopkins University, Department of Neurology, Baltimore, Maryland, United States of America.
Jeffrey D
JD
Rothstein
Department of Neurology, SUNY Upstate Medical University, Syracuse, New York, United States of America.
Jeremy
J
Shefner
Neurosciences Therapy Area Unit, Medicines Discovery and Development, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom.
Arseniy
A
Lavrov
Clinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Nicola
N
Williams
Clinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Phil
P
Overend
Clinical Pharmacology, Science and Study Operations, BioPharm and Infectious Diseases, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Jeffrey
J
Price
BioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Stewart
S
Bates
Clinical Pharmacology Modelling & Simulation (Neurosciences), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Jonathan
J
Bullman
Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
David
D
Krull
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom.
Alienor
A
Berges
BioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
Bams
B
Abila
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom.
Guy
G
Meno-Tetang
Oncology Translational Medicine, Novartis Basel, Switzerland.
Jens
J
Wurthner
D061605:Administration, Intravenous; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009185:Myelin Proteins / Q000378:metabolism*; D000070798:Nogo Proteins
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000594256:ozanezumab