TY - JOUR
T1 - Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis
T2 - a randomized, first-in-human clinical trial
AU - Meininger, Vincent
AU - Pradat, Pierre-François
AU - Corse, Andrea
AU - Al-Sarraj, Safa
AU - Rix Brooks, Benjamin
AU - Caress, James B
AU - Cudkowicz, Merit
AU - Kolb, Stephen J
AU - Lange, Dale
AU - Leigh, P Nigel
AU - Meyer, Thomas
AU - Milleri, Stefano
AU - Morrison, Karen
AU - Orrell, Richard W
AU - Peters, Gary
AU - Rothstein, Jeffrey D
AU - Shefner, Jeremy
AU - Lavrov, Arseniy
AU - Williams, Nicola
AU - Overend, Phil
AU - Price, Jeffrey
AU - Bates, Stewart
AU - Bullman, Jonathan
AU - Krull, David
AU - Berges, Alienor
AU - Abila, Bams
AU - Meno-Tetang, Guy
AU - Wurthner, Jens
PY - 2014
Y1 - 2014
N2 - UNLABELLED: 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.
AB - UNLABELLED: 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.
KW - Administration, Intravenous
KW - Amyotrophic Lateral Sclerosis
KW - Antibodies, Monoclonal
KW - Antibodies, Monoclonal, Humanized
KW - Biological Markers
KW - Dose-Response Relationship, Drug
KW - Female
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Middle Aged
KW - Myelin Proteins
U2 - 10.1371/journal.pone.0097803
DO - 10.1371/journal.pone.0097803
M3 - Article
C2 - 24841795
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 5
M1 - 0097803
ER -