Meininger, VincentPradat, Pierre-FrançoisCorse, AndreaAl-Sarraj, SafaRix Brooks, BenjaminCaress, James B.Cudkowicz, MeritKolb, Stephen J.Lange, DaleLeigh, P. NigelMeyer, ThomasMilleri, StefanoMorrison, Karen E.Orrell, Richard W.Peters, GaryRothstein, Jeffrey D.Shefner, JeremyLavrov, ArseniyWilliams, NicolaOverend, PhilPrice, JeffreyBates, StewartBullman, JonathanKrull, DavidBerges, AlienorAbila, BamsMeno-Tetang, GuyWurthner, Jens2014-07-072014Meininger, V., P. Pradat, A. Corse, S. Al-Sarraj, B. Rix Brooks, J. B. Caress, M. Cudkowicz, et al. 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 9 (5): e97803. doi:10.1371/journal.pone.0097803. http://dx.doi.org/10.1371/journal.pone.0097803.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406965The 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 111330en-USBiology and Life SciencesAnatomyMusculoskeletal SystemImmunologyClinical ImmunologyImmunotherapyImmunityMedicine and Health SciencesClinical MedicineClinical TrialsNeurologyNeurodegenerative DiseasesMotor Neuron DiseasesAmyotrophic Lateral SclerosisPharmacologyAdverse ReactionsPharmacokineticsClinical Research DesignJournal Article2014-07-0710.1371/journal.pone.0097803