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.
A double-blind, two-part, dose-escalation study was performed, in subjects with amyotrophic lateral sclerosis, 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, vital signs, electrocardiogram ( ECG ), and clinical laboratory tests ).
Secondary endpoints included pharmacokinetics, immunogenicity, functional endpoints ( clinical and electrophysiological ), and biomarker parameters.
Overall, Ozanezumab treatment ( 0.01-15 mg/kg ) was well tolerated. The overall incidence of adverse effects 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 adverse effects 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 ) has shown a weak, positive anti-Ozanezumab-antibody result.
Pharmacokinetics 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 amyotrophic lateral sclerosis. ( Xagena )
Meininger V et al, PLoS One 2014; 9:e97803