Amyotrophic lateral sclerosis: moving towards a new classification system.

Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice.

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

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.