Non-clinical development of ozanezumab: a humanised antibody targeting the amino terminus of neurite outgrowth inhibitor A (Nogo-A)

Abstract

Ozanezumab (GSK1223249) is a humanised, Fc-disabled, monoclonal antibody (mAb) which targets the amino terminus of Neurite Outgrowth Inhibitor A (Nogo-A) which is currently being developed for the treatment of amyotrophic lateral sclerosis (ALS). Here we report on the biochemical and structural characterisation of Ozanezumab together with an assessment of pharmacology and non-clinical safety.A minimal binding epitope was characterised and emerging biology and pre-clinical pharmacology provide confidence that targeting the amino terminus of the neurite outgrowth inhibitor A (Nogo-A) through passive immunization may offer a promising approach to treat various neurodegenerative diseases, including ALS. A comprehensive non-clinical assessment of safety has been completed based on a package of in vitro and in vivo studies in rodents, non-human primates and female rabbits (reproductive toxicology only). There was no evidence for toxicological, cardiovascular, respiratory, neurobehavioural, immunogenic, reproductive or delayed toxicity effects in any species following repeat dose treatment with Ozanezumab (biweekly up to doses of 500 mg kg −1 iv for 52 weeks in the non-human primate).Based on these studies there are no non-clinical safety findings that would preclude the development of Ozanezumab in patients. d DMPK, GlaxoSmithKline, UK e Biopharm R&D TPDM Novartis, GlaxoSmithKline, UK This journal is

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial

“…11 These fi ndings led to the therapeutic hypothesis that blockade of Nogo-A signalling could prevent motor neuron loss in ALS. 9,11 In a preclinical study, 15 ozanezumab resulted in a dose-dependent decrease or reversal of neurite outgrowth inhibition in a rat postnatal cerebellar granular neuron culture. Furthermore, the murine parent antibody of ozanezumab had a positive eff ect in the SOD1 G93A transgenic mouse model of ALS, in which it improved spinal motor neuron and motor unit survival, increased skeletal muscle force, 10 and signifi cantly delayed the time to symptom onset (assessed as magnitude of motor defi cit compared with vehicle controls) and time to death (unpublished).…”

“…We selected an ozanezumab dose regimen of 15 mg/kg once every 2 weeks for this study on the basis of analysis of drug biodistribution into muscle, co-localisation of Nogo-A with ozanezumab at the target site (ie, muscle cell membrane), plasma pharmacokinetic data, and the safety profi le from clinical and non-clinical studies. 12,14,15 Patients received ozanezumab or placebo as intravenous infusions over 1 h. A total of 24 infusions were planned, starting at the baseline visit (week 0) and then every 2 weeks up to the last dose at week 46, followed by assessments at week 48 and week 60. Since this dosing regimen had not been tested in human beings previously, we used a two-part study design.…”

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

“…The membrane protein Nogo-A is an inhibitor of neurite outgrowth that was initially identified as a potent myelin-associated inhibitor of axonal growth and regeneration [181]. A colony stimulating factor 1R receptor (CSF1R) and c-kit inhibitor, masitinib (Figure 12), is effective against microglial, macrophage and mast cell activation.…”

“…The membrane protein Nogo-A is an inhibitor of neurite outgrowth that was initially identified as a potent myelin-associated inhibitor of axonal growth and regeneration [ 181 ]. Overexpressed, high amounts of Nogo-A were detected in skeletal muscles of ALS-linked mutant SOD1 mice and in patients with sALS [ 182 ].…”

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

“…Comprehensive pre-clinical toxicological studies into intrathecal Ozanezumab administration were performed in rodents, non-human primates, and female rabbits. The studies did not find any cardiovascular, respiratory, neurobehavioural, immunogenic, reproductive, or delayed toxicity effects in tested species following treatment with Ozanezumab [ 90 , 114 ]. A few clinical trials with Ozanezumab have been conducted in populations of patients with MS and ALS.…”