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

Abstract

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.

Conflict of interest statement

Competing Interests: AL, NW, PO, JP, SB, JB, DK, AB, BA and GM-T are employees of and hold stock in GlaxoSmithKline. JW was a full-time employee of GlaxoSmithKline at the time of study and holds shares in the company. He is now an employee of Novartis. GP was a full-time employee of GlaxoSmithKline at the time of study and holds shares in the company. He is now an employee of Hammersmith Medicines Research. VM has previously received a consultancy fee from GlaxoSmithKline. AC has previously acted as a consultant to GlaxoSmithKline at a single-day advisory board meeting. PNL received travel expenses and consultancy fees for his work on the advisory board of this development. JDR has previously received funding from NIH, MDA, Robert Packard Center for ALS research and has acted as a consultant for Psyadon Pharmaceutical, Biogen Pharma and Cytokinetics. MC is on the GlaxoSmithKline scientific advisory board. P-FP, BRB, JBC, SJK, DL, TM, SM, SA-S and KEM have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Subject disposition flow diagram for Parts 1 and 2.

N, total number of subjects in group; n, number of subjects in category; PK, pharmacokinetics; SAE, serious adverse events. *Two doses, received 4 weeks apart.

Figure 2. Mean plasma ozanezumab concentration-time profiles following single (A) or two (B) IV infusions of ozanezumab.

Figure 3. Co-localization of membrane Nogo-A with ozanezumab in skeletal muscle of individual subjects.

A. Triplicate readings are provided from biopsies in Cohort 7 and 8 (single reading from Cohort 5) dose 2 +D22–26, biopsy taken 22–26 days after the second dose; dose 1 +24H, biopsy taken 24 hours after first dose. B. Nogo-A (red), ozanezumab (green) and co-localization (yellow), in muscle biopsy, 24 hours post-dose.