Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity

Author:

Theil Diethilde12ORCID,Kuhle Jens3,Brees Dominique1,Tritto Elaine1,Pognan François1,Frieauff Wilfried1,Penraat Kelley4,Meseck Emily5ORCID,Valdez Reginald46,Hartmann Andreas1

Affiliation:

1. Novartis Pharma AG, Basel, Switzerland

2. F. Hoffmann-La Roche AG, Basel, Switzerland

3. University Hospital Basel, Switzerland

4. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

5. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

6. Amgen, Inc., Cambridge, Massachusetts, USA

Abstract

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington’s disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.

Funder

Novartis

Publisher

SAGE Publications

Subject

Cell Biology,Toxicology,Molecular Biology,Pathology and Forensic Medicine

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