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Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity
Diethilde Theil1,2, Jens Kuhle3, Dominique Brees1
1Novartis Pharma AG, Basel, Switzerland.
Toxicologic Pathology
|July 13, 2023
Summary
Serum neurofilament light chain (NfL) may help monitor for peripheral neurotoxicity from branaplam. This biomarker detected nerve fiber degeneration in dogs treated with branaplam, even without clinical signs.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Branaplam, a splicing modulator for Spinal Muscular Atrophy Type 1 and Huntington's disease, showed promise but caused peripheral neurotoxicity in preclinical dog studies.
- Monitoring for treatment-related neurotoxicity is crucial for drug development.
Purpose of the Study:
- To investigate serum neurofilament light chain (NfL) as a potential biomarker for branaplam-induced peripheral neurotoxicity in dogs.
- To correlate NfL levels with neuropathological findings and electrophysiological changes.
Main Methods:
- A 30-week study in dogs treated with vehicle, pyridoxine (positive control), or branaplam.
- Assessment included neuropathology, nerve morphometry, electrophysiology, gene expression, and serum NfL concentration monitoring.
Main Results:
- Branaplam-treated dogs showed mild to moderate peripheral nerve fiber degeneration correlating with increased serum NfL.
- No electrophysiological changes or clinical signs were observed in branaplam-treated dogs.
- Pyridoxine-induced neurotoxicity showed elevated NfL with clinical signs and electrophysiological changes.
Conclusions:
- Serum NfL shows potential as an exploratory biomarker for detecting and monitoring peripheral nerve injury associated with branaplam.
- NfL may help identify neurotoxicity even in the absence of clinical signs, aiding drug safety assessments.
