P.271Potential translation of neurofilament light chain (NfL) as a safety biomarker for neurotoxicity in spinal muscular atrophy

Abstract

Branaplam is an orally available small molecule that modulates Survival Motor Neuron 2 (SMN2) transcript splicing and increases generation of full length SMN2 mRNA with inclusion of Exon 7, leading to increased amount of functional SMN protein. It is in clinical development for treatment of Spinal Muscular Atrophy (SMA). Clear evidence of benefit has been shown without clinically apparent dose-limiting toxicities. However, non-clinical safety evaluations of branaplam suggested it may have a neurotoxicity risk. In toxicity studies using daily administration, a branaplam-related subtle peripheral neuropathy was discovered microscopically in juvenile dogs. This effect was potentially caused by stabilization ofmicrotubule polymerisation by branaplam. To investigate whether neurotoxicity is monitorable early, a thirty-week time-course study in dogs was conducted including digital nerve morphometry, measurement of neurofilament light (NfL) serum concentrations , and electrophysiological measurements. A minimal axonal degeneration of large fibers was confirmed at week 21. These findings correlated with release of NfL into serum. No clinical signs or changes in electrophysiological parameters were apparent, suggesting the microscopic findings and the associated serum increase of NfL precede neurologic dysfunction and overt clinical signs. Our data show that NfL is a sensitive marker of peripheral nerve injury and that it may be useful for monitoring the onset of treatment-related peripheral neurotoxicity in SMA patients and potentially, other indications. Differentiating between disease progression/activity and treatment-related adverse effects and understanding the relevance of increased NfL concentrations requires additional investigations. Although it remains unknown whether branaplam has a neurotoxic effect in humans, the weekly regimen used clinically may allow recovery from stabilizing effects on microtubule polymerization and avoid or minimize whatever led to the findings in dogs.