Abstract
ObjectiveTo explore whether the utility of neurofilament light chain
(NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy
development, would be enhanced by obtaining formal qualification from
the US Food and Drug Administration for a defined
context-of-use.MethodsConsensus discussion among academic, industry, and
patient advocacy group representatives.ResultsA wealth of scientific
evidence supports the use of NfL as a prognostic, response, and
potential safety biomarker in the broad ALS population, and as a
risk/susceptibility biomarker among the subset of SOD1 pathogenic
variant carriers. Although NfL has not yet been formally qualified for
any of these contexts-of-use, the US Food and Drug Administration has
provided accelerated approval for an SOD1-lowering antisense
oligonucleotide, based partially on the recognition that a reduction in
NfL is reasonably likely to predict a clinical benefit.InterpretationThe
increasing incorporation of NfL into ALS therapy development plans
provides evidence that its utility-as a prognostic, response,
risk/susceptibility, and/or safety biomarker-is already widely accepted
by the community. The willingness of the US Food and Drug Administration
to base regulatory decisions on rigorous peer-reviewed data-absent
formal qualification, leads us to conclude that formal qualification,
despite some benefits, is not essential for ongoing and future use of
NfL as a tool to aid ALS therapy development. Although the balance of
considerations for and against seeking NfL biomarker qualification will
undoubtedly vary across different diseases and contexts-of-use, the
robustness of the published data and careful deliberations of the ALS
community may offer valuable insights for other disease communities
grappling with the same issues. ANN NEUROL 2023
