Plasma Neurofilament Heavy Chain Levels correlate with disease severity and progression on multiple clinical outcomes in Amyotrophic Lateral Sclerosis (ALS) (S3.004)

Objective: To assess the associations between plasma neurofilament heavy chain (NF-H) levels and outcome measures of disease severity, progression, and survival in a large, global, Phase 3 ALS clinical trial population. Background: Neurofilaments (NF) are a major component of the mature axonal cytoskeleton and are a promising biomarker of neurodegeneration. Elevated levels of NF can be measured in the CSF and blood of ALS patients and have been shown to have diagnostic and prognostic value. In addition, modulation of NF levels in pre-clinical models of neurodegeneration may track with therapeutic response. Thus NF may be a promising biomarker in ALS but their performance in large clinical trials is unknown. In the present study, we measured the baseline NF-H levels in plasma of patients who participated in EMPOWER a large, phase III, randomized, double-blind, placebo-controlled, study of dexpramiprexole and correlated NF-H levels to demographic variables, measures of ALS disease severity and progression over a 12 month period. Design/Methods: Baseline plasma samples of 663 of the total 943 participants were available for this study. NF-H was measured (Simple Plex NF-H assay, Protein Simple) in plasma. Correlations of NF-H with demographic and clinical variables at baseline and the rate of decline over the next 12 months was assessed. Results: Higher plasma NF-H levels were correlated with bulbar onset, lower BMI, lower ALSFRS-R, SVC, and HHD mega score. No correlation was seen with age and sex. Furthermore, higher NF-H levels were correlated with worse decline on ALSFRS-R, SVC, HHD megascore and were an independent predictor of worse survival. Longitudinal change of plasma NF-H levels is currently being examined in this population as well as examining neurofilament light (NF-L) levels. Conclusions: Plasma NFH correlates with multiple measures of ALS disease severity and predicts worse disease progression. This work further supports neurofilament as a promising biomarker in ALS clinical trials. Disclosure: Dr. Han has received personal compensation for activities with Biogen Idec as an employee. Dr. Han holds stock and/or stock options in Biogen Idec. Dr. Liu has received personal compensation for activities with Biogen as an employee. Dr. Ciotti has received personal compensation for activities with Biogen as an employee. Dr. Ferguson has received personal compensation for activities with Biogen as an employee. Dr. Ray has received personal compensation for activities with Biogen Idec. Dr. Ray holds stock and/or stock options in Biogen Idec. Dr. Johns has received personal compensation for activities with Novartis as an employee. Dr. Johns holds stock and/or stock options in Novartis, which sponsored research in which Dr. Johns was involved as an investigator. Dr. Johns holds stock and/or stock options in Novartis. Dr. Johns has received research support from Novartis.