Identification of tofersen PD-response biomarkers in VALOR clinical trial CSF via multiplexed quantitative proteomics

Tofersen, the first approved genetically targeted therapy for amyotrophic lateral sclerosis (ALS), demonstrates significant lowering of plasma neurofilament in adults carrying mutations in the superoxide dismutase 1 (SOD1) gene; however, additional biomarkers of treatment response in ALS are lacking. Here, we analyze longitudinally collected cerebrospinal fluid (CSF) samples from the phase 3 VALOR clinical trial to identify candidate tofersen treatment-response biomarkers in SOD1-ALS via quantitative proteomics. We observe significant modulation from baseline abundance for 56 proteins in tofersen-treated participants relative to placebo, including CSF GPNMB, which is significantly and continuously elevated across all post-baseline timepoints. We orthogonally confirm this observation by GPNMB immunoassay in independent tofersen-treated cohorts. Taken together, these data identify pharmacodynamic-response biomarkers of tofersen treatment that can be measured as early as 4 weeks post-treatment in SOD1-ALS patients and demonstrate the utility of leveraging unbiased proteomic screening integrated with targeted validation methods to identify pharmacodynamic-response biomarkers in clinical trial patient samples.