Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors.

Abstract

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1-amyotrophic lateral sclerosis (SOD1-ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1-ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study's recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1-ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1-ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.