To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and neurofilament levels of tofersen in people with amyotrophic lateral sclerosis (ALS) and confirmed SOD1 mutation (SOD1-ALS).

ALS is a fatal, neurodegenerative disease characterized by loss or dysfunction of motor neurons. Approximately 2% of ALS cases are linked to superoxide dismutase (SOD1) mutations. Over 200 SOD1 mutations have been identified with variation in rate of disease progression. Toxicity of mutant SOD1 protein is due to gain of function, suggesting SOD1 reduction may be therapeutic. Tofersen, a genetically targeted antisense oligonucleotide that targets SOD1 mRNA and reduces SOD1 protein synthesis, is under development for treatment of SOD1-ALS.

This randomized, placebo-controlled, multiple-ascending dose study randomized 50 participants with confirmed SOD1 mutation to receive 4 doses of tofersen or placebo (3:1) for 12 weeks and followed for an additional ~12 weeks. Final primary, secondary, and exploratory endpoint data will be presented.

The majority of adverse events were mild or moderate in severity. Dose-dependent increases in tofersen concentrations in plasma and CSF were observed and a statistically significant reduction of CSF SOD1 (100 mg vs placebo) was also observed. A slowing of functional decline as measured by ALS Functional Rating Scale-Revised scores, slow vital capacity, and muscle strength was observed (100 mg vs placebo), with a greater difference observed between the 100 mg and placebo groups in participants with fast progressing SOD1 mutations. Baseline CSF and plasma phosphorylated neurofilament heavy and neurofilament light were generally highest in faster progressing participants. Treatment with tofersen was associated with a decline in neurofilament over time in contrast to apparent stabilization or increase observed in placebo-treated patients.

These data support further investigation of tofersen in people with SOD1-ALS, and highlight the potential role of neurofilament as a biomarker of disease activity and treatment response in ALS.