In this study, we analyzed the effect of tofersen on clinical parameters (ALSFRS-R, progression rate, muscle strength, and quality of life), biomarkers (phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF) as well as NfL in serum, creatine kinase (CK), and C-reactive protein (CRP) in serum), and safety (adverse events and CSF abnormalities) in a cohort of n = 24 ALS patients with (likely) pathogenic SOD1 variants from ten centers participating in the German tofersen EAP. The gene discussed is NEFH; the disease is amyotrophic lateral sclerosis.