Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.

Tofersen (QALSODY^®) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.