Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with <i>SOD1 </i>Mutations

<p dir="ltr"><b>Declarations</b></p><p dir="ltr"><b>Funding</b> The preparation of this review was not supported by any external funding.</p><p dir="ltr"><b>Authorship and Conflict of interest</b> Aisling McGuigan and Hannah A. Blair are salaried employees of Adis International Ltd/Springer Nature, and declare no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.</p><p dir="ltr"><b>Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability </b>Not applicable.</p><p><br></p><p dir="ltr">Additional information about this Adis Drug Review can be found <a href="http://www.springer.com/gp/adis/products-services/adis-journals-newsletters/adis-drug-reviews" target="_blank"><b>here</b></a>.</p><p><br></p><p dir="ltr"><b>Abstract</b></p><p dir="ltr">Tofersen (QALSODY^®) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (<i>SOD1</i>) mutations. Tofersen is an antisense oligonucleotide that induces <i>SOD1 </i>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 <i>SOD1 </i>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 <i>SOD1 </i>mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.</p><p dir="ltr"><br></p><p dir="ltr">© Springer Nature Switzerland AG 2025</p>