According to three-year data from the VALOR trial and its open-label extension (OLE), early initiation of tofersen therapy was associated with a numerically slower decline in function in patients with ALS caused by mutations in the SOD1 gene.2[3] In the primary phase of VALOR, the primary end-point was a change in ALSFRS-R score to 28. week; the difference between tofersen and placebo on intent-to-treat assessment was 1.4 points (95% CI: -1.3 to 4.1), numerically in favour of tofersen, but was not statistically significant.2 The biological effect was supported by a reduction in serum/neurofilament light chain (NfL), a biomarker of axonal damage, with tofersen treatment.[2] In the open-label part of the study, patients who started treatment earlier showed a numerically slower decline in clinical parameters over up to 3 years compared with patients with delayed treatment, according to published results and post-hoc analyses.[3] Long-term data from VALOR-OLE (and the 104-week results presented) are being used to assess the safety and maintenance of tofersen's effect.The approval and regulatory assessment of tofersen in some areas has been based on an overall combination of mechanism of action, biomarkers, and clinical data, including VALOR and OLE results.2