Long-Term Effects of Tofersen Treatment Evaluated in People with SOD1-ALS

Long-term treatment with Qalsody (tofersen; Biogen, Cambridge, MA) was associated with numerically less functional decline than expected from natural history comparisons in people with SOD1–associated amyotrophic lateral sclerosis (ALS), according to data published online in JAMA Neurology from the phase 3 VALOR clinical trial (NCT02623699) and its open-label extension (OLE; NCT03070119). The findings demonstrate numerical benefits in clinical, biomarker, and survival outcomes over approximately 3 years of follow-up for participants who initiated Qalsody treatment early vs those who started with placebo in the initial trial and switched to Qalsody treatment after 6 months for the OLE. Outcomes were numerically favorable; the analysis was not powered for definitive between-group efficacy because of sample size and crossover.

In VALOR, participants with SOD1-ALS were randomized 2:1 to receive intrathecal treatment with Qalsody 100 mg or placebo for 6 months. Participants were subsequently given the option to receive open-label Qalsody in the OLE. Analyses integrated data from both phases and evaluated outcomes including functional decline, survival, and biomarkers of neurodegeneration. Subgroup analyses were conducted based on baseline plasma neurofilament light (NfL) levels to account for disease heterogeneity. Safety outcomes were assessed across the combined treatment period.

Key findings included the following:

• Participants who initiated Qalsody treatment earlier and those who crossed over from placebo demonstrated numerically less functional decline than expected when compared with natural history cohorts.
• Participants showed reductions in plasma NfL levels from baseline to week 148 of 67% (early-start group) and 64% (placebo/delayed-start group); these NfL level reductions preceded clinical effects.
• Higher baseline NfL levels were associated with faster disease progression, supporting its prognostic value.
• Earlier Qalsody initiation vs later initiation was associated with reduced decline in:
• Clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score, -9.9 vs-13.5 points).
• Muscle strength (handheld dynamometry megascore, -.38 vs -.43 points).
• Respiratory function (slow vital capacity, -13.8% vs -18.1%).
• Quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQoL Dimension, 5-Level Questionnaire score, -.1 vs -.2 points)
• Earlier Qalsody initiation was also associated with a lower risk of death-equivalent events (including permanent ventilation and withdrawal due to disease progression) compared with delayed initiation.
• Serious neurologic adverse events occurred in 8.7% of participants, and were generally manageable with standard care, and resolved in most cases.

Source: Miller TM, Cudkowicz ME, Shaw PJ, et al. Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. JAMA Neurol. Published online December 22, 2025. doi:10.1001/jamaneurol.2025.4946