SOD1-ALS is associated with aggressive neurodegeneration, muscle atrophy, failure, and shorter survival. Tofersen is an antisense oligonucleotide delivered via an intrathecal route that specifically decreases production of SOD1 protein in neurons. Though the 28-week phase 3 VALOR trial primarily focused on evaluating short-term efficacy and biomarker responses, it was unclear if initiating treatment early versus later would have long-term effects, fuelling an integrated analysis of VALOR and its open-label extension trial.
The VALOR trial was a phase 3, double-blind, placebo-controlled clinical trial conducted at 32 sites across 10 countries between March 2019 and July 2021. A total of 108 subjects aged 18 years or older with evident ALS and proven SOD1 pathogenic variants were included. Patients were allocated at a 2:1 ratio for 24 weeks with 100 mg of tofersen or a placebo of tofersen. Post-VALOR, patients were eligible for participation in the open-label extension trial, which ended in August 2024 when all patients received 100 mg of tofersen.
In the combined analysis, the outcomes were compared between the early-start treatment group (those taking tofersen in the trial of recruitment) and the placebo/delayed-start treatment group (those taking a placebo in the VALOR study, followed by tofersen in the OLE study about 6 months later). Of the 108 participants in the study, 95 (88%) went on to the OLE study. The participants accumulated follow-up experience of up to 3.5 years or more of follow-up in the completed OLE study. The total number of weeks of observation varied between 192 and 276 weeks.
Results
Over 148 weeks of follow-up, earlier initiation of tofersen was associated with numerically less decline across multiple clinically meaningful outcomes.
Decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score was −9.9 points in the early-start group compared with −13.5 points in the delayed-start group.
Respiratory function declined by −13.8% versus −18.1% in slow vital capacity, while muscle strength loss measured by handheld dynamometry megascore was −0.38 versus −0.43 points.
Quality-of-life deterioration was also less pronounced with early treatment, including ALS Assessment Questionnaire-5 scores of 17.0 versus 22.5 points and EuroQol 5 Dimension 5 Level scores of −0.1 versus −0.2 points.
Final integrated results of the VALOR trial and open-label extension confirm that tofersen offers a significant and sustainable treatment response in SOD1-ALS patients when initiated early in the disease course. These positive findings form a robust rationale for SOD1-ALS treatment with tofersen and highlight the importance of early diagnosis and timely treatment with a gene-modulating therapeutic regimen.
Reference:
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
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