Phase 3 VALOR Data Further Supports Tofersen’s Impact on ALS Disease Progression, Survival

Investigators recently published an integrated analysis of the phase 3 VALOR study (NCT02623699), which showed that early treatment with tofersen (Qalsody; Biogen) led to slowed neurodegeneration and clinical disease progression as well as improved survival in patients with SOD1 forms of amyotrophic lateral sclerosis (ALS). Additionally, the data further lend support to the use of neurofilament light (NfL) as a prognostic biomarker of ALS disease progression and survival.¹

Published in JAMA Neurology, VALOR was a double-blind, placebo-controlled trial that included 108 patients with ALS spanning 42 unique SOD1 pathogenic variants. Patients in the trial were randomly assigned 2:1 to either early-start tofersen 100 mg or placebo/delayed-start for a 24-week treatment period. Among these, 90% (97 of 108) completed the double-blind portion, and 88% (95 of 108) entered the open-label extension (OLE).

Led by several leaders in ALS research, including Cathy Lomen-Hoerth, MD, PhD, director of the ALS Center at UCSF, the studies were not powered to detect statistically significant differences between the early-start (≥3 years on the drug) and placebo/delayed-start (0.5 years placebo and ≥2.5 or more years taking the drug) groups. Regardless, earlier initiation of tofersen–relative to later initiation–was associated with numerically less decline in measures of clinical function (ALS Functional Rating Scale [ALSFRS-R]-Revised score (–9.9 vs –13.5 points), respiratory function (SVC, –13.8% vs –18.1%), muscle strength (HHD megascore, –0.38 vs –0.43 points), and quality of life (ALSAQ-5 score, 17.0 vs 22.5 points; EQ-5D-5L score, –0.1 vs –0.2 points).

“One big challenge in starting treatments early is that the typical delay in diagnosis of ALS remains long, on average 10 to 16 months, depending on presenting symptoms,” Hoerth wrote in a related column.² “With the advent of targeted treatments, where this degree of delay in treatment comes with measurable consequences, this will become increasingly unacceptable. Traditionally, there has been a reluctance to render the diagnosis of ALS given the low- efficacy treatments and poor prognosis, but this attitude of comfort with a delay in diagnosis will need to be addressed within the broader neurological and medical communities. Aggressive reeducation regarding the need for early diagnosis and referral will be important as more effective therapies emerge.”

In the concluding notes, the study authors wrote that “The substantial benefits of tofersen in SOD1-ALS have resparked enthusiasm for ALS drug development, as these data suggest that, with the right drug treating an upstream cause of disease, large meaningful effects are possible. We expect insights from this experience to empower therapeutic advances in other forms of ALS.”¹

Tofersen, an antisense oligonucleotide, was approved in 2023 as the first treatment for SOD1 ALS, with data from VALOR and its OLE used to support the approval. Tofersen’s approval was unique and groundbreaking as it marked the first time FDA regulators used change in NfL, a surrogate biomarker, to support an accelerated approval decision.²

In the latest published data, maximal reductions in plasma NfL were seen around the 16-mark following treatment initiation and remained consistent throughout the study period. At week 148, investigators observed a 67% reduction in the early-start group and 64% attenuation in the placebo/delayed-start groups, further suggesting tofersen slowed neurodegeneration. As shown in the early data, tofersen demonstrated target engagement, with cerebrospinal fluid (CSF) SOD1 reductions of 21% and 25% in the early-start and placebo/delayed-start groups, respectively, at week 148.

In the related editorial, Hoerth et al noted that “NfL is a relatively nonspecific biomarker of neurodegeneration that is released into the blood in the setting of axonal injury. Even so, it has emerged as a useful measure in ALS, with the first visit value correlating with survival and progression of disability7 and an elevation consistently occurring 6 to 12 months prior to phenoconversion in patients with SOD1-related ALS.8 Because of the reliability of NfL as a biomarker, it is becoming an extremely important part of ALS trial design.”

In the study, comparisons between early-start and placebo/delayed-start tofersen were associated with an HR of 0.64 (95% CI, 0.28-1.46) for risk of death or permanent ventilation (PV) and 0.52 (95% CI, 0.20-1.36) for risk of death. Among faster-progressing patients, median time to event was longer with early-start tofersen for death or PV (253.6 vs 76.0 weeks), death (253.6 vs 115.4 weeks), and the composite of death, PV, or withdrawal due to disease progression (103.6 vs 57.3 weeks), translating to extended event-free survival by approximately 3.4 years, 2.65 years, and 0.89 years, respectively. In the slower-progressing subgroup, median time to event was not reached in either treatment arm.

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To assess whether the strength gains seen with tofersen could be attributable to chance, investigators also modeled expected outcomes using clinical data from the dexpramipexole EMPOWER study. They noted that comparing VALOR/OLE results with 1-year handheld dynamometry (HHD) data from EMPOWER is a conservative strategy, since the likelihood of improvement would be expected to decline over the longer 3-year follow-up in VALOR/OLE.

Even under this conservative assumption, the probability of observing a greater than 20% response with increased strength at 1 year was calculated as 0% (P < .001). In VALOR/OLE, 27.3% of tofersen-treated participants demonstrated strength gains, supporting the interpretation that tofersen may meaningfully slow ALS progression.

In terms of safety, almost every patient experienced a treatment-emergent adverse event (TEAE), with the most common being headache (60.6%), procedural pain (59.6%), fall (47.1%), back pain (47.1%) and pain in extremity (39.4%), among others. The most serious events, occurring in more than 3% of patients, were respiratory failure (12.5%), pneumonia aspiration (11.5%), acute respiratory failure (7.7%), and dysphagia (7.7%), among others. Overall, 9 participants (8.7%) experienced 10 serious neurologic AEs, including myelitis/radiculitis, papilledema and/or increased intracranial pressure, and chemical or aseptic meningitis, all of which were manageable with local standard of care and resolved.

“The benefits of tofersen must be weighed against potential risks,” the study authors wrote. “Most AEs reported during treatment were consistent with the types and severities of AEs seen in patients with SOD1-ALS, common comorbidities, or events observed in the context of lumbar puncture. Some participants experienced serious neurological events, which were manageable with standard of care; most participants continued treatment. The type and rate of events were similar to those previously reported from this dataset and will continue to be monitored and characterized in the postmarketing setting.”

To date, tofersen remains the only FDA-approved therapy for SOD1-ALS, which affect around 2% of patients with ALS. More than a year after tofersen (Qalsody; Biogen) was approved in the US, it gained EU approval for the same indication.

Regarding the newly published data from VALOR, Hoerth and colleagues concluded by saying “Tofersen’s impact on SOD1-related ALS is a first step in allow- ing us to change our rhetoric and describe ALS as a treatable disease and is helping to light the path toward targeted mean- ingful therapies in ALS. Perhaps there will come a day when most patients with ALS will receive therapies that allow rein- nervation to outpace denervation and ALS will be reclassified as a manageable disease.”

REFERENCES
1. 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
2. Elman L, Wymer J, Lomen-Hoerth C. Tofersen, SOD1, and the Treatability of Amyotrophic Lateral Sclerosis. JAMA Neurol. Published online December 22, 2025. 10.1001/jamaneurol.2025.4927
3. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. News release. FDA. April 25, 2023. Accessed January 14, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene