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Clinical Trial

Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis

Timothy M Miller et al. JAMA Neurol. .

Abstract

Importance: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

Objective: To evaluate the long-term effects of tofersen in adults with SOD1-ALS.

Design, setting, and participants: The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).

Intervention and exposure: Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.

Main outcomes and measures: Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.

Results: VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation.

Conclusions and relevance: Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population.

Trial registration: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Miller reported that resources to complete the study were provided by Biogen during the conduct of the study and reported personal fees from Ionis Pharmaceuticals, Biogen, Arbor Bio, and Biomarin outside the submitted work; in addition, Dr Miller had a patent for Ionis licensed and a patent for C2N licensed. Dr Cudkowicz reported board member service for Praxis Precision Medicines and consulting for Novartis, Quralis, Immunity Pharma, Regeneron, Otsuka, and Ono outside the submitted work. Dr Shaw reported grants from Biogen outside the submitted work. Dr Sobue reported personal fees from Biogen during the conduct of the study. Dr Bucelli reported personal fees from Biogen (consultant and advisory board fees) and grants from Biogen (site principal investigator [PI] for multiple Biogen-sponsored trials, including the trials covered in this article) during the conduct of the study as well as personal fees from Regeneron for advisory board service outside the submitted work and serving as site PI for an Ionis-sponsored FUSION trial (NCT04768972) but received no direct personal compensation related to this role and is no longer the PI for this trial. Dr Van Damme reported advisory board fees (paid to institution) from Biogen, Amylyx, Zambon, Ferrer, QurAlis, Argenx, UCB, Augustine Therapeutics, VectorY, Sapreme Technologies, and Novartis as well as grants from CSL Behring (paid to institution) outside the submitted work. Dr Ludolph reported grants from Biogen during the conduct of the study. Dr Andrews reported grants (paid to institution) from Amylyx, Biogen, Cytokinetics, Corcept, Ra Pharma, Biohaven, Clene, Prilenia, and Calico and personal fees for data safety monitoring board service and/or advisory board service from AL-S Pharma, Quralis, Sanofi, Novartis, Apellis, Bristol Myers Squibb, Neurosense, and Akava outside the submitted work. Dr Babu reported grants from Biogen, Ionis, and Denali and consulting fees (paid to institution) from Uniqure and Takeda outside the submitted work. Dr Benatar reported other from Biogen (per patient costs for trial participants) during the conduct of the study as well as personal fees for scientific advisory board service from Biogen, Trace Neuroscience, Evox, Novartis, Woolsey, Eli Lilly, Prilenia, Alector, Alaunos, Arrowhead, Coya, and VectorY outside the submitted work; in addition, Dr Benatar had a patent for Determining the Onset of ALS pending and serves as a nonpaid member of the Board of Trustees of the ALS Association. Dr McDermott reported other from Biogen (funds to support the clinical trial) and grants from Amlyx (consultancy), Verge (data monitoring committee member), the National Institute for Health and Care Research, Motor Neurone Disease Association, My Name’5 Doddie Foundation, and LifeArc outside the submitted work. Dr Bruneteau reported other from Biogen (serving as a site investigator) during the conduct of the study. Dr Al-Chalabi reported grants from the National Institute for Health and Care Research, EU Horizon 2020, Motor Neurone Disease Association, My Name’5 Doddie Foundation, Motor Neurone Disease Scotland, and the Alan Davidson Foundation outside the submitted work; in addition, Dr Al-Chalabi had a patent for use of CSF-neurofilament determinations and CSF-neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases pending and reports consultancies or advisory board service for Amylyx, Apellis, Biogen, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, Sanofi, Voyager Therapeutics, and Wave Pharmaceuticals. Dr Graham reported employment at and stock and/or stock option ownership in Biogen. Dr McNeill reported employment at Biogen during the conduct of the study. Dr Malek reported employment at Biogen during the conduct of the study. Dr Inra reported employment at Biogen during the conduct of the study. Dr Garafalo employment at and stock and/or stock option ownership in Biogen during the conduct of the study. Dr Fradette reported employment at and shareholdership in Biogen during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Change in Outcomes From Baseline to Week 148
Error bars represent 95% CIs (A) or standard errors (B, C and D). Missing data were handled using multiple imputation. ALSFRS-R indicates Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; HHD, handheld dynamometry; LS, least squares; NfL, neurofilament light chain; OLE, open-label extension; SVC, slow vital capacity.
Figure 2.
Figure 2.. Time to Death or Permanent Ventilation
Baseline plasma neurofilament light chain (NfL) was <75.6 pg/mL in the slower-progressing subgroup and ≥75.6 pg/mL in the faster-progressing subgroup. Time to death or permanent ventilation was defined as the time from first dose to death or permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days), whichever came first. Participants who did not meet the end point definition were censored at the last known date they were alive. Only events that were adjudicated by the end point adjudication committee were included. Cross marks indicate censored observations. The dotted line corresponds to week 192, the time point when the last participant enrolled reached the end of the study. ITT indicates intention-to-treat.
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Comment in

References

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