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Tofersen Lowers Disease Markers, Slowing Progression for SOD1-Mutated ALS in Phase 3 Trial

Key findings

  • VALOR was a 28-week phase 3, multicenter, double-blind, randomized, placebo-controlled trial of tofersen for SOD1-mutated amyotrophic lateral sclerosis
  • Randomization of the 108 participants was stratified according to expected rate of disease progression, based on SOD1 mutation type and the estimated slope of the score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R)
  • The primary endpoint was change from baseline to week 28 in the ALSFRS-R total score in the faster-progression subgroup (n=60); the results did not differ significantly different between the tofersen and placebo groups in the double blind period. SOD1 was lowered as expected and neurofilament, a marker of neuronal degeneration, decreased by 50% in the treated group
  • In an analysis of VALOR and the first 52 weeks of an extension trial, there was a signal of differences in clinical endpoints between patients who started tofersen in the randomized phase and those who crossed over later
  • Across VALOR and the extension trial to date, neurologic serious adverse events occurred in 7% of patients receiving tofersen

Neuronal degeneration in amyotrophic lateral sclerosis (ALS) can be caused in rare cases by mutations in SOD1, the gene encoding superoxide dismutase 1. Tofersen, an investigational antisense drug, is designed to reduce the synthesis of the SOD1 protein. Researchers at Massachusetts General Hospital and elsewhere previously observed promising results in a phase 1/2 dose-escalation trial.

In a phase 3 study, though, Merit E. Cudkowicz, MD, MSc, chief of the Department of Neurology and director of the Sean M. Healey & AMG Center for ALS at Mass General, and colleagues found tofersen lowered SOD1 levels and neurofilament but in the first 28 weeks, did not improve clinical endpoints. There was evidence of benefit when results were combined with the first months of an ongoing open-label extension study. They report in The New England Journal of Medicine.


The phase 3 trial, VALOR, was conducted from March 2019 through July 2021 at 32 sites in 10 countries. Randomization was stratified according to the expected rate of disease progression, based on SOD1 mutation type and the estimated slope of the score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R).

In double-blind fashion, 108 patients were randomly assigned 2:1 to have an intrathecal bolus injection through a lumbar puncture of either:

  • A 15-mL solution of tofersen (100 mg) (n=72, including 39 patients predicted to have faster progression)
  • An equivalent volume of placebo (n=36, including 21 patients predicted to have faster progression)

Eight doses were administered over a 24-week period, followed by four to eight weeks of follow-up. The trial was sponsored by Biogen.

28-Week Results

The primary endpoint was the change from baseline to week 28 in the ALSFRS-R total score in the faster-progression subgroup. The ALSFRS-R evaluates four subdomains of function (bulbar, fine motor, gross motor, and breathing), with a total score of 0 (poorest function) to 48 (highest).

Among the 60 patients in the faster-progression subgroup, the change was:

  • Tofersen group: −6.98 points
  • Placebo group: −8.14 points
  • Difference: 1.2 points; 95% CI, −3.2 to 5.5 (P=0.97)

Compared with placebo, tofersen did lead to greater reductions in concentrations of SOD1 in cerebrospinal fluid in the faster-progression subgroup, as well as a greater reduction of neurofilament light chains. 

Extension Phase

After completing VALOR, 95 patients enrolled in a nonrandomized, open-label extension trial of tofersen that is scheduled to last 236 weeks. In the NEJM paper, the researchers report on:

  • 63 early-start participants who initiated tofersen during VALOR (could have faster- or slower-progressing disease)
  • 32 delayed-start participants who received placebo during VALOR

At 52 weeks from the VALOR baseline (data cutoff January 16, 2022), changes from baseline were:

  • ALSFRS-R score: −6.0 points for the early-start cohort vs. −9.5 points for the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4–6.7)
  • Percentage of predicted slow vital capacity: −9.4% vs. −18.6% (difference, 9.2 percentage points; 95% CI, 1.7–16.6)
  • Handheld dynamometry megascore: −0.17 vs. −0.45 (difference, 0.28; 95% CI, 0.05–0.52)

Safety and Adverse Events

Most adverse events across VALOR and the extension trial were mild to moderate in severity and did not cause withdrawal or discontinuation of tofersen. Most adverse events were consistent with ALS disease progression, conditions in the general population, or known side effects of lumbar puncture.

However, 7% of all patients who received tofersen had eight neurologic serious adverse events, including myelitis, chemical or aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, and papilledema.

Data Gathering Continues

The 52-week data suggest that a trial duration longer than 28 weeks may be required to determine the effect of tofersen in patients with ALS. The potential effects of earlier versus delayed initiation of tofersen will continue to be evaluated in the extension trial.

Learn more about the Sean M. Healey & AMG Center for ALS

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Tofersen, an investigational therapy for amyotrophic lateral sclerosis caused by SOD1 mutations, was safe and generally well tolerated over 12 weeks and lowered SOD1 protein levels in cerebrospinal fluid.


The Healey Platform ALS Trial, headquartered at Massachusetts General Hospital, launched in July 2020 and is expected to bring new treatments to patients with amyotrophic lateral sclerosis more quickly and at lower cost than randomized, controlled trials of single agents.