- Long-term use of tofersen appeared to slow decline in SOD1-ALS patients.
- A subgroup of patients who started tofersen early trended toward improvements in function and strength.
- While SOD1 mutations are rare, the findings suggest that ALS may be a treatable disease.
Early initiation of tofersen (Qalsody) was associated with a numerically slower decline in people with SOD1 amyotrophic lateral sclerosis (ALS) compared with delayed treatment, according to data from the VALOR trial and its open-label extension.
Over 3 years, patients who started tofersen sooner had less decline in measures of clinical function based on ALS Functional Rating Scale-Revised scores (-9.9 vs -13.5 points), respiratory function based on slow vital capacity (-13.8% vs -18.1%), and muscle strength based on handheld dynamometry megascores (-0.38 vs -0.43 points), reported Timothy Miller, MD, PhD, of Washington University School of Medicine in St. Louis, and co-authors.
Levels of neurofilament light (NfL), a marker of axonal injury, dropped by 67% in the early-start group and 64% in the delayed-start group at week 148, the researchers wrote in JAMA Neurology. Analyses were not powered to detect significant differences between groups over this period.
Tofersen also extended survival relative to the expected natural history of SOD1-ALS, the researchers said. No new safety concerns were identified.
Notably, a subgroup of SOD1-ALS patients who started treatment early trended toward improvements in function and strength, the researchers observed.
Tofersen, approved for SOD1-ALS in 2023, is an intrathecal antisense oligonucleotide that targets mRNA to reduce SOD1 protein synthesis. Around 2% of ALS cases are caused by SOD1 mutations.
"For people with the SOD1 genetic form of ALS, these results are incredibly hopeful, documenting a substantial effect on slowing this particular form of ALS," Miller told MedPage Today.
The findings have wide-ranging implications, he noted. "First, this study shows that ALS is treatable: that with the right drug, this very tough and typically relentlessly progressive disease may be substantially slowed, with some people even showing improvement," Miller said.
"Second, these results show that this approach using antisense oligonucleotides can be successful in an adult-onset neurodegenerative disease. There are now multiple trials using a similar approach," he continued.
"Third, the biomarker neurofilament, which typically goes up in the setting of ALS, was lowered substantially in this study," he added. "Knowing that neurofilament is substantially lowered in the setting of a successful ALS treatment has tremendous implications for future clinical trials in ALS, allowing us to determine more quickly if a drug may be working."
The potential for improvement in ALS is a first, noted Lauren Elman, MD, of the University of Pennsylvania in Philadelphia, and colleagues in an accompanying editorial. "This would suggest that reinnervation with recovery of strength is outpacing denervation in certain individuals," Elman and co-authors wrote.
"Tofersen's impact on SOD1-related ALS is a first step in allowing us to change our rhetoric and describe ALS as a treatable disease and is helping to light the path toward targeted meaningful therapies in ALS," the editorialists pointed out. "Perhaps there will come a day when most patients with ALS will receive therapies that allow reinnervation to outpace denervation and ALS will be reclassified as a manageable disease."
VALOR was a 28-week, placebo-controlled trial with 108 ALS patients and 42 different SOD1 variants. Participants were randomized to 100-mg tofersen (the early-start group) or placebo (the delayed-start group) for 24 weeks, after which all received tofersen in the open-label extension.
VALOR results showed improvement in NfL with tofersen treatment, but not in muscle strength or motor outcomes. The open-label extension, completed in August 2024, included 95 participants; a total of 46 completed the extension.
The median treatment delay for the delayed-start group was 6 months. Baseline characteristics were similar between groups except for a 12% higher baseline NfL in the early-start cohort, a factor associated with faster progression in earlier ALS studies.
"Importantly, despite the limited sample size, crossover to active treatment at 6 months for the placebo group, and efficacy analyses not powered to detect a statistically significant difference, earlier initiation of tofersen was associated with reduced decline in function, strength, and the risk of death-equivalent events compared to initiation of tofersen approximately 6 months later, while both groups demonstrated numerically less decline across clinical measures than would be expected based on the natural history of ALS," Miller and colleagues noted.
The ongoing ATLAS trial is evaluating the efficacy of tofersen in presymptomatic SOD1 carriers with elevated NfL. The study is expected to finish in 2027.
Disclosures
Tofersen studies were funded by Biogen.
Miller reported relationships with Biogen, Arbor Bio, Biomarin, and Ionis Pharmaceuticals; he had a patent for Ionis licensed and a patent for C2N licensed.
Co-authors reported numerous relationships with pharmaceutical companies and other entities.
Elman reported relationships with Biogen, Genentech, Scholar Rock, Novartis, Catalyst, Edgewise, UpToDate, Guidepoint, and GLG Pharma. The other editorialists had no disclosures.
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