Patients with SOD1-mutated amyotrophic lateral sclerosis (ALS) appeared to benefit from treatment with the intrathecal antisense oligonucleotide tofersen, based on final data from the phase III VALOR trial and its open-label extension (OLE) study published in JAMA Neurology by Miller et al.
“Tofersen [was] designed to reduce SOD1 protein synthesis [and] is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene,” the investigators commented. “[Our long-term findings] provide clear rationale for its use in this population.”
Study Details
For the trial, known as VALOR, a total of 108 patients from 32 sites in 10 countries who were aged at least 18 years with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant were randomly assigned in a 2:1 ratio to receive 100 mg of tofersen or placebo over 24 weeks.
Following this period, 95 of these patients enrolled in the OLE study, of whom 46 completed (early-start group: n = 34 [47%]; placebo/delayed-start [approximately 6 months later] group: n = 12 [33%]). All were treated with tofersen. At completion, total follow-up from VALOR initiation could reach 3.5 years or more (range = 192–276 weeks).
An integrated analysis of the VALOR trial and its OLE study evaluated outcomes with early initiation of tofersen compared with placebo/delayed initiation. Measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival were included as key efficacy endpoints.
Key Findings
Over 148 weeks, earlier vs later initiation of tofersen seemed to be 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). Survival in patients treated with tofersen was found to exceed that predicted based on the expected natural history of SOD1-mutated ALS.
According to the investigators, most adverse events were consistent with disease progression or known procedural effects. All serious neurologic adverse events were reversible, they noted, with few resulting in discontinuation of treatment with tofersen.
“The substantial benefits of tofersen in SOD1-[mutated] 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,” the investigators commented. We expect insights from this experience to empower therapeutic advances in other forms of ALS.”
Timothy M. Miller, MD, of Washington University School of Medicine, St. Louis, is one of the corresponding authors of the article in JAMA Neurology.
Disclosure: This study was funded by Biogen. For full disclosures of the study authors, visit jamanetwork.com.
Source: JAMA Neurology
