Tofersen Fails to Improve Motor Functions in Patients With SOD1 ALS

In patients with amyotrophic lateral sclerosis (ALS) and superoxide dismutase 1 (SOD1) mutations, tofersen, an antisense oligonucleotide, does not lead to functional improvement compared with placebo, according to a randomized phase 3 trial published in The New England Journal of Medicine.

An estimated 2% of ALS cases are caused by SOD1 mutations. Toxic gain of function of the mutant SOD1 protein is believed to be the cause of neuronal degeneration in SOD1 ALS. Tofersen is designed to reduce SOD1 protein synthesis by meditating the degradation of SOD1 messenger RNA. Researchers sought to assess the efficacy and safety of tofersen in adults with SOD1 ALS.

Researchers conducted a phase 3, double-blind, randomized, placebo-controlled VALOR component (part C; ClinicalTrials.gov Identifier: NCT02623699) of a 3-part trial — the first 2 parts were dose-escalation trials designed to evaluate the dose of intrathecal tofersen to be used in part C.

Participants were enrolled between March 2019 and July 2021 at 32 sites in 10 countries. The trial comprised a 4-week screening period, a 24-week treatment period, and a follow-up period of 4 to 8 weeks, which was followed by an ongoing extension phase. All participants were randomly assigned in a 2:1 ratio to receive an intrathecal bolus injection through a lumbar puncture of a 15 mL solution of tofersen (100 mg) or an equivalent volume of placebo over a 24-week period.

The primary study endpoint of VALOR was change from baseline to week 28 in the total score on the ALS Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, in which higher numbers are indicative of better function) among patients who were predicted to have more rapidly progressing ALS. The ALSFRS-R includes 12 items across 4 subdomains of function (ie, bulbar, fine motor, gross motor, and breathing).

Secondary endpoints were changes in total concentration of SOD1 protein in cerebrospinal spinal (CSF), concentration of neurofilament light (NfL) chains in plasma, percentage of predicted slow vital capacity, handheld dynamometry megascore in 16 muscle groups in the arms and legs, time to death or permanent ventilation, and safety.

Following completion of VALOR, all patients were provided with the option of participating in an open-label extension for up to 236 weeks while they remained unaware of their group assignment in VALOR. At week 52, the combined analysis of VALOR and its open-label extension was prespecified, and was designed to allow comparison of early-initiation and delayed-start tofersen in the full intention-to-treat study population.

Individuals with weakness that was attributable to ALS and a confirmed SOD1 mutation were enrolled in the current trial. The primary analysis population comprised the subgroup of patients who fulfilled the trial-defined prognostic criteria for faster-progressing disease. A combined analysis of the randomized component of the study and its open-label extension at 52 weeks compared the results among participants who initiated tofersen at trial entry (ie, early-start group) with those among participants who switched from placebo to tofersen at week 28 (ie, delayed-start cohort).

A total of 108 participants with 42 unique SOD1 mutations were enrolled in the VALOR trial. Among them, 72 were assigned to be treated with tofersen (39 of whom were predicted to experience faster disease progression) and 36 received placebo (21 of whom were predicted to experience faster progression).

The researchers found that tofersen therapy was associated with greater reductions in concentrations of SOD1 in CSF and of NfL chains in plasma compared with placebo. In the faster-progression subgroup (primary analysis), the change in ALSFRS-R score to week 28 was –6.98 points with tofersen vs –8.14 points with placebo (difference, 1.2 points; 95% CI, –3.2 to 5.5; P =.97). Results for the secondary clinical endpoints were not significantly different between the 2 groups.

Overall, 88% (95 of 108) of VALOR participants were enrolled in the open-label extension. At 52 weeks, change in ALSFRS-R score was –6.0 points in the early-start cohort vs –9.5 points in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7). Nonmultiplicity-adjusted differences in favor of early-start tofersen were reported for other endpoints as well.

The occurrence of lumbar puncture–related adverse events (AEs) was common. Neurologic serious AEs, including myelitis, chemical or aseptic meningitis, lumbar radiculopathy,  papilledema, and increased intracranial pressure, were reported in approximately 7% of tofersen-treated participants.

A key limitation of the current study is the fact that the possible signal of differences in clinical endpoints between the early-start cohort and the delayed-start cohort in the combined analysis of VALOR suggests that a trial duration of more than 28 weeks may be needed to establish the effect of tofersen in patients with ALS.

The researchers concluded that “The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the ongoing extension phase.”

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Editor’s note: This article was revised on October 24, 2022 to correct errors introduced during the editing process.