FDA Panel Votes on Tofersen for SOD1 Amyotrophic Lateral Sclerosis

The Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously in favor of accelerated approval of tofersen for the treatment of superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1-ALS).

Tofersen is an investigational antisense medicine that reduces the synthesis of SOD1 protein production by binding to SOD1 mRNA, allowing for its degradation by RNase-H. The application is supported by data from the 28-week, randomized phase 3 VALOR study (ClinicalTrials.gov Identifier: NCT02623699), which compared the efficacy and safety of tofersen to placebo in 108 adults with ALS and a documented SOD1 mutation. Of these patients, 95 enrolled in the ongoing open-label extension (OLE) study (ClinicalTrials.gov Identifier: NCT03070119).

While the study did not meet its primary endpoint of change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared with placebo, treatment with tofersen showed trends of reducing disease progression across secondary and exploratory endpoints.

According to 12-month data, the early initiation of tofersen (at the start of VALOR) compared with delayed-start (6 months later in the OLE study) showed reductions in plasma neurofilament light chain (NfL) levels, a marker of neurodegeneration. A statistical model showed that these reductions in plasma NfL were directly associated with a reduction in worsening of clinical function and prolonged event-free survival. While the median time to death or permanent ventilation (PV) were not estimable due to the limited number of events, findings showed that the risk of death or PV and the risk of death were reduced by 64% and 73%, respectively, in the early-start group compared with the delayed-start group. 

Early initiation of tofersen compared with delayed initiation also resulted in improvements on measures of respiratory function (as measured by slow vital capacity), muscle strength (as measured by the handheld dynamometry megascore), and quality of life (as measured by the 5-item amyotrophic lateral sclerosis assessment questionnaire).

Based on the available evidence, on the question of whether a reduction in plasma NfL concentration in tofersen-treated patients was reasonably likely to predict clinical benefit of tofersen, the committee voted 9 yes and 0 no.

Regarding the potential for traditional approval, the committee voted 3 yes and 5 no with 1 abstention on the question of whether the clinical data from the placebo-controlled study and available long-term extension study results, along with results from the effects on relevant biomarkers, provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS.

Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A decision on the application is expected on April 25, 2023.

Tofersen is currently being evaluated in the phase 3 ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) in clinically presymptomatic adults with a SOD1 genetic mutation and biomarker evidence of disease activity. If tofersen is approved under the accelerated pathway, the ATLAS study would serve as the confirmatory trial for traditional approval, in addition to supportive data from the OLE and real-world evidence.