26 Apr 2023

The U.S. Food and Drug Administration has approved tofersen for the treatment of ALS. Developed originally by Ionis Pharmaceuticals and evaluated in clinical trials by Biogen, the antisense oligonucleotide (ASO) targets expression of superoxide dismutase 1. About 2 percent of people with ALS carry pathogenic variants in this gene, affecting about 330 people in the United States. As with the approval of Biogen’s aducanumab for Alzheimer’s disease almost two years ago, the accelerated approval for tofersen was based not on slowing of disease, but on a drop in a biomarker, in this case levels of neurofilament light chain in the plasma.

Tofersen did not slow clinical decline in a Phase 3 study (Oct 2021 news). Over the course of the 28-week trial, 108 people who got the ASO as a spinal infusion biweekly declined as quickly as did those on a placebo. Still, there were hints of efficacy. Though the differences were not statistically significant, the treatment group trended better on all functional measures, including breathing ability and muscle strength.

SOD1 in the cerebrospinal fluid fell by about 35 percent, and plasma NfL by 55 percent. On March 22, an FDA advisory committee had unanimously agreed that the NfL change was likely predictive of clinical benefit. It voted 5-3 that the clinical data does not provide convincing evidence of effectiveness; one member abstained. For background, see FDA and Biogen briefing documents. Combined results from the Phase 3 trial and an open-label extension suggested that people who were on the drug from the get-go did better than those who switched from placebo by week 52 (Miller et al., 2022). 

Accelerated approval stipulates that efficacy must be proven in subsequent trials. In May 2021 Biogen began a Phase 3 prevention trial in asymptomatic carriers of SOD mutations. It is expected to run until 2027. The primary endpoint will be the proportion of people who develop symptoms of ALS within a year of treatment.—Tom Fagan