Biogen says ALS drug fails pivotal trial, but plans to broaden early access

Biogen reported that its experimental antisense drug tofersen missed the primary endpoint in a Phase III study of adults with amyotrophic lateral sclerosis (ALS) and a confirmed SOD1 mutation. However, it says the top-line findings, presented Sunday at the American Neurological Association (ANA) annual meeting, showed "trends favouring" tofersen across multiple secondary and exploratory measures, including motor and respiratory function, as well as quality-of-life.

The 28-week VALOR trial enroled 108 participants, including 60 who met the study's criteria for rapid progressors, with these making up the primary analysis population. Subjects were randomised to receive tofersen, also known as BIIB067, or placebo. Ninety-five patients who completed the trial went on to take part in the ongoing open-label extension study.

The primary efficacy endpoint of VALOR assessed change from baseline on the Revised ALS Functional Rating Scale (ALSFRS-R) total score to week 28 in the faster-progressing population. The trial showed a non-statistically-significant 1.2-point difference on the ALSFRS-R scale. In the group of patients with slower-progressing disease, the difference was 1.4 points. Analysts at Guggenheim Partners recently said an improvement of at least 2 points would be considered clinically meaningful.

'There is a clinical signal here'

Meanwhile, Biogen touted the drug's performance on some key secondary measures. The first looked at levels of SOD1 protein, a marker of target engagement, in cerebral spinal fluid. The company said differences seen between the tofersen and placebo groups were 38% and 26% in the faster- and slower-progressing populations, respectively. Another key endpoint measured change in plasma neurofilament light chain (NfL), a potential marker suggestive of a slowing in neuronal degeneration. The company said that in this case, differences between the tofersen and placebo groups were 67% and 48% in the faster- and slower-progressing populations, respectively.  

"Despite the fact that there was no statistically significant difference in the primary endpoint, there is a clinical signal here," according to lead investigator Timothy Miller, who added that "the wait for new options has been long and difficult for the ALS community, and we welcome this important research advancement."

In the faster-progressing population, Biogen also said trends favoured tofersen on measures of respiratory function, where the difference compared to placebo in percent-predicted slow vital capacity was 7.9, and on muscle strength, which was tested using a hand-held dynamometer. The company pointed to "similar trends" seen on exploratory patient-reported measures of disease severity, quality-of-life and fatigue. Biogen noted that median time to death and time to death or permanent ventilation could not be estimated for survival analyses due to the low number of events over the 28-week period.

Meanwhile, most side effects in trial patients were mild-to-moderate, including headache and back pain. However, serious neurologic events were reported in 4.8% of patients receiving tofersen in VALOR and its open-label extension, including two cases of myelitis, while 5.6% of tofersen patients dropped out of the study due to adverse events.

Wider access programme

The company, which licensed tofersen from Ionis Pharmaceuticals, and began offering compassionate-use access to the treatment earlier this year for a subset of the SOD1-ALS population with the most rapidly progressive disease, said it is engaging with regulators, the medical community and other stakeholders around the world to determine potential next steps. Alfred Sandrock, head of R&D at Biogen, said that "following discussions with investigators, bioethicists, and having listened to the voice of patient advocacy groups, we will broaden early access to tofersen to all eligible SOD1-ALS patients through our already established expanded access programme."

For more, see ViewPoints: Biogen may again test FDA's flexibility with tofersen.

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