An antisense therapy for amyotrophic lateral sclerosis has posted negative results in a Phase 3 trial, according to topline data presented October 17 at the annual meeting of the American Neurological Association. Timothy Miller of Washington University School of Medicine, St. Louis, led Biogen’s VALOR trial. It tested tofersen, an antisense oligonucleotide directed against SOD1. At ANA, Miller reported that in a 28-week study, tofersen failed to slow decline on the revised ALS Functional Rating Scale (ALSFRS-R), though trends on several secondary endpoints favored the drug. Tofersen hit its target, lowering SOD1 in cerebrospinal fluid by nearly half. It also suppressed plasma neurofilament light, a marker of neurodegeneration, by two-thirds.

  • In Phase 3, the SOD1 ASO tofersen failed to slow decline in ALS.
  • All endpoints in this tiny trial trended in favor of drug.
  • Plasma NfL, a marker of neurodegeneration, dropped by two-thirds.

“The neurofilament change suggests slowing of the neurodegenerative disease process. Taken together, I consider all of this promising, despite the fact that the study did not meet the primary endpoint,” Miller wrote to Alzforum.

“This [trial] was a historical step on the path to targeted treatments for this serious disease,” Sabrina Paganoni at Massachusetts General Hospital, Boston, wrote to Alzforum, noting this was the first Phase 3 antisense trial for a genetic form of ALS. “The trial’s dataset is extremely rich, and it will be important to continue to examine the data and learn as much as possible from the study, which will determine the next steps for this investigational product.”

Tofersen, which was developed by Ionis Pharmaceuticals, had shown hints of efficacy in a small Phase 2 dose-finding study of 50 participants. The treatment slowed functional and physical decline and lowered CSF NfL, particularly in participants whose disease was progressing fast. However, the groups were too small for the trial to have statistical power (May 2019 conference news). Trials for SOD1-ALS are necessarily small, because only 2 percent of people with ALS—a rare disease to begin with—carry such mutations.

For Phase 3, Biogen recruited 108 SOD1-ALS patients, but confined the primary efficacy analysis to the 60 participants with faster-progressing disease. Among these, 39 received 100 mg tofersen as an infusion into the spinal cord every two weeks for six months, and 21 received placebo. At the end of the study, those on drug had slipped slightly less on the ALSFRS-R, by 7 points rather than 8 points for the placebo group. This difference was statistically insignificant. Participants on tofersen also declined slightly less on measures of breathing ability, muscle strength, and patient-reported quality of life.

Among the 48 participants whose disease progressed more slowly, outcomes also consistently favored tofersen, but again without reaching statistical significance. It is unclear how much statistical power this small study had to detect a treatment effect, and Biogen did not answer questions on this point.

Of the 108 participants, 95 enrolled in the open-label extension study, where all participants receive tofersen. The slower progressors, who were enrolled into VALOR first, now have 76 weeks of total data, while the faster progressors have 40 weeks. In participants in either group who switched from placebo to tofersen, both SOD1 and NfL dropped to nearly the levels in the treatment group. On other measures, decline slowed slightly during the OLE period compared to the blinded period; even so, the treatment group maintained a numerical advantage over the previous placebo group. This pattern is typically considered indicative of disease modification.

“When evaluating overall the clinical effects including looking at the OLE, there is a slowing of decline in the fast-progressing group, and stabilizing in the slower-progressing group,” Miller wrote to Alzforum.

In a survival analysis that measured time to either death, needing ventilation to breathe, or withdrawing from the study due to worsening of the disease, people who had been on tofersen from the beginning lasted longer than did those who were switched from placebo to tofersen. In addition, in an analysis of 17 fast-progressing VALOR participants who carried the particularly aggressive A4V SOD1 mutation, the median survival time was 1.5 years, surpassing the 1.2 years typically seen with this mutation.

Most adverse events were related to the spinal infusions or are common in ALS, including pain at the infusion site, headaches, falls, and pain in the back or limbs. However, people on tofersen had a higher risk of neurologic conditions, with five such events in the treatment group versus none on placebo. These included two people who developed myelitis, an inflammation of the spinal cord, which resolved with treatment. The other events were inflammation of a nerve in the lower back, inflammation of the meninges around the spinal cord, and an unspecified “nervous system disorder.”

Biogen has not yet disclosed future plans for tofersen. “Biogen is actively engaging with regulators, the medical community, patient-advocacy groups, and other key stakeholders around the world to determine potential next steps,” a spokesperson wrote to Alzforum.

In Huntington’s disease, the ASO therapy tominersen was discontinued in Phase 3 for lack of efficacy, despite halving huntingtin protein levels (Mar 2018 news). This and other failures, such as weak data for anti-tau antibodies, have led some to question whether suppressing aggregating proteins is the best approach in neurodegenerative disease (Oct 2021 news).—Madolyn Bowman Rogers


  1. The VALOR trial was an important study for the field. This was the first time that an antisense oligonucleotide was evaluated for a genetic form of ALS in a Phase 3 clinical trial.

    This was a historical step on the path to targeted treatments for this serious disease. I applaud Dr. Miller and collaborators for sharing these hot-off-the-press results in such a timely and transparent manner.

    The results are complex: The trial’s dataset is extremely rich and it will be important to continue to examine the data and learn as much as possible from the study, which will determine the next steps for this investigational product.

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News Citations

  1. Antisense Oligonucleotides: Can They Take on ALS, SMA, Prions?
  2. Antisense Therapy Cuts Huntingtin Protein in CSF by Half
  3. Target or Decoy: Are Drug Developers Chasing the Right Thing?

Further Reading