RNA Therapy Shows No Benefit for ALS or FTD

July 10, 2023

Article

Wave Life Sciences is discontinuing WVE-004.

WVE-004 did not show clinical benefit in treating patients with amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) and Wave Life Sciences will discontinue development of the RNA therapy.

“Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field. While we again saw substantial reductions of poly(GP) with multiple doses, we are deeply disappointed that we were not able to see any evidence of potential benefits that would be expected to drive meaningful outcomes for these patients,” Paul Bolno, MD, MBA, president and chief executive officer, Wave Life Sciences, said in a statement. “C9-ALS/FTD is complex and made all the more challenging by the absence of a clinically validated biomarker. Our hope is that these data can help advance future research, and we are committed to sharing results with the community at an upcoming medical congress. On behalf of everyone at Wave, I wish to sincerely thank the participants, their families, the clinical sites, and our study advisory committees for their participation and support.”

The company announced topline results from the phase 1b/2a FOCUS-C9 study (NCT04931862) evaluating WVE-004 as an investigational treatment for C9orf72-associated ALS and FTD (C9-ALS/FTD). Participants received10, 20, 30, or60 mgsingle doses of WVE-004 or placebo, or 10 mg every 12 weeks or 4 weeks.

Investigators found that the therapy was safe and well-tolerated across doses, with mostly mild adverse events. One serious adverse event was related to WVE-004 and another was related to the procedure. Investigators assessed biomarkers and saw sustained reductions in poly(GP) from baseline, but this was not found to be associated with a clinical benefit at 24 weeks as measured by changes in ALSFRS-R or Dementia Staging Instrument plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration Behavior and Language Domains scores. Elevations in neurofilament light were observed; these were not correlated with any clinical changes. In the cohort treated every 4 weeks, ALSFRS-R scores had a reduction in mean change compared to placebo patients at week 24 (P <.0001) but the scores were not statistically different from natural history decline data.

“These data do reinforce that our preclinical data on target engagement and pharmacology are translating in the clinic. Looking forward, our lead programs in Huntingtondisease (HD), Duchenne muscular dystrophy (DMD) and Alpha-1 antitrypsin deficiency are designed to leverage biomarkers correlated with functional outcomes, making us more confident in the future of these programs and our emerging preclinical pipeline,” Bolno added.

Data from Wave’s program in HD, from the phase 1/2a SELECT-HD study evaluating WVE-003, are expected in the second half of 2023. The company's WVE-N531 program for DMD is being advanced into phase 2 clinical study after promising exon 52 skipping data observed in the Part A proof-of-concept study.