Wave Life Sciences Announces Topline Results from Phase 1b/2a FOCUS-C9 Study of WVE-004 for C9orf72-associated Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Potent and durable target engagement observed across cohorts, including with 10 mg doses administered every 12 weeks which were also generally safe and well-tolerated
WVE-004 did not show clinical benefit compared with placebo; additionally, poly(GP) reductions did not correlate with clinical outcomes -- Wave to discontinue development of WVE-004
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CAMBRIDGE, Mass., May 23, 2023 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage RNA medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced topline results from the Phase 1b/2a FOCUS-C9 study evaluating WVE-004 as an investigational treatment for C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). The results include data from a planned analysis of the study, where participants received multiple 10 mg doses of WVE-004 or placebo every 12 weeks (Q12W) or every 4 weeks (Q4W), as well as an additional 20 mg single dose cohort.
WVE-004 was generally safe and well-tolerated across doses, with most adverse events presenting as mild in intensity. There were no clinically meaningful changes in cerebrospinal fluid (CSF) protein or white blood cell count and no new safety signals since the previous data update in April 2022.
Robust, sustained reductions in poly(GP) from baseline were observed, with a maximal mean reduction of 48% (p<0.0001) in the Q12W dose and 50% (p=0.0001) in the Q4W dose of WVE-004. Poly(GP) is a pharmacodynamic biomarker indicating WVE-004 is lowering C9orf72 hexanucleotide repeat expansion (G4C2) transcripts, which are hypothesized to contribute to pathogenesis in C9-ALS/FTD. However, no clinical benefit was observed at 24 weeks, and reductions in poly(GP) were not associated with stabilization or improvement in functional outcomes. Based on these data, and in the absence of biomarkers reasonably likely to predict clinical outcomes, Wave has decided to discontinue development of WVE-004.
“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,” said Paul Bolno, MD, MBA, President and CEO of Wave Life Sciences. “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.”
Continued Dr. Bolno: “These data do reinforce that our preclinical data on target engagement and pharmacology are translating in the clinic. Looking forward, our lead programs in Huntington’s disease, Duchenne muscular dystrophy 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.”
Wave remains on track to share data from its Phase 1b/2a SELECT-HD study in Huntington’s disease investigating WVE-003 in the second half of 2023. The company is also rapidly advancing WVE-N531 for Duchenne muscular dystrophy amenable to exon 53 skipping into the potentially registrational Part B (Phase 2) clinical study, following its best-in-class exon skipping data observed in the Part A proof-of-concept study. Wave is also on track to bring the industry’s first RNA editing compound, WVE-006, into a clinical trial in Alpha-1 antitrypsin deficiency in the second half of 2023. In addition, the company continues to advance preclinical research with its modalities that restore or repair endogenous proteins, including additional RNA editing programs, and expects to share an update on its preclinical pipeline highlighting new data in the third quarter of 2023.
Topline FOCUS-C9 Results
Participants in the Q12W cohort receive two 10 mg doses and participants in the Q4W cohort receive four 10 mg doses; participants are followed for 24 weeks. Key observations from the planned analysis of the study include:
Exploratory biomarker results: CSF neurofilament light chain (NfL)
Exploratory clinical outcomes
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