Wave Life Sciences announces update from PoC study of WVE-N531

Wave Life Sciences announced an update from the initial cohort of the Phase 1b/2a proof-of-concept study of WVE-N531 in three boys with Duchenne muscular dystrophy amenable to exon 53 skipping. High muscle concentrations of WVE-N531 and exon skipping were observed six weeks after initiating biweekly multidosing at 10 mg/kg, achieving proof-of-concept in the study. WVE-N531 also appeared safe and well-tolerated. "These data provide early evidence that WVE-N531 is working as intended, leading to substantial exon skipping after just three consecutive doses. This is the earliest timepoint at which exon skipping has been reported in a clinical trial of boys with DMD," said Anne-Marie Li-Kwai-Cheung, CDO. "While dystrophin was below the lower limit of detection, it is expected that dystrophin protein production would lag splicing of the RNA transcript. We are encouraged by these early results and are evaluating next steps for the program, including the continuation of this initial cohort. We would like to express our sincerest gratitude to the boys, their families, and the investigators who participated in the study." Three ambulatory boys participated in this open-label, intra-patient dose escalation clinical trial. The boys received single escalating doses of 1, 3, 6 and 10 mg/kg; and in the multidose portion of the study, the same boys received three doses of 10 mg/kg every other week. A muscle biopsy was taken two weeks after the third and final dose. Results included: WVE-N531 resulted in a mean tissue concentration of 42 micrograms/gram; RNAscope results indicated WVE-N531 is reaching the nucleus in muscle cells; WVE-N531 resulted in mean exon skipping of 53% as measured by RT-PCR; Mean dystrophin production was 0.27% of normal as measured by Western blot, which was below the level of quantification; Plasma concentrations and other pharmacokinetic parameters following a single dose of 10 mg/kg demonstrate a half-life of 25 days, which may support monthly dosing; Adverse events were all mild, except for a COVID-19 infection of moderate intensity. There were no serious adverse events, no trends in labs, and no oligonucleotide class-related safety events.