Background: WVE-N531 is an investigational stereopure antisense oligonucleotide being developed as a potential therapy for patients with DMD amenable to exon 53 skipping. WVE-N531 contains Wave’s PN (phosphoryl guanidine) chemistry, which had a substantial impact on muscle exposure, exon skipping and dystrophin restoration in preclinical studies.
Objective: To report results of Part A of an ongoing Phase 1b/2a open-label, proof-of-concept study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical effects of intravenous WVE-N531 in boys with DMD amenable to exon 53 skipping.
Approach: Three ambulatory boys participated in this intra-patient dose-escalation clinical trial (NCT04906460). 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 occurred 2 weeks after the third and final dose.
Results: After the 6-week multidose portion of the study, WVE-N531 reached a mean concentration of 42 ug/g in muscle tissue, with RNAscope (in situ hybridization) providing evidence that WVE-N531 reached the nucleus. Mean exon skipping was 53% (range, 48-62%) as measured by RT-PCR. The half-life of WVE-N531 was 25 days in plasma at 10 mg/kg. Mean dystrophin production was 0.27% (BLQ) of normal as measured by western blot. Adverse events were all mild, except for a COVID-19 infection of moderate intensity. There were no serious adverse events, no concerning trends in laboratory data, and no oligonucleotide class-related safety events.
Conclusions: The preliminary data provide evidence that WVE-N531 is leading to substantial exon skipping after three biweekly doses and suggests impact of PN chemistry at the level of muscle tissue. Although measured dystrophin was low, it is expected that dystrophin production would lag RNA splicing. Extended dosing and follow up are needed to confirm increased production of dystrophin over time.