P22 WVE-N531 yields 53% mean exon 53 skipping in skeletal muscle of boys with Duchenne muscular dystrophy (DMD) after three biweekly doses

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. Part A of a Phase 1b/2 open-label study (NCT04906460) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous WVE-N531 in boys with DMD amenable to exon 53 skipping. Three ambulatory boys participated in this intra-patient dose-escalation clinical trial. The boys received single escalating doses of 1, 3, 6 and 10 mg/kg, followed by three doses of 10 mg/kg every other week in the multidose portion of the study. A muscle biopsy occurred 2 weeks after the third and final dose. After three biweekly 10 mg/kg doses in the multidose portion of the study, WVE-N531 reached a mean concentration of 42 µg/g (6.1 µM) in muscle tissue, with RNAscope (in situ hybridization) demonstrating 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 protein was 0.27% (BLQ) of normal as measured by western blot. All adverse events were mild, except for a COVID-19 infection of moderate intensity. Adverse events related to study drug (headache, pruritic rash) were mild, transient, and resolved without sequelae. There were no serious adverse events, no trends in laboratory data, and no oligonucleotide class-related safety events. The preliminary data provide evidence that WVE-N531 is leading to substantial exon skipping after three biweekly doses and demonstrates an impact of PN chemistry in enabling high drug exposure in human muscle tissue. It is expected that dystrophin production would follow RNA splicing; extended dosing and follow up are needed to confirm increased production of dystrophin over time. 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. Part A of a Phase 1b/2 open-label study (NCT04906460) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous WVE-N531 in boys with DMD amenable to exon 53 skipping. Three ambulatory boys participated in this intra-patient dose-escalation clinical trial. The boys received single escalating doses of 1, 3, 6 and 10 mg/kg, followed by three doses of 10 mg/kg every other week in the multidose portion of the study. A muscle biopsy occurred 2 weeks after the third and final dose. After three biweekly 10 mg/kg doses in the multidose portion of the study, WVE-N531 reached a mean concentration of 42 µg/g (6.1 µM) in muscle tissue, with RNAscope (in situ hybridization) demonstrating 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 protein was 0.27% (BLQ) of normal as measured by western blot. All adverse events were mild, except for a COVID-19 infection of moderate intensity. Adverse events related to study drug (headache, pruritic rash) were mild, transient, and resolved without sequelae. There were no serious adverse events, no trends in laboratory data, and no oligonucleotide class-related safety events. The preliminary data provide evidence that WVE-N531 is leading to substantial exon skipping after three biweekly doses and demonstrates an impact of PN chemistry in enabling high drug exposure in human muscle tissue. It is expected that dystrophin production would follow RNA splicing; extended dosing and follow up are needed to confirm increased production of dystrophin over time.