Duchenne Agent WVE-N531 Shows Targeted Exon Skipping in Phase 1/2 Study


After 6 weeks of treatment, WVE-N531 was found to be safe, well-tolerated, and resulted in mean dystrophin production that was below the level of quantification.

Laurent Servais, MD, PhD, professor of pediatric neuromuscular diseases, MDUK Oxford Neuromuscular Center

Laurent Servais, MD, PhD

Wave Life Sciences has announced positive findings from its phase 1/2a proof-of-concept study (NCT04906460), which showed that its investigational agent WVE-N531 led to significant concentrations of exon skipping in ambulatory boys with Duchenne muscular dystrophy (DMD) after just 3 weeks of biweekly multidosing at 10 mg/kg.1

WVE-N531, the first exon-skipping candidate from Wave to use its next-generation PN chemistry, resulted in a mean tissue concentration of 42 micrograms/gram, as well as resulted in mean exon skipping of 53% (range, 48% to 62%) as measured by RT-PCR. The therapeutic was also safe and well-tolerated, as all adverse events, except for a COVID-19 infection of moderate intensity, were all mild.

"There remains a significant unmet need in DMD for new treatment options. It is exciting to see this level of exon skipping in a short period of time, especially since skipping would be expected to increase over a longer dosing interval," primary investigator Laurent Servais, MD, PhD, professor of pediatric neuromuscular diseases, MDUK Oxford Neuromuscular Center, said in a statement.1 "Based on the data, it appears Wave’s next-generation chemistry has led to significantly improved pharmacology. Expression of dystrophin after longer exposure will, of course, be key to confirm the promise of these early data. I look forward to the continued progression of clinical research for WVE-N531."

The analysis featured 3 ambulatory boys who were on escalating doses of 1,3,6, and 10 mg/kg in the multidose portion of the trial, followed by 3 doses of 10 mg/kg every other week. With the first patients dosed in October 2021, the trial is expected to include approximately 15 total individuals who have a documented mutation of the DMD gene that is amenable to exon 53 skipping intervention. Individuals are between the ages of 5 and 18 years, are male, have a score of at least 1 on item 1 or 2 of the shoulder component of the Performance of the Upper Limb, and have stable pulmonary and cardiac function.

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Treatment with WVE-N531 resulted in mean dystrophin production that was 0.27% of normal, considered below the level of quantification, as measured by Western blot. Using RNAscope, investigators concluded that the agent’s impact reached the nucleus of muscle cells. Following a single dose of 10 mg/kg, plasma concentrations and other pharmacokinetic parameters demonstrated a half-life of 25 days, which the company concluded may support monthly dosing. In terms of safety, there were no serious AEs, no trends in labs, and no oligonucleotide class-related safety events.

"These data indicate PN chemistry can improve potency, distribution and durability of splicing oligonucleotides without needing peptide or antibody conjugates, clearly demonstrating the increasing potential of Wave’s PRISM platform," Paul Bolno, MD, MBA, president and chief executive officer, Wave Life Sciences, said in a statement.1 "This is Wave’s third clinical trial in 2022 to demonstrate the impact of PN chemistry, as well as our third clinical trial to demonstrate translation of preclinical data in humans. In 2023, we are looking forward to determining next steps for WVE-N531, advancing our silencing clinical programs, and bringing a whole new modality into the clinic with our RNA editing and upregulation capability."

In a preclinical study, treatment with WVE-N531 resulted in dose-dependent increases in dystrophin production of up to 71% among patient-derived myoblasts in vitro. Treatment with an agent using the company's PN chemistry also led to 100% survival rate at 40 weeks in a cohort of double knockout mice, a severe and rapidly fatal in vivo model lacking both dystrophin and utrophin. In the same preclinical studies, mice treated with compounds designed with Wave's first-generation chemistry had a median survival of less than 12 weeks.2

1. Wave Life Sciences provides positive update on proof-of-concept study for WVE-N531 in Duchenne muscular dystrophy. News release. December 19, 2022. December 19, 2022. https://www.globenewswire.com/news-release/2022/12/19/2576214/0/en/Wave-Life-Sciences-Provides-Positive-Update-on-Proof-of-Concept-Study-for-WVE-N531-in-Duchenne-Muscular-Dystrophy.html
2. Wave Life Sciences announces initiation of dosing in phase 1b/2a clinical trial of WVE-531 in Duchenne muscular dystrophy. News release. Wave Life Sciences. September 29, 2021. Accessed September 30, 2021. https://www.biospace.com/article/releases/wave-life-sciences-announces-initiation-of-dosing-in-phase-1b-2a-clinical-trial-of-wve-n531-in-duchenne-muscular-dystrophy/
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