First Patients Dosed in Trial of WVE-N531 in Duchenne Muscular Dystrophy


In preclinical mouse models lacking both dystrophin and utrophin, treatment with an agent using the company's PN chemistry resulted in 100% survival at 40 weeks, setting up the therapy for this phase 1b2/a trial.

Michael Panzara, MD, MPH

Michael Panzara, MD, MPH

According to a recent announcement, Wave Life Sciences has initiated the first dosing of its investigational agent WVE-N531 in a phase 1b/2a clinical trial, where the drug will be evaluated for efficacy and safety in boys with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping. Clinical data to enable decision-making on next steps for the drug will be generated through 2022.1

WVE-N531, the first exon–skipping candidate from Wave to use its next-generation PN chemistry, will be assessed in up to 4 dose levels in an expected cohort of 15 boys with DMD ages 5 to 12 years. The agent also becomes the first candidate systematically administered by intravenous infusion to utilize its novel PN backbone chemistry modifications. In addition to researching the safety and tolerability of the ascending doses, investigators will also look at pharmacokinetics, or muscle concentration, and pharmacodynamics, shown by the effect on dystrophin expression.

"There remains a significant unmet need for DMD treatments that restore sufficient functional dystrophin protein in muscle, thus addressing the underlying cause of disease in a way that likely establishes clinical benefit," Michael Panzara, MD, MPH, chief medical officer, and head, Therapeutics Discovery and Development, Wave Life Sciences, said in a statement.1 "Our preclinical data suggest that the incorporation of PN chemistry into WVE-N531 has the potential to overcome the issues of poor intracellular access often seen with exon-skipping approaches to DMD, including our prior clinical program. We expect to generate clinical data through 2022 that will enable decision-making on further development of WVE-N531, as well as other PN-modified exon skipping compounds."

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Treatment with WVE-N531 in a preclinical study 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.

Wave Life has an extensive program of investigational treatments for several neurological diseases and conditions that has reported a number of ups and downs in recent years. In 2019, they announced the discontinuation of the development of suvodirsen, an investigational treatment geared towards patients with mutations amenable to exon 51 skipping after an interim analysis of an open-label extension study showed no change from baseline in dystrophin expression in either dose groups. At the time, the company also announced the suspension of a trial for WVE-N531.2

Most recently, the company announced the initiation of dosing in the phase 1b/2a SELECT-HD trial (NCT05032196), which will evaluate their investigational agent WVE-003 in patients with Huntington disease (HD).3 Although, that news came months after the company discontinued trials of its 2 other HD agents, WVE-120102 and WVE-120101, which failed to show efficacy.

Other recent news included the first dosing of WVE-004, an investigational treatment for C9orf72 associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The phase 1b/2a FOCUS-C9 trial (NCT04931862) is expected to enroll 50 participants, with dose escalation and dosing frequency dependent on analysis from an independent data safety monitoring board.4 Panzara recently sat down to discuss the key takeaways and future opportunities of WVE-004. Watch his commentary below as he outlined the FOCUS-C9 study and how it will shape the clinical program.

1. 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.
2. Wave life sciences announces discontinuation of suvodirsen development for Duchenne muscular dystrophy. News release. Wave Life Sciences. December 16, 2019. Accessed September 30, 2021.
3. Wave Life Sciences announces initiation of dosing in phase 1b/2a SELECT-HD clinical trial of WVE-003 in Huntington’s Disease. News release. September 9, 2021. Accessed September 30, 2021.
4. Wave Life Sciences announces initiation of dosing in phase 1b/2a FOCUS-C9 clinical trial of WVE-004 in amyotrophic lateral sclerosis and frontotemporal dementia. News release. July 20, 2021. Accessed September 30, 2021.
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