Duchenne Agent WVE-N531 Shows Promising Results in Phase 2 FORWARD-53 Trial

Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS

(Credit: Wave Life Sciences)

Newly announced interim data from the phase 2 FORWARD-53 study (NCT04906460) showed that treatment with Wave Life Sciences’ WVE-N531, an investigational antisense oligonucleotide, resulted in substantial dystrophin expression among boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. The company expects to complete the trial in the first quarter of 2025, and anticipates using feedback from regulators to provide guidance for an accelerated approval.¹

A total of 11 enrolled boys amenable to exon 53 skipping received 10 mg/kg infusions of WVE-N531 every 2 weeks (Q2W), with muscle biopsies taken after 24 and 48 weeks of dosing. At 24 weeks, interim results revealed a mean absolute muscle content-adjusted dystrophin expression of 9.0% (range, 4.6%-13.9%) and a mean absolute unadjusted dystrophin expression that was 5.5% of normal (range, 3.3%-8.3%), as measured by Western Blot. Notably, 89% of ambulatory participants (n = 10) achieved muscle content-adjusted dystrophin levels of at least 5%.

Across the 24-week interim treatment period, the therapy was shown to be safe and well tolerated, with treatment-related adverse events (AEs) that were mild in intensity. Overall, there were no serious AEs, no study discontinuations because of AEs, and no safety events related to the mechanism of action of WVE-N531 as an antisense oligonucleotide. In addition, investigators recorded the muscle tissue half-life of the therapy to be an estimated 61 days, further supporting a monthly dosing regimen moving forward.

"The high and consistent dystrophin levels at this interim timepoint are compelling and speak to the potential of WVE-N531 for boys amenable to exon 53 skipping, where better therapeutic options are urgently needed,” Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, chief development officer at Wave Life, said in a statement.¹ "It is also known that dystrophin is expressed as multiple functional isoforms and we are encouraged that the two isoforms observed on our Western Blot data are consistent with Becker muscular dystrophy patients who display milder disease. This observation is further supported by our interim data showing myofiber regeneration and improvements in muscle health."

She added, "We look forward to delivering data from the complete FORWARD-53 study in the first quarter of 2025, and would like to express our deepest gratitude to the boys, families and study staff who are participating in the study.”

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Using reverse transcription polymerase chain reaction, mean exon skipping with WVE-N531 was 57% (range, 31%-75%). In terms of localization, the antisense oligonucleotide was detected in myocyte nuclei in all participants and in myogenic stem cells in the majority of participants. Through treatment with WVE-N531, patients with DMD had improvements in muscle health, including an increase in the mean percentage of myocytes with internalized nuclei and an improvement in myofiber size and diameter between the previously completed Part A study and FORWARD-53.

During the 24 weeks of treatment, investigators also observed significant decreases in creatine kinase (CK) and aspartate aminotransferase (AST) levels, serum biomarkers typically elevated in the presence of muscle damage. Notably, the reduction in CK was numerically larger than normally seen with the introduction of steroids in DMD, and the changes in CK and AST were highly correlated (P <.0001).

Laurent Servais, MD, PhD

"Exon skipping is a promising approach to treat DMD and is compatible with all others that are approved or in development. However, it has been challenging for the field to achieve dystrophin levels that can significantly improve clinical outcomes. Achieving mean muscle content-adjusted dystrophin of 9% is a meaningful step forward,” principal investigator Laurent Servais, MD, PhD, a professor of pediatric neuromuscular disease at the University of Oxford, said in a statement.¹ "The safe and tolerable profile and the option for monthly dosing is also encouraging and has the potential to greatly contribute to quality of life of treated boys in comparison with current weekly dosing."

Servais and colleagues previously completed a phase 1/2a proof-of-concept study (NCT0490646) of WVE-N531 that included 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. In the study, treatment with the agent resulted in a mean tissue concentration of 42 micrograms/gram, as well as resulted in mean exon skipping of 53% (range, 48%-62%), as measured by RT-PCR. Notably, through WVE-N531, patients had mean dystrophin production that was 0.27% of normal, considered below the level of quantification, as measured by Western blot.²

REFERENCES
1. Wave Life Sciences Announces Positive Interim Data from FORWARD-53 Clinical Trial Evaluating WVE-N531 in Boys with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping. Wave Life Sciences. September 24, 2024. Accessed September 25, 2024. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-interim-data-forward-53
2. Wave Life Sciences provides positive update on proof-of-concept study for WVE-N531 in Duchenne muscular dystrophy. News release. December 19, 2022. Accessed September 25, 2024. 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