WVE-N531 Improves Muscle Health in Latest Phase 2 Trial of Duchenne Muscular Dystrophy

Laurent Servais, MD, PhD

Newly announced 48-week positive data from the phase 2 FORWARD-53 study (NCT04906460) showed that treatment with investigational WVE-N531 (Wave Life Sciences) was safe and led to the first-ever improvement in muscle health with exon skipping in patients with Duchenne muscular dystrophy. Following recent feedback from the FDA, the company intends to file a new drug application (NDA) in 2026 for accelerated approval, with data to support monthly dosing at launch.¹

The updated data featured 11 boys with DMD amenable to exon 53 skipping who advanced to the extension portion of the study and were receiving monthly doses of WVE-N531. Results revealed stabilization of dystrophin expression through treatment, with a mean of 7.8% (95%, 5.4-10.3%) between weeks 24 and 48 of dosing. Measured by western blot, the 48-week mean dystrophin expression was 6.4% (95% CI, 3.8-9.0%).

WVE-N531, an exon skipping oligonucleotide, led to significant and unprecedented improvements in several checkpoints of muscle health at 48 weeks, further demonstrating disease-modifying impacts. Between weeks 24 and 48, muscle pathology showed significant improvements, including a decrease in necrosis and inflammation scores from 2 to 1, reduced markers of inflammation (MCP-1 and IL-6), and a 28.6% reduction in muscle fibrosis (P <.001). Serum creatine kinase (CK) levels decreased by 50% (P <.001) despite a stable corticosteroid regimen, alongside improved myofiber organization and uniformity.

"As a clinician deeply involved in patient care and research in muscle diseases like Duchenne, I am encouraged by these data for WVE-N531 that show dystrophin restoration and several markers of improved muscle condition," principal investigator Laurent Servais, MD, PhD, professor of pediatric neuromuscular disease at the University of Oxford, said in a statement.¹ "To see a clinically meaningful and statistically significant difference on TTR versus natural history in a Phase 2 study is another encouraging finding. I am looking forward to the continued development of WVE-N531."

After 48 weeks of treatment with WVE-N531 (n = 10), investigators observed a statistically significant and clinically meaningful 3.8-second improvement in time-to-rise (TTR) vs natural history cohorts (P <.05), considered the largest such improvement at 48 weeks relative to any approved dystrophin restoration therapy. Relative to natural history, those on WVE-N531 also demonstrated positive trends in North Star Ambulatory Assessment, with non-significant improvements of 1.2 points. Notably, treated patients (n = 11) also showed positive trends in grip strength as the study went along.

Based on these findings, along with previously reported positive interim 24-week data, Wave plans to initiate a confirmatory trial using dystrophin expression as a surrogate end point. The NDA filing, expected to come in 2026, will be based on data from FORWARD-53, which will include additional analyses to support monthly dosing. Of note, the company still expects to engage with the FDA with the new 48-week data, including functional outcomes, and its planned confirmatory trial of WVE-N531.

"WVE-N531’s demonstrated ability to reach both myofibers and myogenic stem cells – the regenerative muscle cells – and sustain dystrophin restoration over time is impacting muscle health in ways never before seen in DMD," Paul Bolno, MD, MBA, president and chief executive officer at Wave, said in a statement.¹ "With these transformational data and feedback from FDA in hand, we are now moving toward our first NDA filing, which puts us on the path toward becoming a commercial company."

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FORWARD-53 featured boys aged 5-11, with biopsy data from 8 ambulatory participants and safety and functional assessments from all. In the study, the difference between the 24-week and 48-week mean dystrophin measurements was within the established 30-35% inter-assay variability of the western blot, with consistency between these timepoints confirmed through orthogonal assay. Between 24 and 48 weeks, 88% (7 of 8) of boys achieved greater than 5% average dystrophin. Notably, mean exon skipping reached steady state at 6 weeks and was consistent through 48 weeks of dosing with a mean of 54% (95% CI, 46-63%).

In terms of safety, the treatment was considered well-tolerated after 48 weeks, with treatment-related adverse events (TEAEs) that were mild to moderate in intensity. Overall, there were no serious AEs and no discontinuations because of safety concerns.

Interim results at 24 weeks, announced in September 2024, 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%). 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.

REFERENCES
1. Wave Life Sciences Announces Positive Data from FORWARD-53 Clinical Trial in DMD Including Significant Functional Benefit and Reversal of Muscle Damage after 48 Weeks of Dosing with WVE-N531. News release. Wave Life Sciences. March 26, 2025. Accessed March 26, 2025. https://www.globenewswire.com/news-release/2025/03/26/3049527/0/en/Wave-Life-Sciences-Announces-Positive-Data-from-FORWARD-53-Clinical-Trial-in-DMD-Including-Significant-Functional-Benefit-and-Reversal-of-Muscle-Damage-after-48-Weeks-of-Dosing-wit.html
2. 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 March 26, 2025. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-interim-data-forward-53