Positive Phase II Data for WVE-N531 in DMD

The analysis was conducted after 48 weeks of treatment with 10 mg/kg WVE N531 dosed every two weeks (Q2W).

FORWARD-53 achieved all trial goals, demonstrating sustained and industry-leading exon skipping, muscle concentrations and dystrophin restoration through 48 weeks and a 61-day tissue half-life that supports monthly dosing. WVE N531 continues to be safe and well-tolerated.

Additionally, the data demonstrate substantial decreases in inflammation and necrosis, a statistically significant reversal of muscle fibrosis (28.6% reduction between week 24 to 48; p<0.01), and a transition from regeneration to maturation of muscle. A 50% decline (<0.001) in creatine kinase (CK), as well as decreases in IL-6 and MCP-1, were also observed. Time-to-Rise (TTR) data demonstrate a statistically significant and clinically meaningful 3.8-second improvement versus natural history (p<0.05), which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. Additional functional benefits were observed on the North Star Ambulatory Assessment (NSAA) versus natural history, and in hand grip strength versus baseline.

“Despite progress in Duchenne, there remains a significant unmet need for therapeutics that meaningfully impact disease progression. These data demonstrate a promising continuum from dystrophin restoration, to regeneration and maturation of muscle tissue, to functional improvement,” said Pat Furlong, founder and president of Parent Project Muscular Dystrophy. “Paired with monthly administration and a continued favorable safety profile, WVE N531 represents a significant step forward – not just for individuals amenable to exon 53 skipping, but also for the broader exon skipping field. PPMD looks forward to working with Wave as they expediently bring WVE N531 and their broader exon skipping pipeline to the Duchenne community.”

“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,” said Laurent Servais, MD, PhD, Professor of Paediatric Neuromuscular Disease at the University of Oxford and Principal Investigator in FORWARD-53. “To see a clinically meaningful and statistically significant difference on TTR versus natural history in a Phase II study is another encouraging finding. I am looking forward to the continued development of WVE N531.”

Wave also announced  that the company met with the FDA  on WVE N531 to discuss its interim 24-week data and initial plans for the confirmatory trial, where the Agency confirmed that the accelerated approval pathway using dystrophin expression as a surrogate endpoint remains open. Based on the FDA feedback and the 48-week data, Wave intends to file a New Drug Application (NDA) in 2026 for accelerated approval of WVE N531  the new 48-week data, including functional outcomes, and its planned global 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,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “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.”

Continued Dr. Bolno, “Most importantly, we are inspired by the opportunity ahead to deliver life-changing medicines to this community. We expect WVE N531 to become the first-line treatment of choice for boys amenable to exon 53 skipping, including the 40-50% in the US who are not being treated with approved exon skippers due in part to the burden of weekly infusions coupled with limited efficacy. Additionally, we are accelerating our near-term clinical programs for other exons, which based on preclinical data, suggest a best-in-class exon skipping franchise. We are incredibly grateful to the trial participants and their families, as well as all our collaborators across the DMD community for their contributions to this program and all our DMD research over the past decade.”

WVE N531, as well as Wave’s programs for exons 52, 51, 45 and 44, leverage best-in-class oligonucleotide chemistry, including PN backbone chemistry and stereochemical control, enabling industry-leading muscle delivery and potency without requiring antibody or peptide conjugates. Preclinical data for Wave’s PN chemistry-containing exon skipping candidates have also demonstrated significantly higher dystrophin and drug concentrations in the heart and diaphragm versus skeletal muscle. Collectively, WVE N531 plus Wave’s exon 52, 51, 45 and 44 programs would address ~40% of the DMD population and represent a >$2.4 billion total market opportunity in the United States alone. Wave expects to submit multiple clinical trial applications (CTAs) for other exon skipping programs in 2026.

Detailed Results from FORWARD-53; Eleven boys amenable to exon 53 skipping (age 5-11; 10 ambulatory and 1 non-ambulatory) are enrolled in the ongoing open-label FORWARD-53 trial. Biopsy data are from eight of the 11 boys (all ambulatory and who had biopsies at 24 and 48 weeks) while safety and functional outcome assessments were available for all participants. All 11 boys have advanced to the extension portion of the study where they are now receiving monthly doses of WVE-N531.

Results after 48 weeks of 10 mg/kg dosing every two weeks include:

Safety and Tolerability; WVE N531 was safe and well-tolerated through 48 weeks. All treatment-related adverse events were mild to moderate in intensity.

• There were no Serious Adverse Events and no discontinuations due to any causes.

Results from Muscle Biopsies; Dystrophin and exon skipping:  i. Dystrophin expression stabilized between 24 and 48 weeks of dosing with a mean of 7.8% [95% CI: 5.4-10.3%; 24-week dystrophin was 9.0% (95% CI: 6.5-11.5%) and 48-week dystrophin was 6.4% (95% CI: 3.8-9.0%); muscle content-adjusted dystrophin as measured by western blot]. The difference between the 24- and 48-week mean dystrophin measurements is within the established 30-35% inter-assay variability of the western blot, and consistency between these timepoints was confirmed with an orthogonal assay.. a.  88% of boys (7/8) achieved greater than 5% average dystrophin between 24 and 48 weeks. b.  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%).

Reversal of muscle damage: Participants showed significant and unprecedented improvements in multiple indicators of muscle health through 48 weeks, indicating a shift from dystrophic muscle towards healthy muscle. These data include: i.  Decreases of the median muscle necrosis and inflammation scores from 2 to 1(representing mild damage) in muscle pathology. ii. Decreases in markers of inflammation (MCP-1 and IL-6).  iii. A statistically significant decline in the amount of muscle fibrosis between 24 and 48 weeks (mean decrease of 28.6%, p<0.01).

•  iv. A 50% decrease (p<0.001) in serum creatine kinase (CK), which occurred on top of a stable corticosteroid regimen. v. Improved organization and uniformity of myofibers in muscle tissue. v. Decreases in number of stem cells and internalized nuclei, indicative of myofiber maturation between week 24 and 48.

Functional Assessments

• i.Benefits were seen in multiple functional assessments among WVE N531-treated boys (n=10), including Time-to-Rise (TTR) and North Star Ambulatory Assessment (NSAA), compared with a matched exon 53 natural history control group (n=18.)  a.  TTR showed a statistically significant and clinically meaningful 3.8-second difference (p<0.05) favoring WVE N531 compared witnatural history. The minimal clinically important difference (MCID) for TTR was 1.4 seconds, based on the baseline functional characteristics of boys in the study. b. NSAA showed positive trends favoring WVE N531 relative to natural history (1.2-point improvement; not significant) .  ii. Positive trends were also observed among WVE N531-treated boys (n=11) on grip strength versus baseline.

Additional Upcoming Milestones Across Wave’s Clinical RNA Medicines Pipeline
Wave expects multiple additional milestones across its clinical pipeline of RNA medicines in 2025, including: i. WVE-006 (GalNAc-conjugated RNA editing oligonucleotide for alpha-1 antitrypsin deficiency): Wave expects to deliver 200 mg multi-dose data and 400 mg single-dose data from the Phase 1b/IIa RestorAATion-2 trial in 2025.. ii. WVE-007 (GalNAc-conjugated siRNA for obesity, designed to silence INHBE mRNA): Wave expects to deliver clinical data from the Phase 1 INLIGHT trial in the second half of 2025, including safety, tolerability and biomarkers reflective of healthy weight loss. iii. WVE-003 (allele-selective silencing for Huntington’s disease): Wave expects to submit an Investigational New Drug application in the second half of 2025 for its potentially registrational Phase II/III trial of WVE-003.