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

Mean muscle content-adjusted dystrophin expression of 9.0% and unadjusted dystrophin of 5.5%, with high consistency across participants, in a prespecified analysis; dystrophin was comprised of two isoforms consistent with Becker muscular dystrophy patients who display milder disease

Data demonstrated meaningful improvement in serum biomarkers for muscle health, with localization of WVE-N531 in myogenic stem cells and regeneration of myofibers

Skeletal muscle concentrations of ~41,000 ng/g combined with 61-day tissue half-life support monthly dosing going forward; preclinical data suggest participants may have even higher concentrations in heart and diaphragm

WVE-N531 was safe and well tolerated: treatment-related adverse events were all mild, no serious adverse events, no discontinuations and no oligonucleotide class-related events

Wave expects feedback on a pathway to accelerated approval from regulators, as well as the complete 48-week FORWARD-53 data, in 1Q 2025

Wave to host investor conference call and webcast at 8:30 a.m. ET today

CAMBRIDGE, Mass., Sept. 24, 2024 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced positive interim data from the ongoing Phase 2 FORWARD-53 study of WVE-N531, which is an exon skipping oligonucleotide being investigated in boys with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping. The interim analysis was conducted after 24 weeks of 10 mg/kg dosing every two weeks (Q2W), and WVE-N531 demonstrated substantial dystrophin expression and that it was safe and well tolerated.

“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,” said Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Chief Development Officer at Wave Life Sciences. “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. 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.”

“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,” said Laurent Servais, MD, PhD, Professor of Paediatric Neuromuscular Disease at the University of Oxford and Principal Investigator in FORWARD-53. “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.”

Detailed Interim Results from FORWARD-53Eleven 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. The study is designed to administer 10 mg/kg infusions of WVE-N531 Q2W and muscle biopsies are taken after 24 and 48 weeks of dosing. Results from this interim analysis include:

Safety and Tolerability

• WVE-N531 was safe and well tolerated. Treatment-related adverse events (four events total in three participants) were mild in intensity. There were no serious adverse events and no study discontinuations due to any causes.
• There were no oligonucleotide class-related safety events.

Efficacy

• Dystrophin: Dystrophin results from a pre-specified analysis of ambulatory boys showed:
  • Mean absolute muscle content-adjusted dystrophin expression was 9.0% (range: 4.6-13.9%) and mean absolute unadjusted dystrophin expression was 5.5% of normal (range: 3.3-8.3%), as measured by Western Blot.
  • The dystrophin expression was quantified from two isoforms consistent with those observed in Becker muscular dystrophy patients who display milder disease.
  • 89% of ambulatory participants achieved muscle content-adjusted dystrophin levels of at least 5%.
• Exon skipping: Mean exon skipping was 57% (range: 31-75%) as measured by RT-PCR.
• Localization: WVE-N531 was detected in myocyte nuclei in all participants and in myogenic stem cells in the majority of participants. Myogenic stem cells are the progenitor cells for new myoblasts, which give rise to new myocytes and ultimately aid in skeletal muscle regeneration.
• Improvements in muscle health: Participants showed multiple indicators of improvement 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.
• Serum biomarkers for muscle health: Creatine kinase (CK) and aspartate aminotransferase (AST) are serum biomarkers that are elevated in the presence of muscle damage. In the interim data, there were significant decreases in CK and AST levels from baseline. The reduction in CK was numerically larger than is typically seen with the introduction of steroids in DMD. Changes in CK and AST were highly correlated (p