WVE-N531 is an investigational splicing oligonucleotide with phosphoryl guanidine (PN) chemistry currently being developed as a potential therapy for patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. FORWARD-53 is an ongoing Phase 2 open-label study designed to evaluate the safety, tolerability, pharmacodynamics, pharmacokinetics, and clinical effects of WVE-N531 in boys with exon 53-amendable DMD. All participants are receiving 10 mg/kg intravenous infusions of WVE-N531 every other week (Q2W). Muscle biopsies are taken after 24 and 48 weeks of dosing. The primary endpoint is dystrophin protein levels as measured by western blot.
WVE-N531 demonstrated positive interim results following 24 weeks of Q2W dosing (N=11; age 5-11; 10 ambulatory and 1 non-ambulatory). In a prespecified analysis of ambulatory participants, mean absolute muscle content-adjusted dystrophin expression was 9.0%, and mean absolute unadjusted dystrophin was 5.5%, with high consistency across participants as measured by western blot; 89% of ambulatory participants achieved muscle content-adjusted dystrophin levels of at least 5%. Dystrophin expression was quantified from two isoforms.
The mean skeletal muscle concentration of ~41,000 ng/g combined with the 61-day tissue half-life supports monthly dosing going forward. Furthermore, data showed meaningful improvement in serum biomarkers for muscle health, such as creatine kinase, and localization of WVE-N531 in myogenic stem cells and regeneration of myofibers. WVE-N531 was safe and well tolerated; all treatment-related adverse events were mild, with no serious adverse events, no discontinuations, and no oligonucleotide class-related events. FORWARD-53 is ongoing, and Wave expects to deliver 48-week FORWARD-53 data in 1Q 2025.