In Duchenne Muscular Dystrophy (DMD) a lack of dystrophin protein results in severe, progressive muscle atrophy, eventual loss of ambulation, respiratory insufficiency, cardiomyopathy, and premature death. Despite advances, there remains a substantial unmet need for treatments that reach cardiac and respiratory muscles, where restoration of dystrophin may be essential to improve respiratory and cardiac function and extend survival. WVE-N531 is an investigational stereopure exon 53 skipping antisense oligonucleotide that contains PN (phosphoryl guanidine) chemistry. WVE-N531 was designed to address the limitations of first-generation exon-skipping oligonucleotides that had modest exposure in non-human primate (NHP) muscle tissue, including in the heart and diaphragm.
This study evaluated the concentrations of WVE-N531 in cardiac, diaphragm, and skeletal muscle tissue of NHPs. WVE-N531 was administered every other week via intravenous infusion to cynomolgus monkeys for 6 weeks at 5, 15, or 45 mg/kg (n=2 per dose group). Muscle concentrations of WVE-N531 were measured at 2 days post-last dose using hybridization-ligation enzyme-linked immunosorbent assay. The mean tissue concentrations of WVE-N531 were 12.1, 57.2, and 93.1 µg/g in heart; 2.3, 10.8, and 15.9 µg/g in diaphragm; 0.263, 2.17, and 18.0 µg/g in skeletal muscle (tibialis anterior); after administration of four doses of 5, 15, and 45 mg/kg, respectively. The 15 mg/kg dose level in the monkey study was approximately equivalent to 10 mg/kg in patients based on plasma AUC values.
These data suggest that chemical modifications to WVE-N531, including PN chemistry, have profoundly affected its pharmacology. WVE-N531 achieved high mean concentrations in skeletal muscle in NHPs, with even higher general exposure observed in the heart and diaphragm. Together, these data illustrate WVE-N531’s excellent tissue uptake and distribution in both skeletal and non-skeletal muscles.