WVE-N531 is an investigational stereopure splicing oligonucleotide with PN (phosphoryl guanidine) chemistry, currently being evaluated in an ongoing open-label Phase 2 clinical trial (FORWARD-53) in boys with DMD amenable to exon 53 skipping. Eleven boys (age 5-11; 10 ambulatory and 1 non-ambulatory) initially received WVE-N531 at 10 mg/kg every other week. All 11 boys have advanced to the extension portion of the study where they are now receiving monthly doses of WVE-N531.
The FORWARD-53 study has demonstrated positive results following 48 weeks of dosing with WVE-N531. WVE-N531 was safe and well-tolerated through 48 weeks; all treatment-related adverse events were mild to moderate in intensity, with no serious adverse events or discontinuations. Muscle content-adjusted dystrophin expression, by western blot, stabilized between 24 and 48 weeks of dosing and averaged 7.8%. Eighty-eight percent of boys (7/8) achieved greater than 5% average dystrophin between 24 and 48 weeks. Mean exon skipping was consistent through 48 weeks of dosing, achieving an average of 54% between weeks 24 and 48 as measured by RT-PCR.
WVE-N531 effectively targets both myofibers and muscle stem cells, which is expected to restore regenerative capacity within dystrophic muscles. Muscle histology showed a transition from regeneration to maturation of myofibers, with a statistically significant reduction in muscle fibrosis (28.6% reduction between week 24 to 48; p<0.01), and decreases of the median muscle necrosis and inflammation scores from 2 to 1 (representing minimal damage). A 50% decline (p<0.001) in creatine kinase, as well as decreases in IL-6 and MCP-1, were also observed. Time-to-Rise results demonstrated a 3.8-second mean improvement versus natural history (statistically significant; p<0.05); this value was above the Minimal Clinically Important Difference of 1.4 seconds. Additional functional benefits were observed on the North Star Ambulatory Assessment versus natural history, and in hand grip strength versus baseline.