Background: Duchenne muscular dystrophy (DMD) is characterized by chronic sarcolemmal instability, leading to continuous muscle damage and elevated serum biomarkers such as creatine kinase (CK), aspartate aminotransferase (AST), and alanine transaminase (ALT). S969 is a mutation-agnostic, oral multi-kinase inhibitor designed to transcriptionally upregulate α7β1 integrin, which serves as a critical structural surrogate for missing dystrophin.
Methods: A blinded crossover study was conducted in Golden Retriever Muscular Dystrophy (GRMD) dogs (n=4). Animals were randomized into two groups receiving either 40 mpk S969 or a color-matched placebo daily for 16 weeks. After an 8-week washout period, treatments were reversed for a second 16-week period. Serum biochemistry (CK, AST, ALT) was assessed at baseline and every 4 weeks. Additional outcomes included a 6-minute walk test (6MWT) with pre- and post-exercise CK collection and T1-weighted hindlimb MRI to assess muscle size and contrast.
Results: S969 treatment resulted in rapid and significant reductions in clinical biomarkers of muscle damage. CK levels decreased to approximately 50% of baseline and placebo levels during the 40 mpk S969 treatment phase. Parallel significant reductions were observed for transaminase levels (AST and ALT). While on S969, the ΔCK post-6MWT was approximately 2-fold lower than on placebo, indicating enhanced membrane protection during active use. MRI analysis showed a trend toward smaller muscle size, potentially reflecting reduced dystrophic edema, while stabilized T1-weighted contrast suggested mitigation of progressive fibrosis.
Conclusions: These findings demonstrate that oral S969 rapidly stabilizes the muscle membrane in the primary large animal model of DMD. The ~50% reduction in serum CK is a robust indicator of therapeutic target engagement and sarcolemmal reinforcement. These results support the clinical advancement of S969, which is currently undergoing IND-enabling studies.