DMD CLINICAL THERAPIES II: P.132Identification of developmental myosin positive fibres acts both as a clinical biomarker for muscle disease and an important component of the process to confirm ezutromid target engagement

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The expression of developmental and neonatal myosin heavy chains can be detected in newly formed regenerating skeletal myofibres 2-3 days after injury and remain for 2-3 weeks. These myosin isoforms are transiently expressed during regeneration and replaced when adult fast and slow myosins become prevalent. Therefore, the presence of developmental myosin heavy chain (MHCd) provides a very specific biomarker of regenerating fibres in pathologic skeletal muscle including DMD. Utrophin is also expressed in regenerating myofibres, following a similar restricted expression profile to MHCd. Summit have utilised novel automated immunohistochemistry imaging algorithms, in partnership with Flagship Biosciences, to quantify expression of developmental myosin heavy chain (MHCd) and utrophin in DMD patient muscle biopsies. This technology was utilised in the current Phase 2 open label study of ezutromid administered to 40 ambulatory patients with DMD where key secondary endpoints are from muscle biopsies; collected at baseline (n=40) and treatment Week 24 (n=25) or Week 48 (n=15). Compared to baseline, the Week 24 biopsies demonstrated a statistically significant decrease in the number of fibres expressing MHCd; the average reduction was -2.61% (95% CI -4.33, -0.90) from mean baseline of 11.37%; a relative reduction of 23%. This suggests a significant decrease in the number of fibres undergoing the natural repair process following damage. Additional functionality of the algorithms developed allows for assessment of expression heterogeneity across fibres and quantification of MHCd expression and utrophin expression in the same fibre. The individual fibre specific data analyses quantifying MHCd and utrophin comparing baseline to both Week 24 biopsies and Week 48 biopsies will be presented including those profiles that potentially distinguish a utrophin profile specific to ezutromid modulation.