349P Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, sevasemten (EDG-5506), in Becker muscular dystrophy (BMD)

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.680
• Main Authors: Barthel, B., Madden, M., Thaler, L., Evanchik, M., Koch, K., Donovan, J., Collins, S., Phan, H., Russell, A.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.689

Sevasemten (EDG-5506) is a selective inhibitor of fast skeletal muscle myosin, designed to protect skeletal muscle from contraction-induced injury in Becker and Duchenne muscular dystrophy. In a Phase 1b open-label study (ARCH, NCT05160415), adults with BMD (N=12) were administered 10-20 mg of sevasemten daily for up to 24 months. We previously observed rapid reductions in muscle injury biomarkers, including creatine kinase (CK) and fast skeletal Troponin I (TNNI2), which were maintained through 12 months. Here, we used Somascan proteomic analysis to assess changes in muscle injury biomarkers and muscle fiber type-specific proteins with continued treatment up to 24 months. We also characterize the plasma proteomic changes characteristic of chronic sevasemten administration. Circulating levels of TNNI2 and CK decreased significantly (p = 0.01 and 0.05, respectively) after short-term sevasemten treatment (1 – 2 months) and were maintained at low levels throughout the study period of 24 months. Similarly, an expanded set of proteins specific to contraction-induced skeletal muscle injury were quickly and robustly reduced following sevasemten treatment through the duration of the study. Further, reduced levels of proteins suggestive of muscle protection were associated with fast fiber-specific subsets over that of slow fiber subsets. Multivariate analysis also identified a subset of proteins that were specific to chronic administration that were observed to be unchanged at short-term time points. This subset was highly enriched with proteins associated with inflammatory and tissue remodeling processes. Several individual proteins associated with pro- or anti-inflammatory responses were shifted towards levels seen in sex-matched unaffected individuals. We demonstrate that circulating indicators of muscle injury are reduced after short-term sevasemten therapy and maintained through 24 months of treatment. Further, we show that chronic treatment with sevasemten elicits changes to inflammatory proteomic signatures that shift towards those seen in healthy individuals.