Sevasemten Reduces Muscle Injury Biomarkers of Becker Muscular Dystrophy in Latest Analysis

Ben Barthel, PhD

An analysis of the phase 2 CANYON trial (NCT05291091) showed that treatment with 10 mg of investigational sevasemten (Edgewise Therapeutics) led to reductions in notable muscle injury biomarkers in adults with Becker muscular dystrophy (BMD). Overall, the data supports the development of the first-in-class skeletal myosin inhibitor to preserve muscle and function in BMD.¹

CANYON is a placebo-controlled, double-blind study that featured 40 adults and 29 adolescents with BMD who were randomly assigned to either sevasemten or placebo for a 12-month treatment period, followed by a 4-week follow-up period. After 1 month of treatment, those assigned to sevasemten 10 mg daily showed significant reductions in a broad panel of proteins previously identified as associated with muscle injury (P <.0001). Notably, these reductions were sustained through 6-12 months of treatment (P <.0001).

These data were presented as part of a poster at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16-19 in Dallas, Texas, by Ben Barthel, PhD, principal scientist at Edgewise Therapeutics. In the analysis, the most responsive proteins were TNNI2 (P <.001), fast skeletal regulatory light chain (P <.001), and Calpain-3 (P <.001). In addition, the 1-year changes in muscle injury proteins in the placebo subgroup were not significantly different from the natural history (P = .01), whereas the sevasemten subgroup showed a significant reduction compared with natural history (P <.001).

In BMD, proteins like TNNI2 (troponin I2), fast skeletal regulatory light chain, and Calpain-3 play roles in muscle function and repair. TNNI2 is part of the troponin complex critical for calcium-mediated skeletal muscle contraction. The fast skeletal regulatory light chain modulates myosin activity, impacting muscle strength and endurance. Calpain-3, a protease involved in sarcomere maintenance and repair, helps regulate muscle remodeling and regeneration. Dysregulation or compensatory changes in these proteins can influence muscle function and repair in BMD, contributing to variability in disease severity.

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Considered the largest placebo-controlled interventional trial in BMD, additional results showed a wide range of individual responses with sevasemten during the treatment period; however, those with higher levels of muscle injury proteins at baseline tended to be more responsive to treatment than those with lower injury levels. Above all, these new data add to the growing treatment profile of sevasemten, complimenting previously reported positive topline data announced in December 2024.²

In CANYON, sevasemten, formerly known as EDG-5506, met its primary end point in change of creatine kinase (CK) levels in patients with BMD. Over the 6-to-12-month period, results showed a 28% average difference in CK decrease among sevasemten-treated patients vs those on placebo (P = .02). In addition, investigators observed a between-group difference on the secondary end point of change in North Star Ambulatory Assessment (NSAA), favoring the sevasemten group by 1.1 points (P = .16) across all adult participants.

Prior to CANYON, the agent was tested in the an open-label, single-center study called ARCH, which featured 12 ambulatory males aged 18 to 55 with a dystrophin mutation and a Becker phenotype, who were followed for 24 months. At the conclusion of the 24-month period, the study revealed a –0.2 mean change in NSAA with sevasemten, which significantly diverged from a natural history average change of –2.4.³

The GRAND CANYON study, an extension of the CANYON trial, is a multicenter, double-blind, placebo-controlled cohort that aims to further assess the efficacy and safety of sevasemten in adults with BMD, using change in NSAA over an 18-month period as the primary end point. Anticipated to enroll 120 patients, the study will provide supplemental data to support a future marketing application if the results are positive. Following the positive results released in late-2024, the company announced it plans to work with the FDA and European Medicines Agency towards authorization filing strategies for the agent in BMD.

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REFERENCES
1. Barthel B, Improved Plasma Signature of Contraction-Induced Muscle Injury with Sevasemten in Becker Muscular Dystrophy in the CANYON Phase II Trial. Presented at: 2025 MDA Clinical & Scientific Conference. March 16-19; Dallas, TX. ABSTRACT LB432
2. Edgewise Therapeutics Announces Positive Topline Results from the CANYON Phase 2 Trial of Sevasemten in Individuals with Becker Muscular Dystrophy (Becker). News release. December 16, 2024. Accessed March 19, 2025. https://www.businesswire.com/news/home/20241216264915/en/Edgewise-Therapeutics-Announces-Positive-Topline-Results-from-the-CANYON-Phase-2-Trial-of-Sevasemten-in-Individuals-with-Becker-Muscular-Dystrophy-Becker
3. Phan H, Collins S, Russell A, et al. Effects of sevasemten (EDG-5506), a fast myosin modulator, on function and biomarkers of muscle damage in adults with Becker muscular dystrophy (Becker). Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO