Sevasemten Meets Primary End Point in Phase 2 CANYON Trial of Becker Muscular Dystrophy

Craig M. McDonald, MD, Distinguished Professor and Chair at the UC Davis Health Department of Physical Medicine and Rehabilitation

Edgewise Therapeutics has announced positive topline data from its phase 2 CANYON trial (NCT05291091), with results showing that investigational sevasemten, formerly known as EDG-5506, met its primary end point in change of creatine kinase (CK) among patients with Becker muscular dystrophy. Based on these encouraging findings, the company plans to work with the FDA and European Medicines Agency towards authorization filing strategies for the agent in Becker.¹

The placebo-controlled, double-blind study featured 40 adults and 29 adolescents with Becker who were randomly assigned to either sevasemten or placebo for a 12-month treatment period, followed by a 4-week follow-up period. All told, over months 6 through 12, results revealed a 28% average difference in CK decrease among sevasemten-treated patients vs those on placebo (P = .02). According to Edgewise, this was the largest interventional trial to date in Becker and the first to achieve its primary end point.

Sevasemten, an orally administered first-in-class skeletal myosin inhibitor, is designed to protect muscle against contraction-induced muscle damage in muscle dystrophies including Becker and Duchenne (DMD). The agent, which selectively limits the exaggerated muscle damage caused by the absence or loss of functional dystrophin, was considered well-tolerated in the new data, with no new safety concerns identified in treated patients.

"Becker muscular dystrophy is a devastating neuromuscular disease characterized by rapid progression once functional decline begins. This landmark study presents compelling biomarker data and promising signals that suggest the potential for functional stabilization with administration of sevasemten," principal investigator Craig M. McDonald, MD, Distinguished Professor and Chair at the UC Davis Health Department of Physical Medicine and Rehabilitation, said in a statement.¹ "Becker has no approved therapies. I look forward to the results of the GRAND CANYON pivotal cohort with the hope of bringing the first treatment option to this patient population."

GRAND CANYON, an extension to CANYON, is expected to complete recruitment by the first quarter of 2025. This multicenter, double-blind, placebo-controlled cohort further evaluates efficacy and safety of sevasemten in adults with Becker, using change in the North Star Ambulatory Assessment (NSAA) over an 18-month period as the primary end point. The study, anticipated to include 120 patients with the disease, will serve as supplemental supporting data for a future marketing application, if positive.

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After 12 months of treatment, results from CANYON showed a difference on the secondary end point of change in NSAA, favoring the sevsemten group by 1.1 points (P = .16) across all adult participants. NSAA scores remained stable over time in the sevasemten treated group, similar to the observations in the previously completed ARCH study (NCT05160415). Notably, while there was only 12 patients in the control group, NSAA declined similarly to that observed in previous natural history studies.

From months 3 to 6, sevasemten-treated patients demonstrated a 77% decrease (P <.001) in plasma fast skeletal muscle troponin 1 (TNNI2), a secondary target-specific biomarker of fast skeletal damage. In comparison with placebo, those on active treatment showed improved trends on the 10-meter walk/run, 4-stair climb, and 100-meter timed test. Of note, Edgewise mentioned that there was an imbalance between adult participants in the sevasemten and placebo groups with the sevasemten group having more advanced disease at baseline on all functional measures and MRI.

Joanne Donovan, MD, PhD

"We are very encouraged by the CANYON results in Becker and the potential of this novel muscle-targeted therapeutic," Joanne Donovan, MD, PhD, chief medical officer at Edgewise, said in a statement.¹ "This confirmed our previous observations in the ARCH study of significant decreases in biomarkers of muscle damage and similarly we are seeing evidence of preservation of function in Becker patients."

ARCH, an open-label, single-center study, included 12 ambulatory males aged 18 to 55 years with a dystrophin mutation and a Becker phenotype, not on corticosteroids, who were followed for 24 months. At the conclusion of the 24-month treatment period, investigators observed a –0.2 mean change in NSAA with sevasemten, which significantly diverged from a natural history average change of –2.4.²

These data, presented earlier this year at the 2024 American Academy of Neurology Annual Meeting, showed rapid and sustained decreases of relevant biomarkers of muscle damage, including CK, TNNI2, and myoglobin, after 24 months of treatment. Over that time, there was no significant change in hand grip strength or measures of endurance, explained through 100-Meter Timed Test Velocity and Maximum Grip Strength.

Donovan sat down with NeurologyLive in September to discuss the therapeutic promise behind sevasemten and the possibilities of becoming the first FDA-approved treatment for Becker. In the podcast episode below, she discussed the mechanism behind the drug, the previous failures in drug development for Becker, and how previous trials paved the way for CANYON and GRAND CANYON.

REFERENCES
1. 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 December 17, 2024. 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
2. 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. ABSTRACT