A Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Effect of EDG-5506 on Biomarker Response to Exercise in Adults with Becker Muscular Dystrophy, McArdle Disease, or Limb-Girdle Muscular Dystrophy

The primary objective of this study is to assess the **safety** of sevasemten in adults with neuromuscular diseases, specifically Becker Muscular Dystrophy (BMD), McArdle Disease, and Limb-Girdle Muscular Dystrophy Type 2I (LGMD2I). Additionally, the study aims to evaluate the effect of sevasemten treatment on biomarkers of muscle damage in these patient populations. Understanding the safety profile and biomarker response is clinically relevant as it may inform the therapeutic potential and risk-benefit ratio of sevasemten in managing these conditions.

Secondary objectives include:

• Assessing biomarker response to sevasemten treatment in adults with BMD, McArdle Disease, or LGMD2I.
• Evaluating the change in individual safety parameters in these patients.
• Investigating the pharmacokinetics of sevasemten concentrations in the specified patient groups.

The clinical trial involves a study population comprising both **male** and **female** participants, aged between 18 to 75 years, depending on the specific neuromuscular condition. The trial focuses on individuals diagnosed with **Becker Muscular Dystrophy**, **McArdle Disease**, or **Limb-Girdle Muscular Dystrophy Type 2I**. Participants with Becker Muscular Dystrophy or Limb-Girdle Muscular Dystrophy Type 2I are required to be between 18 to 65 years of age, while those with McArdle Disease may enroll up to 75 years of age. The trial population includes individuals who are capable of complying with the study's exercise protocol and have no concurrent medical conditions that could impair their ability to participate. Participants must be fluent in Danish or English and willing to adhere to contraception requirements as outlined in the protocol. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and the selection process ensures that participants have a molecular diagnosis consistent with their condition and no active muscle injury at the time of screening.

The clinical trial is a **Phase 2 randomized, double-blind, placebo-controlled study** designed to evaluate the effect of **EDG-5506** on biomarkers of muscle damage in adults with **Becker Muscular Dystrophy**, **McArdle Disease**, or **Limb-Girdle Muscular Dystrophy**. The trial aims to assess the safety and efficacy of the investigational product, EDG-5506, administered orally in tablet form. The study is expected to last approximately 78 weeks, with participant involvement spanning the same duration. The trial will commence with a screening visit to determine eligibility based on specific inclusion criteria, such as age and molecular diagnosis, and to ensure the absence of concurrent medical conditions that could impair participation.

Following successful screening, participants will be randomized to receive either EDG-5506 or a placebo. The trial includes multiple follow-up visits to monitor the incidence, frequency, and severity of adverse events, as well as changes in serum creatine kinase levels from baseline to week 16 and week 52. Secondary endpoints include the assessment of treatment-emergent abnormal laboratory test results, changes in safety laboratory parameters, vital signs, and cardiac and pulmonary function. The study will also measure steady-state plasma concentrations of sevasemten.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the overall safety and efficacy of the treatment. Participants may be withdrawn from the study if they experience significant adverse events, are unable to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial is scheduled to end by August 2025, with recruitment having started in December 2022.

The clinical trial involves the administration of **EDG-5506**, an investigational medication developed by Edgewise Therapeutics Inc. **EDG-5506** is formulated as a tablet and is administered orally. The maximum daily dose is 15 mg, with a total maximum dose of 6020 mg over a treatment period of 78 days. The active substance, **EDG-5506**, is of chemical origin. The trial aims to evaluate the safety and efficacy of this compound in adults with Becker Muscular Dystrophy, McArdle Disease, or Limb-Girdle Muscular Dystrophy. Participants' compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is referred to as "Test IMP (EDG-5506) without active substance" and does not contain any active pharmaceutical ingredients. The placebo is utilized to assess the effect of **EDG-5506** on biomarker response to exercise, providing a baseline for comparison. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding and integrity.

The efficacy of the investigational product, **EDG-5506**, in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence, frequency, and severity of adverse events and serious adverse events in participants treated with **EDG-5506** or placebo, as well as the change in serum creatine kinase (CK) levels from baseline to week 16. Secondary endpoints will evaluate the change in serum CK from pre-exercise baseline to week 52, the incidence of treatment-emergent abnormal laboratory test results, and changes from baseline in safety laboratory parameters, vital signs, physical and neurological examinations, electrocardiogram (ECG) parameters, cardiac function assessed by echocardiogram, and pulmonary function assessed by spirometry (FEV1, FVC). Additionally, the Columbia Suicide Severity Rating Scale (C-SSRS) will be utilized to assess any changes in suicide risk, and steady-state plasma concentrations of sevasemten will be measured.