A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of EDG-5506 on Safety, Biomarkers, Pharmacokinetics, and Functional Measures in Adults and Adolescents with Becker Muscular Dystrophy

Trial ID: 2022-500090-13-00
Protocol: EDG-5506-201
Sponsor: Edgewise Therapeutics Inc.

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Diseases & Conditions

Becker's muscular dystrophy

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of sevasemten in both adult and adolescent participants with Becker Muscular Dystrophy (BMD). This is clinically relevant as it aims to ensure that the treatment is safe for use in this patient population, which is crucial for the development of effective therapies. Additionally, the study seeks to assess the effects of sevasemten on serum creatine kinase (CK) levels in adults, which is an important biomarker for muscle damage in BMD.

Secondary objectives include:

Assessing the effects of sevasemten on the North Star Ambulatory Assessment (NSAA) total score and loss of function in adults with BMD.
Evaluating the impact of sevasemten on functional measures and biomarkers of muscle fiber damage, such as serum myoglobin and TNNI2, in adults with BMD.
Investigating the pharmacokinetics (PK) of sevasemten in both adult and adolescent participants with BMD.
Assessing changes in individual safety parameters in both adult and adolescent participants with BMD.
Evaluating the effects of sevasemten on upper leg muscle fat fraction in adults with BMD.

Participants

The clinical trial involves a total of **89 participants** diagnosed with **Becker Muscular Dystrophy (BMD)**. The study population comprises male subjects exclusively, with an age range of 12 to 50 years. Participants are divided into cohorts based on age, with both adolescent (12-17 years) and adult (18-50 years) groups included. The selection criteria required participants to have a documented dystrophin mutation and a phenotype consistent with BMD. Additionally, participants must have a history of being ambulatory beyond certain ages, depending on steroid use, and must be able to complete specific physical assessments, such as the 100-meter timed test and the North Star Ambulatory Assessment. The trial does not include female subjects or vulnerable populations. Participants were selected based on their ability to comply with the study's requirements, including informed consent and contraception guidelines. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

Plans and Procedures

The clinical trial is a **Phase 2 randomized, double-blind, placebo-controlled study** designed to evaluate the effect of **EDG-5506** on safety, biomarkers, pharmacokinetics, and functional measures in adults and adolescents with **Becker Muscular Dystrophy (BMD)**. The trial is structured to include multiple cohorts, each with specific objectives related to safety, tolerability, and efficacy. The study is expected to span a total duration of approximately 52 weeks, with an estimated end date in December 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic confirmation of dystrophin mutation, and ability to perform specific physical assessments. Following successful screening, participants will be randomized to receive either the investigational product, **EDG-5506**, or a placebo, administered orally in tablet form. The maximum daily dose is set at 20 mg, with a total dose not exceeding 7000 mg over the treatment period.

Study visits will be scheduled at regular intervals to monitor safety and efficacy outcomes. These visits will include assessments of adverse events, changes in serum creatine kinase levels, and functional measures such as the North Star Ambulatory Assessment. Pharmacokinetic evaluations will also be conducted to measure the steady-state plasma concentration of **EDG-5506**. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be made to evaluate the primary and secondary endpoints.

Participant involvement is expected to last for the full duration of the trial, approximately 52 weeks, unless early termination is warranted. Conditions that may lead to early withdrawal include the occurrence of serious adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide comprehensive data on the safety and efficacy of **EDG-5506** in the target population, contributing valuable insights into the management of **Becker Muscular Dystrophy**.

Treatment

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 20 mg, with a total maximum dose of 7000 mg over a treatment period of up to 52 weeks. The active substance in **EDG-5506** is of chemical origin, and the medication is not formulated for pediatric use. The trial aims to evaluate the safety, biomarkers, pharmacokinetics, and functional measures in adults and adolescents with Becker Muscular Dystrophy.

In addition to the experimental medication, a placebo is utilized in the 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 used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know who is receiving the active medication or the placebo. The placebo is also administered orally in a similar tablet form to match the experimental treatment.

Efficacy

The efficacy of the investigational product **EDG-5506** in the clinical trial will be assessed through a series of primary and secondary endpoints. For Cohort 6, the primary efficacy endpoint is the change from baseline in the total North Star Ambulatory Assessment (NSAA) score at Month 18. This assessment will provide insights into the functional improvements in participants with Becker Muscular Dystrophy (BMD). Secondary endpoints for Cohort 6 include the Month 18 change from baseline in the 100-meter timed test, 10-meter walk/run, stride velocity (95th percentile), and the total North Star Assessment for Limb-Girdle Type Muscular Dystrophies (NSAD) score. Additionally, changes in the fat fraction of upper leg muscles, as assessed by MRI, and serum biomarkers such as creatine kinase (CK), fast skeletal muscle troponin I (TNNI2), and myoglobin will be evaluated.

For Cohorts 1 and 2, secondary endpoints include the Month 12 change from baseline in the total NSAA score, cumulative loss of function on the NSAA over 12 months, and changes in serum myoglobin and TNNI2 levels averaged across Months 6, 9, and 12. Pharmacokinetics of sevasemten will be measured by steady-state plasma concentration, and the incidence of treatment-emergent abnormal laboratory test results will be monitored. The efficacy assessments will be conducted at specified time points, including baseline, Month 12, and Month 18, using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adults (aged 18 to 50 years, inclusive, at the time of Screening visit) with a documented dystrophin mutation and phenotype consistent with Becker Muscular Dystrophy (BMD), and history of being ambulatory beyond 16 years of age without steroids; history of being ambulatory beyond 18 years of age with steroids, OR adolescents (12 to 17 years, inclusive) with genetic confirmation of dystrophin mutation and a phenotype consistent with Becker Muscular Dystrophy (BMD) as determined by the Investigator AND EITHER: a. An in-frame mutation in the dystrophin gene (DMD) OR b. If an out-of-frame mutation in the dystrophin gene (DMD), as seen in approximately 10% of BMD individuals, the ability to Stand from Supine <10 seconds, as individuals with DMD are uniformly unable to Stand from Supine in <10 seconds after 10 years of age.
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Male sex at birth.
Able to complete the 100-meter timed test in <200 seconds with or without use of mobility aid devices
Able to perform the North Star Ambulatory Assessment (NSAA) and achieve a score of 5 to 32, inclusive for adults (aged 18-50 years, inclusive at the time of Screening visit) OR a score of ≥5 for adolescents (aged 12-17 years, inclusive) at the Screening visit
Willing to comply with contraception requirements described in Section 5.3.1 of the protocol.

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Exclusion Criteria

Medical history or clinically significant physical examination/laboratory result that, in the opinion of the investigator, would render the participant unsuitable for the study.
Moderate or severe renal or hepatic impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). eGFR will be based on Cystatin C formula [eGFR = 133 x min(Scys/0.8, 1) -0.499 x max (Scys/0.8, 1)-1.328 x 0.996Age].
Positive test for hepatitis C antibody (unless negative hepatitis C virus polymerase chain reaction), hepatitis B surface antigen, or human immunodeficiency virus antibody.
Receipt of oral corticosteroids for the treatment of BMD in the previous 6 months. - Receipt of low dose ≤5 mg equivalent per day oral corticosteroids for indications other than BMD or receipt for a short duration (≤10 days in previous 6 months), along with receipt of chronic inhaled/intranasal steroids, is permitted.
Receiving moderate or strong cytochrome P450 CYP3A4 inhibitors or inducers.
Receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the screening visit in the present study.
Participants who, in the opinion of the Investigator, would not be a suitable candidate for participation in the study.
Medical history or other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior, recent (within the past year) history of substance abuse or dependency or laboratory result or abnormality that may increase the risk of study participation or, in the Investigator’s judgment, make the participant inappropriate for the study.
History of malignant neoplastic disease (except for adequately treated non-melanomatous skin carcinoma).
Echocardiogram ejection fraction <40%.
A 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
Forced vital capacity (FVC) predicted <60% or using daytime (mechanical or noninvasive) ventilatory support.
Participants with a known allergy to sevasemten or its excipients.
Participants who are submitted to an institution by virtue of an order of a court or government authority to comply with Section 40a No. 2 of the German Medical Products Act.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	30 Sept 2022	14
Denmark	Not Recruiting	30 Sept 2022	5
France	Not Recruiting	30 Sept 2022	11
Germany	Not Recruiting	30 Sept 2022	3
Italy	Not Recruiting	30 Sept 2022	20
The Netherlands	Not Recruiting	30 Sept 2022	—
Spain	Not Recruiting	30 Sept 2022	23
Netherlands	—	—	5