Phase 2 Study of Vesleteplirsen (SRP-5051) for Dose Determination and Efficacy in Duchenne Muscular Dystrophy Patients Amenable to Exon 51-Skipping Therapy

The primary objective of this Phase 2 study is to evaluate the **safety** and tolerability of multiple ascending doses of SRP-5051, administered intravenously every 4 weeks, in patients with **Duchenne Muscular Dystrophy** amenable to exon 51-skipping treatment. The study aims to determine the maximum tolerated dose (MTD) of SRP-5051. This is clinically relevant as establishing the MTD is crucial for ensuring patient safety and optimizing therapeutic efficacy in subsequent treatment phases.

The secondary objectives include:

• Determining the pharmacokinetics (PK) of SRP-5051 in plasma and urine at each of the multiple ascending doses.
• Evaluating exon-skipping levels in skeletal muscle tissue following SRP-5051 treatment.
• Assessing the ongoing safety and tolerability of SRP-5051 treatment.
• Evaluating, via immunohistochemistry, the percent dystrophin-positive fibers (PDPF) and mean intensity following SRP-5051 treatment.

These secondary objectives are essential for understanding the drug's pharmacological profile, its biological effects on muscle tissue, and its long-term safety, which are critical for the development of effective treatments for Duchenne Muscular Dystrophy.

The clinical trial involves a total of **40 participants** diagnosed with **Duchenne Muscular Dystrophy**. The study population consists exclusively of male subjects, as female subjects are not included. Participants are within the age range of 7 to 17 years, indicating a focus on pediatric and adolescent individuals. The trial population was selected based on specific inclusion criteria, including a genetic diagnosis of Duchenne Muscular Dystrophy with an out-of-frame deletion mutation of the DMD gene amenable to exon 51-skipping treatment. Participants have either been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug administration or have not received corticosteroids for at least 12 weeks prior. Additionally, participants are required to have stable pulmonary function, with a forced vital capacity of at least 40% of the predicted value and no requirement for nocturnal ventilation. The trial does not include any female subjects, and the population is considered vulnerable due to the nature of the disease and age group involved. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 2**, two-part, multiple-ascending-dose study designed to evaluate the safety, tolerability, and efficacy of **vesleteplirsen** (SRP-5051) in patients with **Duchenne Muscular Dystrophy** amenable to exon 51-skipping treatment. The trial is structured as a randomized, double-blind, controlled study. The trial is expected to last until January 31, 2029, with recruitment having commenced on April 30, 2019. The study is divided into two parts: Part A focuses on determining the maximum tolerated dose (MTD) of vesleteplirsen, while Part B evaluates the dystrophin protein level in skeletal muscle tissue at the doses selected based on data from Part A.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as a genetic diagnosis of Duchenne Muscular Dystrophy and stable pulmonary function. Following the screening, participants will receive intravenous doses of vesleteplirsen every four weeks. The primary endpoints include the incidence of adverse events in Part A and the change from baseline in dystrophin protein level at Week 28 in Part B. Secondary endpoints involve pharmacokinetic assessments and changes in exon-skipping levels and dystrophin-positive fibers.

The expected length of participant involvement varies, with Part A lasting up to 75 weeks and Part B extending to Week 304. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or failure to adhere to the study protocol. Participants will have follow-up visits to monitor safety and efficacy, culminating in an end-of-study visit to assess final outcomes and gather comprehensive data for analysis.

The clinical trial involves the administration of **VESLETEPLIRSEN** (SRP-5051), an investigational medication developed by Sarepta Therapeutics Inc. This experimental drug is provided in a **vial for intravenous use** and is classified as a nucleic acid-based therapeutic. The active substance, vesleteplirsen, is designed for patients with Duchenne Muscular Dystrophy amenable to exon 51-skipping treatment. The medication is administered intravenously every four weeks. The dosing regimen is determined based on the outcomes of the initial phase of the study, with the aim to establish the maximum tolerated dose. The trial does not specify a maximum daily or total dose amount, and the treatment period is set for a maximum of 300 days.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of vesleteplirsen. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study aims to evaluate the safety, tolerability, and efficacy of vesleteplirsen in increasing dystrophin protein levels in skeletal muscle tissue, which is a critical factor in the management of Duchenne Muscular Dystrophy.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of **Vesleteplirsen** (SRP-5051) on patients with Duchenne Muscular Dystrophy amenable to exon 51-skipping treatment. The primary efficacy endpoint for Part B of the study is the change from baseline in dystrophin protein level at Week 28. This will be measured in skeletal muscle tissue following intravenous administration of the investigational product every four weeks. Secondary endpoints include the change from baseline in exon-skipping levels and the change from baseline in percent dystrophin-positive fibers (PDPF) and mean intensity, as measured by immunofluorescence assay at Week 28.

Pharmacokinetic parameters will also be evaluated as secondary endpoints, including plasma and urine concentrations of Vesleteplirsen at multiple time points post-infusion. The incidence of adverse events (AEs) will be monitored throughout the study, with specific attention to baseline up to Week 304 for Part B. These assessments will be conducted using validated laboratory tests and assays to ensure accuracy and reliability of the data collected. The schedule for these measurements is structured to capture both immediate and long-term effects of the treatment, providing a comprehensive evaluation of its efficacy and safety profile.