Efficacy and Safety Evaluation of Casimersen and Golodirsen in Duchenne Muscular Dystrophy Patients Amenable to Exon 45 or 53 Skipping: A Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **SRP-4045** and **SRP-4053** (combined-active group) compared with placebo on ambulation and muscle function in patients with Duchenne Muscular Dystrophy, as measured by the 4-step ascend velocity. This is clinically relevant as it directly assesses the potential improvement in mobility and functional capacity, which are critical outcomes for patients with this progressive neuromuscular disorder.

Secondary objectives include:

• Double-blind period: Evaluate the effect of SRP-4045 and SRP-4053 on dystrophin protein expression in biopsied muscle tissue, measured by Western blot quantification and immunohistochemistry fiber intensity.
• Assess functional status using the 6-minute walk test (6MWT), 10-meter walk/run (10MWR), 4-step ascend velocity, rise from floor velocity, and North Star Ambulatory Assessment (NSAA).
• Evaluate the safety and tolerability of SRP-4045 and SRP-4053.
• Open-label treatment period: Assess the long-term effects of SRP-4045 and SRP-4053 on functional status up to 144 weeks.
• Evaluate the long-term safety and tolerability of SRP-4045 and SRP-4053.
• Pharmacokinetic objective: Evaluate the pharmacokinetic properties of SRP-4045 and SRP-4053 using a population pharmacokinetic model.

The clinical trial involves a total of **247 participants** diagnosed with **Duchenne Muscular Dystrophy** (DMD) amenable to exon 45 or 53 skipping. The study population consists exclusively of male subjects, aged between 6 and 13 years for those amenable to exon 53 skipping, and between 7 and 13 years for those amenable to exon 45 skipping. Participants were selected based on a confirmed genetic diagnosis of DMD with specific exon deletions, as documented by a genetic report. All participants are required to have stable pulmonary function and intact biceps brachii muscles, or alternative upper arm muscle groups, for biopsy purposes. Additionally, they must have been on a stable dose of oral corticosteroids for at least 24 weeks prior to the study and, if applicable, on a stable dose of other medications such as ACE inhibitors or beta-blockers for at least 12 weeks. The trial population is characterized by a mean 6-minute walk test (6MWT) distance of 300 to 450 meters, achieved without assistance. Participants' lifestyle considerations include maintaining a stable medication regimen and, if sexually active, adhering to specific contraceptive measures. The study does not include female subjects and involves a vulnerable population due to the age and health condition of the participants.

The clinical trial is designed to evaluate the efficacy and safety of **SRP-4045** and **SRP-4053** in patients with **Duchenne Muscular Dystrophy** amenable to exon 45 or 53 skipping. This is a randomized, double-blind, placebo-controlled, multicenter study with an open-label extension. The trial aims to assess the effect of the investigational drugs on ambulation and muscle function, specifically measuring the 4-step ascend velocity. The study is expected to conclude by September 2025, with recruitment having commenced in May 2017.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, genetic diagnosis, and pulmonary function. Following successful screening, participants will be randomized to receive either the investigational drug or placebo. The double-blind period will last for 96 weeks, during which primary endpoints, such as changes in 4-step ascend velocity, will be evaluated. Secondary endpoints include changes in 6-minute walk test (6MWT) distance and dystrophin protein expression.

Study visits will occur at regular intervals to monitor safety and efficacy, with assessments including physical examinations, laboratory tests, and functional tests. The end-of-study visit will mark the completion of the double-blind phase, after which participants may enter an open-label extension to receive the active drug. The total duration of participant involvement is anticipated to be up to 144 weeks, including the open-label phase.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it in their best interest. The trial is conducted in accordance with ethical guidelines, ensuring informed consent is obtained from all participants or their legal guardians. The investigational drugs, **golodirsen** and **casimersen**, are administered intravenously, with dosing based on body weight. The study is not classified as a low-intervention trial and adheres to phase III clinical trial standards.

The clinical trial involves the administration of **Golodirsen (SRP-4053)**, an experimental medication formulated as a **concentrate for solution for infusion**. The active substance, **golodirsen**, is a nucleic acid-based compound. The medication is administered via **intravenous use** at a dosage of 30 mg/kg, with a maximum total dose of 4320 mg/kg over a treatment period of 144 weeks. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance through regular assessments.

Another experimental medication used in the trial is **Casimersen (SRP-4045)**, which is also a nucleic acid-based compound. It is provided as a **solution for infusion** and administered intravenously. The dosing regimen mirrors that of Golodirsen, with a dosage of 30 mg/kg and a maximum total dose of 4320 mg/kg over 144 weeks. The administration of Casimersen is carefully monitored to ensure adherence to the dosing schedule and to evaluate its efficacy and safety in the study population.

The trial also includes the use of a **0.9% sodium chloride** solution, which serves as a placebo. This solution is utilized to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in a manner consistent with the experimental treatments to maintain the integrity of the study design.

The efficacy of the investigational products SRP-4045 and SRP-4053 in patients with Duchenne Muscular Dystrophy will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline at Week 96 in the 4-step ascend velocity, measured in steps per second. Secondary endpoints include changes from baseline at Week 96 in the 6-minute walk test (6MWT) and rise from floor velocity, as well as changes at Week 144 in the 4-step ascend velocity. Additional secondary endpoints involve changes from baseline at Week 96 in the 10-meter walk/run (10MWR) velocity and the quantity of dystrophin protein expression, as measured by Western blot of biopsied muscle tissue. The intensity of dystrophin expression in biopsied muscle tissue will also be evaluated using immunohistochemistry (IHC) at Weeks 48 or 96. Furthermore, changes in the North Star Ambulatory Assessment (NSAA) total score at Week 96 will be assessed.

These efficacy parameters will be collected and analyzed at specified timepoints, including Weeks 48, 96, and 144, using validated scales and laboratory tests. The assessments will be conducted in a double-blind, placebo-controlled manner, with an open-label extension to ensure comprehensive evaluation of the investigational products' effects on ambulation and muscle function. The trial is designed to provide robust data on the efficacy of SRP-4045 and SRP-4053 in improving clinical outcomes for patients with Duchenne Muscular Dystrophy.