Dose-Escalation and Comparative Study of Eteplirsen in Duchenne Muscular Dystrophy Patients with Exon 51 Skipping Mutations

The primary objective of this study is to evaluate the **safety** and tolerability of weekly intravenous doses of 100 mg/kg and 200 mg/kg of eteplirsen in patients with **Duchenne Muscular Dystrophy** (DMD) who have deletion mutations amenable to exon 51 skipping. This is clinically relevant as it aims to determine the optimal dosing regimen that maximizes therapeutic benefits while minimizing adverse effects, thereby improving patient outcomes in this population.

Secondary objectives include:

• Evaluating the effect of high doses of eteplirsen (100 mg/kg and 200 mg/kg) compared to 30 mg/kg on ambulatory performance, pulmonary function, and dystrophin expression.
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of doses higher than 30 mg/kg.
• Evaluating the safety and tolerability of these higher doses administered weekly.

The clinical trial involves a total of **123 participants** diagnosed with **Duchenne Muscular Dystrophy** (DMD). The study population consists exclusively of male subjects, aged between 4 to 13 years, who are ambulatory and able to perform specific motor function tests. Participants were selected based on their genetic profile, specifically those with an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping. All participants are required to have stable pulmonary function and must have been on a stable dose of oral corticosteroids for at least 12 weeks prior to the study. The trial does not include female subjects and focuses on a vulnerable population due to the nature of the disease. Lifestyle considerations include the ability to walk independently without assistive devices and the requirement for participants to have intact biceps muscles for biopsy purposes. The trial ensures that participants and their guardians understand and comply with all study requirements, including informed consent and assent where applicable.

The clinical trial is designed to evaluate the **safety** and efficacy of high doses of **eteplirsen** in patients with **Duchenne Muscular Dystrophy** (DMD) who have deletion mutations amenable to exon 51 skipping. This study is structured as a randomized, double-blind, dose-finding, and comparison trial, preceded by an open-label dose escalation phase. The trial is expected to span approximately four years, with an estimated end date in October 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, ambulatory status, and genetic mutation. The open-label phase will assess the safety and tolerability of weekly intravenous doses of 100 mg/kg and 200 mg/kg of eteplirsen. Following this, the double-blind phase will compare these higher doses to a 30 mg/kg dose, focusing on motor function outcomes in ambulant DMD patients.

Study visits will include regular follow-up assessments to monitor safety and efficacy, with primary endpoints such as changes in the North Star Ambulatory Assessment (NSAA) total score at specified weeks. Secondary endpoints will evaluate additional functional measures and **skeletal muscle dystrophin** expression. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 144 weeks.

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 necessary for their safety. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the well-being of the participants.

The clinical trial involves the administration of **eteplirsen**, a **solution for infusion** developed by Sarepta Therapeutics Inc. Eteplirsen, also known by its sponsor product code AVI-4658, is a phosphorodiamidate morpholino oligomer designed for exon 51 skipping in patients with Duchenne Muscular Dystrophy (DMD). The active substance, eteplirsen, is of nucleic acid origin. The pharmaceutical form of eteplirsen is a solution for infusion, and it is administered intravenously. The dosing regimen includes weekly intravenous doses of 30 mg/kg, 100 mg/kg, and 200 mg/kg, with the primary objective of evaluating the safety, tolerability, and efficacy of these doses on motor function in ambulant DMD patients with confirmed deletion genotypes amenable to exon 51 skipping. The maximum treatment period for eteplirsen in this study is 114 weeks.

In addition to the experimental treatment, the study design includes a double-blind dose-finding and dose-comparison part, where the effects of high doses of eteplirsen (100 mg/kg and 200 mg/kg) are compared with a lower dose of 30 mg/kg. This part of the study aims to investigate the impact of these doses on motor function and to evaluate the higher doses for dose comparison. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of high doses of **eteplirsen** on motor function in patients with Duchenne Muscular Dystrophy (DMD) who have deletion mutations amenable to exon 51 skipping. The primary efficacy endpoint for the double-blind dose finding and dose comparison part of the study is the change from baseline in the North Star Ambulatory Assessment (NSAA) total score at Week 72 or Week 96 for conditional efficacy interim analysis, and at Week 144 for the final analysis. Secondary efficacy endpoints include changes from baseline at Week 144 in time to rise (TTRISE) from the floor, 10-meter walk/run time, 6-minute walk test (6MWT), timed 4-step stair ascend test, and forced vital capacity percent predicted (FVC%p). Additionally, the time to loss of ambulation (LOA) through Week 144 will be evaluated.

Further assessments will include changes from baseline at Week 24, Week 48, or Week 144 in skeletal muscle dystrophin expression, measured by Western blot quantitation, immunohistochemistry (IHC) fiber intensity by immunofluorescence, exon skipping quantitation by droplet digital polymerase chain reaction (ddPCR), and percent dystrophin-positive fibers (PDPF) by immunofluorescence. Pharmacokinetic (PK) parameters will also be assessed through plasma and muscle biopsy analyses. The schedule for these assessments is structured to capture data at specified intervals, ensuring a comprehensive evaluation of the treatment's efficacy over the course of the trial.