Evaluation of the Safety and Efficacy of Delandistrogene Moxeparvovec in Non-Ambulatory and Ambulatory Duchenne Muscular Dystrophy Patients

The primary objective of this Phase 3, multinational, randomized, double-blind, placebo-controlled study is to evaluate the change from baseline in the total score of **Performance of Upper Limb (PUL) (Version 2.0)** at Week 72 in subjects with **Duchenne Muscular Dystrophy**. This objective is clinically relevant as it assesses the efficacy of the gene transfer therapy, Delandistrogene Moxeparvovec, in improving upper limb function, which is crucial for enhancing the quality of life in both non-ambulatory and ambulatory patients.

Secondary objectives include:

• Change from baseline in percent predicted **Forced Vital Capacity (FVC)** at Week 72.
• Change from baseline in percent predicted **Peak Expiratory Flow (PEF)** at Week 72.
• Quantity of Delandistrogene Moxeparvovec dystrophin expression at Week 12 as measured by Western Blot.
• Change from baseline in **Patient-Reported Outcomes Measurement Information System (PROMIS)** score in upper extremity function to Week 72.
• Number of participants with a treatment emergent adverse event (TEAE), adverse event of special interest (AESI), and serious adverse event (SAE) from baseline up to Week 124.
• Change from baseline in the **North Star Ambulatory Assessment (NSAA)** total score at Week 72 for Cohort 2 only.
• Change from baseline in global circumferential strain as measured by cardiac MRI at Week 72.
• Change from baseline in PUL (Version 2.0) middle domain score at Week 72.

The clinical trial involves a total of **53 participants** diagnosed with **Duchenne Muscular Dystrophy** (DMD). The study population is exclusively male, with an age range of **8 to 18 years**. Participants were selected based on a definitive diagnosis of DMD, confirmed through documented clinical findings and prior genetic testing, excluding any deletion mutations in exon 8 and/or 9. The trial includes both non-ambulatory and ambulatory cohorts, with the latter requiring participants to be within the specified age range at the time of screening. All participants are required to have a stable daily dose of oral corticosteroids for at least 12 weeks prior to screening, with the expectation that the dose will remain constant throughout the study, except for adjustments due to weight changes. Additionally, participants must not have elevated Recombinant Adeno-Associated Virus Serotype rh74 (rAAVrh74) antibody titers as per protocol-specified requirements. The trial does not include female subjects and involves a vulnerable population, given the nature of the disease and the age of the participants.

The clinical trial is a **Phase 3**, multinational, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of **delandistrogene moxeparvovec** in both non-ambulatory and ambulatory subjects diagnosed with **Duchenne Muscular Dystrophy** (DMD). The trial involves the administration of the investigational product, delandistrogene moxeparvovec, via intravenous infusion, with a saline solution serving as the placebo. The study is expected to run until June 2028, with recruitment having commenced in May 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a definitive diagnosis of DMD, age, and corticosteroid use. The trial is divided into two cohorts: non-ambulatory and ambulatory subjects, with specific inclusion criteria for each. Following the screening, participants will be randomized to receive either the investigational product or placebo. The primary endpoint is the change from baseline in the total score of the Performance of Upper Limb (PUL) at Week 72. Secondary endpoints include changes in forced vital capacity, peak expiratory flow, and dystrophin expression, among others.

Study visits will include baseline assessments, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit. The expected duration of participant involvement is approximately 72 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the therapeutic potential of delandistrogene moxeparvovec in managing DMD, contributing to the understanding of gene transfer therapy in this patient population.

The clinical trial involves the administration of **Delandistrogene moxeparvovec-rokl**, an experimental gene therapy product. This investigational medication is formulated as a **solution for injection/infusion** and is administered via **intravenous use**. The active substance, **delandistrogene moxeparvovec**, is a structurally diverse substance designed for gene transfer therapy. The maximum daily and total dose is set at 13,300,000,000,000 vector genomes (vg)/mL, with a treatment period limited to a single administration. This product is specifically formulated for pediatric use and has been designated as an orphan drug. The therapy is intended to deliver the gene of interest, **delandistrogene moxeparvovec dystrophin**, using an adeno-associated virus (AAV) vector, and it is not classified as a genetically modified organism (GMO).

The trial also includes a **placebo** control, which consists of a **0.9% sodium chloride solution** for intravenous infusion. This saline solution is a standard, marketed product that will be supplied by the study site. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The saline solution serves as a comparator to evaluate the safety and efficacy of the experimental gene therapy in subjects with **Duchenne Muscular Dystrophy**. The administration of the placebo follows the same route and frequency as the experimental treatment to ensure consistency in the study protocol.

The efficacy of the investigational product, **Delandistrogene moxeparvovec**, in the clinical trial will be assessed through a series of predefined primary and secondary endpoints. The primary endpoint is the change from baseline in the total score of the Performance of Upper Limb (PUL) Version 2.0 at Week 72. This endpoint will be measured using a validated scale to evaluate the functional abilities of the upper limbs in subjects with Duchenne Muscular Dystrophy.

Secondary endpoints include several measures to provide a comprehensive assessment of efficacy. These include the change from baseline in percent predicted Forced Vital Capacity (FVC) and Peak Expiratory Flow (PEF) at Week 72, which are indicators of respiratory function. Additionally, the quantity of **Delandistrogene moxeparvovec** dystrophin expression will be measured at Week 12 using Western Blot analysis. Other secondary endpoints involve changes in patient-reported outcomes, such as the PROMIS score in upper extremity function, and the North Star Ambulatory Assessment (NSAA) total score for Cohort 2 at Week 72. Cardiac function will be evaluated by measuring the change from baseline in global circumferential strain using cardiac MRI at Week 72. The middle domain score of PUL Version 2.0 will also be assessed at Week 72.

Data collection will occur at specified time points, with the primary endpoint being assessed at Week 72. The secondary endpoints will be measured at various intervals, including Week 12 and Week 72, depending on the specific parameter. The analysis will involve comparing changes from baseline to these time points to determine the efficacy of the treatment. The trial will also monitor the number of participants experiencing treatment-emergent adverse events, adverse events of special interest, and serious adverse events to ensure a comprehensive evaluation of both efficacy and safety.