Evaluation of Safety and Efficacy of Delandistrogene Moxeparvovec and Imlifidase in Duchenne Muscular Dystrophy Patients with Pre-existing rAAVrh74 Antibodies

The primary objective of this study is to evaluate the **change from baseline** in the quantity of **Delandistrogene Moxeparvovec** dystrophin protein expression in subjects with **Duchenne muscular dystrophy** (DMD) who have pre-existing antibodies to **rAAVrh74**. This is measured by Western blot adjusted by muscle content, immunofluorescence (IF) fiber intensity, and IF percent dystrophin-positive fibers (PDPF) at baseline and at Week 12. Additionally, the mean concentration of vector genome copies in muscle tissue biopsy, following Delandistrogene Moxeparvovec administration, is assessed at Week 12. These measures are clinically relevant as they provide insights into the therapeutic efficacy of gene transfer therapy in enhancing dystrophin expression, which is crucial for improving muscle function in DMD patients.

Secondary objectives include:

• Determining the maximum observed plasma concentration (Cmax) of **Imlifidase** up to Day 7.
• Assessing total **IgG** in serum after Imlifidase administration up to Week 12.
• Evaluating rAAVrh74 antibody titers after Imlifidase administration up to Hour 120.
• Measuring the concentration of vector genome copies using polymerase chain reaction in serum after Delandistrogene Moxeparvovec administration up to Day 7.
• Recording the number of participants with a treatment-emergent adverse event (TEAE), adverse event of special interest (AESI), and serious adverse event (SAE) up to Week 104.

The clinical trial focuses on participants diagnosed with **Duchenne muscular dystrophy (DMD)**. The study population comprises male subjects, as female subjects are not included. Participants are categorized within the age range of 2 to 18 years, reflecting a vulnerable population due to the nature of the condition. The trial does not provide specific information on the total number of participants, as the sponsor has not disclosed this data. Selection criteria include a definitive diagnosis of DMD confirmed by clinical findings and genetic testing, the ability to cooperate with motor assessment testing, and specific genetic mutations in the DMD gene. Participants are required to maintain 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 related to weight changes. The trial does not include any female subjects, and the sponsor has not provided additional lifestyle considerations such as diet or physical activity. The study population was selected based on specific inclusion criteria, ensuring that participants meet the necessary requirements for the trial's objectives.

The clinical trial is designed to evaluate the **safety** and efficacy of **Delandistrogene Moxeparvovec** (SRP-9001) following **Imlifidase** infusion in participants with **Duchenne muscular dystrophy** (DMD) who have pre-existing antibodies to recombinant adeno-associated virus serotype (rAAVrh74). This is an open-label, systemic gene delivery study, categorized as a Phase 3 trial. The trial employs a non-randomized, open-label design, focusing on the primary endpoints of changes in dystrophin protein expression and vector genome copies in muscle tissue, measured at baseline and week 12. Secondary endpoints include the maximum observed plasma concentration of Imlifidase, total IgG in serum, and antibody titers post-administration, with assessments extending up to week 104.

The trial is expected to commence recruitment on January 17, 2024, and conclude by June 30, 2027. 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, elevated rAAVrh74 antibody titers, and stable corticosteroid use. Following the screening, participants will receive the investigational products via **intravenous use**. Subsequent follow-up visits will occur at specified intervals to monitor safety, tolerability, and therapeutic outcomes, with the final visit marking the end of the study.

Participant involvement is anticipated to last until the end of the study, with conditions for early termination including the occurrence of serious adverse events or non-compliance with study protocols. The trial aims to provide comprehensive data on the therapeutic potential of gene transfer therapy in DMD patients with pre-existing antibodies, contributing valuable insights into the management of this rare disease.

The clinical trial involves the administration of **Imlifidase**, marketed under the name Idefirix, which is provided as an 11 mg powder for concentrate for solution for infusion. This experimental medication is a recombinant cysteine protease and IgG endopeptidase derived from *Streptococcus pyogenes*. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The frequency and specific dosing schedule are determined by the study protocol, and participant compliance is monitored throughout the trial. Imlifidase is not a pediatric formulation and holds an orphan drug designation under the number EU/3/16/1826.

Another experimental treatment used in the study is **Delandistrogene moxeparvovec-rokl**, also known by the sponsor product code SRP-9001. This medication is a solution for injection/infusion and is administered intravenously. Delandistrogene moxeparvovec is an adeno-associated virus serotype RH74 containing the human micro-dystrophin gene, designed for systemic gene delivery. The trial aims to evaluate the safety, tolerability, and expression of this gene therapy in subjects with Duchenne Muscular Dystrophy who have pre-existing antibodies to rAAVrh74. This product also holds an orphan drug designation, EU/3/20/2250, and is not formulated for pediatric use. The dosing schedule and administration details are specified in the study protocol, with compliance monitoring in place to ensure adherence to the treatment regimen.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints focus on the change from baseline in the quantity of **Delandistrogene Moxeparvovec** dystrophin protein expression. This will be measured by Western blot adjusted by muscle content, as well as by immunofluorescence (IF) fiber intensity and percent dystrophin-positive fibers (PDPF) in biopsied muscle. These measurements will be taken at baseline and at week 12. Additionally, the mean concentration of vector genome copies in muscle tissue biopsy will be evaluated using polymerase chain reaction (PCR) at week 12 following the administration of Delandistrogene Moxeparvovec.

Secondary endpoints include the maximum observed plasma concentration (Cmax) of **Imlifidase** up to day 7, total IgG in serum after Imlifidase administration up to week 12, and rAAVrh74 antibody titers up to hour 120. The concentration of vector genome copies in serum will also be measured using PCR up to day 7. Furthermore, the number of participants experiencing treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) will be recorded up to week 104. These assessments will provide comprehensive data on the efficacy of the treatment regimen in subjects with Duchenne Muscular Dystrophy who have pre-existing antibodies to rAAVrh74.