AFFINITY DUCHENNE: RGX-202 Gene Therapy in Participants With Duchenne Muscular Dystrophy (DMD)

A Phase 1/2 Open-label, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Intravenous RGX-202 Gene Therapy in Males With Duchenne Muscular Dystrophy (DMD)

RGX-202 is a gene therapy designed to deliver a transgene for a novel microdystrophin that includes functional elements of naturally-occurring dystrophin including the C-Terminal (CT) domain. This is a multicenter, open-label dose evaluation clinical study to assess the safety, tolerability and clinical efficacy of a one-time intravenous (IV) dose of RGX-202 in participants with Duchenne.

Duchenne muscular dystrophy (Duchenne) is a rare genetic disorder, caused by mutations in the gene responsible for making dystrophin, a protein of central importance for muscle cell structure and function. The absence of functional dystrophin protein in individuals with Duchenne results in cell damage during muscle contraction leading to cell death, inflammation, and fibrosis in muscle tissues, and ultimately progressive muscle weakness. RGX-202 is designed to use the AAV8 vector to deliver a transgene to muscle cells that encodes a novel microdystrophin that includes the functional elements of naturally occurring dystrophin including the C-Terminal (CT) domain. This is a Phase 1/2, multicenter, open-label, dose evaluation clinical study to assess the safety, tolerability, pharmacodynamics (microdystrophin protein levels), pharmacokinetics, and preliminary clinical efficacy of RGX-202 in 2 dose groups over 52 weeks when administered by one-time intravenous infusion (IV) in ambulatory male pediatric participants with Duchenne. Six ambulatory, pediatric participants (ages 4-11 years old) with Duchenne are expected to enroll in two dose groups, with doses of 1x10^14 genome copies (GC)/kg body weight (n=3) and 2x10^14 GC/kg body weight (n=3). The first 3 participants in each dose group will be dosed in staggered fashion, at least 4 weeks apart, following increasing body weight: ≤20kg, ≤30kg and ≤40kg. After an independent safety data review for each dose group, an expansion phase of the trial may allow for up to six additional participants to be enrolled at each dose (for a total of up to nine participants in each dose group). A total of up to 18 participants may be enrolled in the study. A comprehensive, short-term, prophylactic immunosuppression regimen will be administered during treatment to mitigate a potential immune response.

Longitudinal trajectory (mean and change from baseline) in North Star Ambulatory Assessment (NSAA) raw and total score

RGX-202 microdystrophin protein levels determined in muscle biopsy and vector genome concentrations in muscle

Vector genome concentrations as measured by polymerase chain reaction [PCR] to RGX-202 deoxyribonucleic acid [DNA] in serum.

Vector genome concentrations as measured by polymerase chain reaction [PCR] to RGX-202 deoxyribonucleic acid [DNA] in urine.

Inclusion Criteria: DMD gene mutation in exons 18 and above, and a clinical picture consistent with typical DMD. Participant is able to walk 100 meters independently without assistive devices, as assessed at screening. Participant is able to complete the TTSTAND per protocol-specific criteria. Participant has been on a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks prior to screening. Clinical laboratory test results, including hepatic and renal function, are within the normal range during screening, or if abnormal, are not clinically significant, in the opinion of the investigator. Exclusion Criteria: Participant has any condition that would contraindicate treatment with immunosuppression. Participant has received ataluren (a protein restoration therapy) or an exon-skipping therapy for the treatment of DMD within 6 months of study entry or is unable to refrain from taking ataluren or exon-skipping therapy for a duration of 5 years from the time of RGX-202 administration. Participant has received any investigational or commercial gene therapy product over his lifetime. Participant is currently taking any other investigational intervention or has taken any other investigational intervention within 3 months prior to the scheduled Day 1 intervention. Participant has detectable AAV8 total binding antibodies in serum. Participant has impaired cardiac function defined as a left ventricular ejection fraction on screening cardiac MRI <55%. Participant is not a good candidate for the study, in the opinion of the investigator.