P.130 RGX-202: An investigational AAV8 gene therapy coding for a novel microdystrophin as a treatment for Duchenne muscular dystrophy

Abstract

RGX-202 is an investigational one-time gene therapy for the treatment of Duchenne muscular dystrophy (Duchenne) that utilizes a NAV AAV8 vector, a muscle specific promoter (Spc5-12), and an optimized microdystrophin transgene. The microdystrophin coding sequence involves codon optimization, depletion of CpG dinucleotides, and an extended coding region for the C-Terminal (CT) domain found in naturally occurring dystrophin. Preclinical studies in mdx mice demonstrated a dose proportional increase of RGX-202 vector DNA and microdystrophin in skeletal and heart muscle and restoration of the dystrophin-associated complex (DAPC) at the sarcolemma, indicating the potential benefit of the CT domain. Moreover, after a single intravenous (IV) injection of RGX-202, mdx mice showed significant improvements in dystrophic muscle pathology (muscle lesions and fibrosis) and function (in vitro force, and automated gait analysis) at doses > 1e14 GC/kg. A Phase I/II trial, AFFINITY DUCHENNE, is a multicenter, open-label dose escalation study to evaluate the safety, tolerability and clinical efficacy of a one-time IV dose of RGX-202 in patients with Duchenne. Six ambulatory, pediatric patients (ages 4 to 11 years old) with Duchenne are expected to enroll in 2 cohorts at doses of 1x10¹⁴ genome copies (GC)/kg body weight (n=3) and 2x10¹⁴ GC/kg body weight (n=3). An expansion may allow for up to 6 additional participants to be enrolled at each dose for a total of up to 9 participants at each dose and 18 participants in the study. Additional inclusion criteria are based on dystrophin gene mutations in exons 18-58, a functional assessment, and AAV seronegative status. Endpoints include safety, immunogenicity assessments, RGX-202 microdystrophin levels in muscle, functional assessments (North Star Ambulatory Assessment and timed function tests), and muscle preservation (MRI).