PWI-005 - PHARMACOMETRICS-BASED APPROACH TO DEMONSTRATE CLINICAL EVIDENCE OF DELANDISTROGENE MOXEPARVOVEC BIOLOGICAL EFFICACY AND MECHANISM OF ACTION IN PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY.

L. East, S. Mason, T. Singh, J. Richardson, R. Potter, S. Lewis, L. Rodino-Klapac; Sarepta Therapeutics, Inc.

Background: Delandistrogene moxeparvovec, an rAAV vector-based gene therapy, is designed to deliver a transgene encoding an engineered and functional dystrophin protein in Duchenne muscular dystrophy (DMD). As of Aug 2023, it is approved in the USA and UAE for treating ambulatory pediatric patients (pts) aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene. A novel population exposure–response (ER) modeling approach was used to evaluate the relationship between delandistrogene moxeparvovec muscle tissue transduction (vector genome concentration [VGC]) and biological response across a broad DMD population (aged 4–20 years; ambulant and non-ambulant pts).

Methods: Muscle biopsies were obtained from 75 pts with DMD treated with a single intravenous dose of delandistrogene moxeparvovec (1.33×10¹⁴ vg/kg) in Studies 101 (SRP-9001-101; NCT03375164; n=3), 102 (SRP-9001-102; NCT03769116; n=41), or 103 (SRP-9001-103; NCT04626674; Cohorts 1–3, n=31); 3 doses were used in Study 102 (6.29×10¹³, 8.94×10¹³, and 1.33×10¹⁴ vg/kg). VGC was quantified by droplet digital PCR. Percent dystrophin-positive fibers (PDPF) and fiber intensity (FI) were quantified via immunofluorescence; total protein expression was quantified via western blot (WB). Population non-linear mixed-effect modeling was performed, and the impact of covariates was assessed (e.g. demographics, disease state, immunogenicity, and concomitant medications).

Results: Increased dose-dependent VGC and protein expression were observed with increased doses. A clear linear relationship was observed between protein expression (FI and WB) and VGC. A robust nonlinear relationship with a clear saturable response was observed between VGC and PDPF; the therapeutic dose (1.33×10¹⁴ vg/kg) approached maximum membrane-localized protein expression. Body mass index was the only statistically significant covariate in the PDPF-ER relationship.

Conclusion: This body of work presents the first population ER modeling on an AAV-based gene therapy modality. These findings support the therapeutic delandistrogene moxeparvovec dose by demonstrating robust biological efficacy as well as clinical evidence for the proposed mechanism of action in a broad DMD population, and are consistent with dose-ranging studies performed in DMD^MDX mice.