PK/PD modeling to inform clinical development of an adeno-associated virus gene transfer therapy for DMD


Pre-Clinical Research

Poster Number: Virtual


Lilly East, Sarepta Therapeutics, Inc., Rachael Potter, Sarepta Therapeutics, Inc., John Snedeker, Sarepta Therapeutics, Inc., Alex Haile, Sarepta Therapeutics, Inc., Chris Wier, Sarepta Therapeutics, Louise Rodino-Klapac, PhD, Sarepta Therapeutics, Inc.

Background: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy developed to address the root cause of Duchenne muscular dystrophy (DMD) through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin.

Objective: To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) relationships between tissue vector genome exposure, biological efficacy, and functional outcome in an animal model of DMD (DMDmdx mice) following treatment with delandistrogene moxeparvovec.

Methods: The vector biodistribution, expression, and clinical dose selection of delandistrogene moxeparvovec were evaluated using a novel application of a PK/PD modeling approach applied to data collected from DMDmdx mice. We analyzed PK/PD relationships between dose, tissue vector genome exposure, SRP-9001 dystrophin protein expression (percent dystrophin-positive fibers [PDPF] and western blot), and functional improvement (relative specific force from tibialis anterior and diaphragm).

Results: Linear kinetics with a dose-proportional increase in tissue drug exposure were demonstrated across the nearly 10-fold dose range (4.43×1013–4.01×1014 vg/kg), and in all tissues. The relationship between tissue vector exposure and PD endpoints (PDPF, motor function outcome) showed a saturable response across a wide range of vector exposures. The vector exposure at 1.33×1014 vg/kg (the clinical dose) approached the maximum treatment response. Relative specific force and PDPF were significantly correlated (P=4.43×10–6). However, the relationship appeared to be nonlinear, with increased PDPF expression approaching the maximal functional improvement. Relative specific force and western blot were not significantly correlated.

Conclusions: For the first time, biodistribution, biomarker, and functional efficacy data were used to quantify and demonstrate PK/PD relationships for an adeno-associated virus (AAV)-based gene transfer therapy in a DMD animal model. The results continue to support the expected therapeutic benefit and clinical dose of delandistrogene moxeparvovec, an AAV-based gene transfer therapy.

This study was funded by Sarepta Therapeutics.