PK/PD Modeling to Inform Clinical Development of an Adeno-associated Virus Gene Transfer Therapy for Duchenne Muscular Dystrophy
Lilly East1, Rachael Potter1, John Snedeker1, Alex Haile1, Chris Wier1, Louise Rodino-Klapac1
1Sarepta Therapeutics, Inc.
Objective:
To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between tissue vector genome exposure, biological efficacy and functional outcome in an animal model of Duchenne muscular dystrophy (DMD) (DMDmdx mice) following treatment with delandistrogene moxeparvovec (SRP-9001).
Background:
Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin.
Design/Methods:
We evaluated vector biodistribution, expression, and clinical dose selection of delandistrogene moxeparvovec using a novel application of a PK and 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 (4.43x1013–4.01x1014 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 1.33x1014 vg/kg (the clinical dose) approached the maximum treatment response. Relative specific force and PDPF were significantly correlated (P=4.43x10–6). 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.