Abstract Details

Title PK/PD Modeling to Inform Clinical Development of an Adeno-associated Virus Gene Transfer Therapy for Duchenne Muscular Dystrophy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S48 - Therapeutics for Muscle Disease (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

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.

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) (DMD^mdx mice) following treatment with delandistrogene moxeparvovec (SRP-9001).

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 DMD^mdxmice. 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.

Authors/Disclosures
Lilly East, PhD PRESENTER	Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics.
Rachael Potter	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Louise R. Rodino-Klapac (Sarepta Therapeutics)	Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.