Developing a robust Quantitative Systems Pharmacology model of adeno-associated virus (AAV) based gene therapy for clinical applications

Satyajit Rao, Jatin Narula, Zhiwei Zhang, Haobin Luo, Glen Ko, Cynthia J Musante, Nessy Tania

Link to poster

INTRODUCTION: AAV GENE THERAPY

• Adeno-associated virus (AAV): A promising vector to deliver functional gene to patients with monogenic disorders
• Following infusion (IV) vectors reach target tissue, transduce cells, and cells express therapeutic protein

MOTIVATION: QSP APPROACH FOR GENE THERAPY

• As a new treatment modality, exposure-response for AAV gene therapy is not established yet
• Quantitative Systems Pharmacology modeling approach can integrate all available data (in vitro, pre-clinical in vivo) to guide human translation and dose prediction

OBJECTIVES: LIVER TARGETED GENE THERAPY MODEL

Leverage QSP model for clinical application in Pfizer’s Hemophilia B gene therapy trial to predict:

• Cohort mean and individual patient Factor IX levels in blood
• Dose-response prediction at higher doses
• Dynamics following IV dosing

METHODS: QSP FRAMEWORK FOR HEMOPHILIA B GENE THERAPY

• AAV Distribution: A minimal PBPK framework to capture biodistribution of vector capsids to liver following IV dosing
• AAV Intracellular Processing and Transduction: Receptor binding, Endocytosis, Nuclear transport, Uncoating steps modeled
• Transgene Expression and Protein Distribution: Transcription, Translation and Pharmacokinetics of distribution of secreted Factor IX

CONCLUSIONS:

• Detailed QSP models capturing biological mechanisms between exposure and response can be calibrated integrating data from multiple studies
• Well-calibrated pre-clinical model and a clinical translation strategy can be used to inform dose selection and predict dynamics as well as dose-response relationships
• Models can offer testable predictions for mechanistic hypotheses

FUTURE APPLICATIONS:

• Adapt the Hemophilia B calibrated model for other liver targeted applications such as Hemophilia A
• Calibrate model to other AAV serotypes used in liver-targeted GTx
• Hypothesize mechanisms for observed non-linear (threshold-like) dose response in Hemophilia A gene therapy clinical trials

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