PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper

Kavita, Uma; Sun, Kefeng; Braun, Manuela; Lembke, Wibke; Mody, Hardik R.; Kamerud, John; Yang, Tong‐Yuan; Braun, Ian; Fang, Xiaodong; Gao, Wei; Gupta, Swati; Hofer, Magdalena; Liao, Michael Z.; Loo, Lina; McBlane, Fraser; Ménochet, Karelle; Stubenrauch, Kay-Gunnar; Upreti, Vijay V.; Vigil, Adam; Wiethoff, Christopher M.; Xia, Cindy Q.; Zhu, Xu; Jawa, Vibha; Chemuturi, Nagendra V.

doi:10.1208/s12248-023-00842-1

AAPS J

2023

DOI: 10.1208/s12248-023-00842-1

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PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper

Uma Kavita

Kefeng Sun

Manuela Braun

et al.

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Cited by 4 publications

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Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

Ford,

Karatza,

Mody

et al. 2024

Clin Pharma and Therapeutics

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Adeno‐associated virus (AAV) vector‐based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered “immune‐privileged” with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one‐time gene delivery has the potential to provide long‐term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV‐based retina gene therapy related to preclinical to clinical translation; first‐in‐human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model‐informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology.

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Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

Ford,

Karatza,

Mody

et al. 2024

Clin Pharma and Therapeutics

Self Cite

View full text Add to dashboard Cite

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Quantitative Systems Pharmacology Models: Potential Tools for Advancing Drug Development for Rare Diseases

Neves‐Zaph,

Kaddi

2024

Clin Pharma and Therapeutics

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Rare diseases, affecting millions globally, present significant drug development challenges. This is due to the limited patient populations and the unique pathophysiology of these diseases, which can make traditional clinical trial designs unfeasible. Quantitative Systems Pharmacology (QSP) models offer a promising approach to expedite drug development, particularly in rare diseases. QSP models provide a mechanistic representation of the disease and drug response in virtual patients that can complement routinely applied empirical modeling and simulation approaches. QSP models can generate digital twins of actual patients and mechanistically simulate the disease progression of rare diseases, accounting for phenotypic heterogeneity. QSP models can also support drug development in various drug modalities, such as gene therapy. Impactful QSP models case studies are presented here to illustrate their value in supporting various aspects of drug development in rare indications. As these QSP model applications continue to mature, there is a growing possibility that they could be more widely integrated into routine drug development steps. This integration could provide a robust framework for addressing some of the inherent challenges in rare disease drug development.

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Prospective approaches to gene therapy computational modeling – spotlight on viral gene therapy

Choules,

Bonate,

Heo

et al. 2023

J Pharmacokinet Pharmacodyn

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Clinical studies have found there still exists a lack of gene therapy dose-toxicity and dose-efficacy data that causes gene therapy dose selection to remain elusive. Model informed drug development (MIDD) has become a standard tool implemented throughout the discovery, development, and approval of pharmaceutical therapies, and has the potential to inform dose-toxicity and dose-efficacy relationships to support gene therapy dose selection. Despite this potential, MIDD approaches for gene therapy remain immature and require standardization to be useful for gene therapy clinical programs. With the goal to advance MIDD approaches for gene therapy, in this review we first provide an overview of gene therapy types and how they differ from a bioanalytical, formulation, route of administration, and regulatory standpoint. With this biological and regulatory background, we propose how MIDD can be advanced for AAV-based gene therapies by utilizing physiological based pharmacokinetic modeling and quantitative systems pharmacology to holistically inform AAV and target protein dynamics following dosing. We discuss how this proposed model, allowing for in-depth exploration of AAV pharmacology, could be the key the field needs to treat these unmet disease populations.

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PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper

Cited by 4 publications

References 63 publications

Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

Clinical Pharmacology Perspective on Development of Adeno‐Associated Virus Vector‐Based Retina Gene Therapy

Quantitative Systems Pharmacology Models: Potential Tools for Advancing Drug Development for Rare Diseases

Prospective approaches to gene therapy computational modeling – spotlight on viral gene therapy

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