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

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  • Emerging Trends in Preclinical and Clinical Development of Cell and Gene Therapies
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Abstract

Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.

Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.

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Acknowledgements

The authors would like to thank IQ TALG for support of this work. We acknowledge Bing Hu (Alexion) and Naidong Weng (Glaxo Smith Kline) for initial input. We are extremely grateful to Erin Graham and Frances Xin (Spark Therapeutics Inc., Roche) for formatting the manuscript and aiding with the placement of references. Figures were made using Servier Medical Art, a free service at smart.servier.com and a valid Roche license from BioRender.com. V.J and N.C are co-leads of the IQ working group.

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Authors and Affiliations

  1. Spark Therapeutics, Inc., Philadelphia, Pennsylvania, 19104, USA

    Uma Kavita & Magdalena Hofer

  2. Takeda Development Center Americas Inc., 125 Binney St, Cambridge, Massachusetts, 02142, USA

    Kefeng Sun & Nagendra Chemuturi

  3. Bayer AG, Pharmaceuticals R&D, 13342, Berlin, Germany

    Manuela Braun

  4. Integrated Biologix GmbH, 4051, Basel, Switzerland

    Wibke Lembke

  5. Genentech Inc., South San Francisco, California, USA

    Hardik Mody & Michael Z. Liao

  6. Pfizer, Andover, Massachusetts, 01810, USA

    John Kamerud

  7. Janssen R&D LLC., Spring House, Pennsylvania, 19477, USA

    Tong-Yuan Yang

  8. Bayer AG, 42113, Wuppertal, Germany

    Inka V. Braun

  9. Asklepios BioPharmaceutical, Inc., Research Triangle, North Carolina, 27709, USA

    Xiaodong Fang

  10. EMD Serono Research & Development Institute, Inc., Billerica, Massachusetts, 01821, USA

    Wei Gao

  11. AbbVie, 2525 Dupont Drive, Irvine, California, 92612, USA

    Swati Gupta

  12. Vertex Pharmaceuticals Boston, Boston, Massachusetts, 02210, USA

    LiNa Loo

  13. Novartis, Basel, Switzerland

    Fraser McBlane

  14. UCB Pharma Ltd., SL1 3WE, Slough, UK

    Karelle Menochet

  15. Roche Diagnostics GmbH, 82377, Penzberg, Germany

    Kay-Gunnar Stubenrauch

  16. Amgen, South San Francisco, California, 94080, USA

    Vijay V. Upreti

  17. Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, 06877, USA

    Adam Vigil

  18. Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Christopher M. Wiethoff

  19. ReNAgade Therapeutics, Cambridge, Massachusetts, 02142, USA

    Cindy Q. Xia

  20. AstraZeneca, Waltham, Massachusetts, 02451, USA

    Xu Zhu

  21. Bristol Myers Squibb, Lawrence Township, New Jersey, 08648, USA

    Vibha Jawa

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  1. Uma Kavita
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U.K, K.S and NC wrote, drafted, and finalized the manuscript. All authors have contributed to the contents, review, and references of the article.

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Correspondence to Uma Kavita or Kefeng Sun.

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Kavita, U., Sun, K., Braun, M. et al. PK/PD and Bioanalytical Considerations of AAV-Based Gene Therapies: an IQ Consortium Industry Position Paper. AAPS J 25, 78 (2023). https://doi.org/10.1208/s12248-023-00842-1

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