Interspecies normalization of dose response relationship for adeno-associated virus-mediated hemophilia gene therapy: application to first-in-human dose prediction

Abstract

Establishing dose response relationships in targeted patients is foundational in the development of therapeutic drugs including gene therapy products. Enlightened by interspecies normalization of plasma drug concentration-time curves using Dedrick plot, the author of this manuscript first demonstrated the feasibility of normalizing dose-response relationship of adeno-associated virus (AAV)-mediated hemophilia gene therapy products in multiple species to a species-invariant scale. Preclinical dose-response relationships of eight AAV vectors were normalized using an exponent of 0.25 and applied to first-in-human (FIH) dose prediction. The performance of this dose-response normalization approach for FIH dose prediction was compared to that of direct body weight-based dose conversion and allometric scaling approaches. The study results suggested that in addition to hemophilia dogs and non-human primates, inclusion of larger animal models (e.g., swine and cattle) in preclinical dose-finding studies of AAV vectors might improve the performance of interspecies dose-response normalization approach. Furthermore, it was found that AAV capsid-specific T cell responses in hemophilia patients might cause underprediction of FIH dose while novel bioengineered capsids with a high transduction efficiency specifically in human hepatocytes might cause overprediction of FIH dose. These factors should be considered when dose-response is extrapolated from preclinical species to patients.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding.

Author Declarations

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The study used ONLY openly available human data collected from literature.

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Data Availability

All data produced in the present work are contained in the manuscript.

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