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.