Interspecies normalization of dose-response relationship for adeno-associated virus-mediated haemophilia gene...

The aim of this study is to develop an approach to predict human dose-response relationship and first-in-human (FIH) dose for adeno-associated virus (AAV)-mediated haemophilia gene therapy.

Preclinical dose-response relationships of 7 AAV vectors were normalized to a species-invariant scale using an exponent of 0.25, and the normalized dose-response relationship was then used for 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 (vg/kg) conversion and allometric scaling approaches.

A power regression analysis of normalized factor VIII (FVIII) or factor IX (FIX) showed a moderate-to-strong correlation between FVIII or FIX and vector dose across 3 species (R² ranged 0.59 to 0.89), indicating it was feasible to normalize dose-response in multiple species to a species-invariant scale. When the mean values of normalized FVIII or FIX at each dose level were used for regression, the R² values of the 7 vectors were improved to be >0.84. The FIH doses predicted by the 3 approaches were ranked as allometric scaling > dose-response normalization > direct vg/kg conversion for all vectors except for rAAV2-hAAT-FIX and scAAV2/8-LP1-hFIXco. Among the 7 vectors, dose-response normalization, direct vg/kg conversion and allometric scaling generated accurate FIH dose predictions for 2, 2 and 3 vectors, respectively.

This study first demonstrated that it is feasible to normalize dose-response relationship of AAV-mediated haemophilia gene therapy in multiple species to a species-invariant scale. The normalized dose-response relationship from preclinical species was successfully extrapolated to patients for FIH dose prediction.