First-in-Patient Dose Prediction for Adeno-Associated Virus-Mediated Hemophilia Gene Therapy Using Allometric Scaling.

In this study, the author compared the performance of two allometric scaling approaches and body-weight-based dose conversion approach for first-in-patient (FIP) dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy using preclinical and clinical efficacy data of nine AAV vectors. In general, body-weight-based direct conversion of effective doses in monkeys or dogs was more likely to underestimate FIP dose but worked for one bioengineered vector with a high transduction efficiency specifically in humans. In contrast, allometric scaling between gene efficiency factor (log GEF) and body weight (log W) was likely to overestimate FIP dose but worked for two vectors with capsid-specific T-cell responses in patients. The third approach, allometric scaling between log GEF and W-0.25 was appropriate for FIP dose prediction in the absence of T-cell responses to AAV vectors or a dramatic difference in vector transduction efficiency between animals and humans.