First-in-Patient Dose Prediction for Adeno-Associated Virus-Mediated Hemophilia Gene Therapy

Rational first-in-patient dose selection is critical for successful clinical development of gene therapy. In this presentation, the speaker will compare the performance of two allometric scaling approaches, interspecies dose-response normalization, and body weight-based dose conversion approach for first-in-patient dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy. The performance of the four approaches were examined using preclinical and clinical dose-response data of ten different AAV vectors. Overall, body weight-based direct conversion of effective doses in monkeys or dogs is more likely to underestimate human dose. In contrast, allometric scaling between gene efficiency factor (logGEF) and body weight (BW) is likely to overestimate human dose for hemophilia B gene therapy. Overall, the third approach, allometric scaling between logGEF and BW^-0.25 is more appropriate for human dose prediction in hemophilia B gene therapy. Intense immunogenicity response such as T-cell response against capsid can substantially cause underprediction of first-in-patient dose.