Clinical Utility Indexes (CUIs) provide a quantitative, integrated measure of efficacy and safety within a scalable platform. Traditionally, benefit and risk are assessed through exposure-response (ER) analyses and compared qualitatively to choose a dose. CUIs transform this by combining multiple ER geometries into a single, reproducible, and flexible dose/PK exposure-dependent metric, often represented as a bell-shaped curve, with the peak CUI mapped to a nominal dose or regimen.

Quantitative Systems Pharmacology (QSP) is increasingly applied in MIDD frameworks and regulatory interactions, though challenges remain in ensuring transparency and credibility. This webinar will share insights from the group’s work, including considerations on virtual populations, regulatory submission examples, proposed minimum evaluation criteria, and ongoing challenges highlighting areas in need of further regulatory guidance.

This webinar will focus on the PKPD models developed and used end-to-end to design and execute a Phase 1 study for a first brain-penetrant PROTAC ARV-102. Core PKPD models were developed using nonclinical data and included allometrically scaled PK parameters and animal-derived PD parameters for target engagement. Model simulations were used to select a dose range for the first in human study and the PKPD models were updated to refine the dose response. The iterative modeling-experimentation resulted in a successful Phase 1 study and illuminated important translational relationship of PROTAC PKPD between animals and humans.