Design of a First-in-Human Study for ARV-102, a Brain-Penetrant PROteolysis TArgeting Chimera (PROTAC) LRRK2 Degrader, Using Pharmacokinetic (PK)-Pharmacodynamic (PD) Modeling

Description of session (include background & scientific importance): In this talk, I will describe the PKPD models we developed and applied to design and execute the first-in-human study of a brain-penetrant PROTAC. The initial PKPD models were built using nonclinical data, incorporating allometrically scaled PK parameters and animal-derived PD parameters for target engagement. Model simulations were used to select a dose range for escalation and to optimize the sampling strategy, given the limited number of CSF samples feasible in human participants.

As the study progressed, we iteratively refined the PKPD models using data from each completed dose cohort, allowing us to adjust dose increments and ultimately determine the optimal stopping point once all necessary information was obtained. This two-year, iterative modeling-experimentation process led to a successful Phase 1 study, achieving both of its primary objectives: assessing the drug’s safety in humans and establishing the dose-response relationship for target engagement. Additionally, the study provided key insights into the translational relationship between PROTAC PKPD in the CNS and peripheral tissues in animals and humans.