Mind the PK/PD disconnect: QSP modeling approaches for long-acting RNAi therapeutics
Jeff Kearns, Director, Translational Modeling & Simulation, Novartis Biomedical, Cambridge, MA
Jeff Kearns, of Novartis Biomedical, co-leads the translational modeling & simulation group there. In the past, he has held positions in small pharma at Forma Therapeutics and Merrimack Pharmaceuticals. At Novartis, his portfolio spans cardiovascular/metabolic, neuroscience, and renal disease areas and both traditional and novel modalities. In recent years, Jeff has had specific interest in RNAi and has held several modeling and company leadership roles to expand the development of the Novartis RNAi platform.
The field of RNAi therapeutics is rapidly expanding and evolving, with a growing number of first, next, and best-in-class compounds across disease areas. These include many liver-targeting compounds that apply the GalNAc-ASGPR delivery system and emerging examples of delivery to extra-hepatic tissues like skeletal muscle and brain that use different approaches. The opportunities for model-informed drug discovery and development (MID3) are almost unbounded.
In this talk, Mr. Kearns will share perspectives on the state of the art for QSP modeling in this space, including the general pharmacology principles inherent to long-acting RNAi therapies that every modeler needs to understand. Foundational to these principles is a PK/PD disconnect that is established via the short timescale of systemic PK and prolonged durability of tissue drug exposure and PD. He will describe the modeler’s toolkit for both empirical (K-PD) and mechanistic (PBPK/PD) approaches. The second half of the talk will focus on the application of these principles and toolkits to real world examples from discovery to early development. The vignettes will include forward/reverse translation approaches between preclinical species and human, compound characterization, and dosing strategies.