041: Predicting Clinical PK/PD & Impacts of Organ Impairment to Support Clinical Development of siRNA-based Therapeutics Using a Mechanistic Physiologically Based Pharmacokinetic & Pharmacodynamic (PBPK-PD) Platform Model

Statement of Purpose: Quantitative modeling approaches have been used to help bridge the characteristic temporal disconnect between short plasma PK and prolonged PD observed for siRNA based-therapies. The objective of this work was to use PBPK-PD modeling approaches to understand the factors that underlie sequence related differences for predicting GalNAc-siRNA PK and PD in humans. We also aim to mechanistically model hepatic and renal impairment to investigate the factors that affect GalNAc-siRNA PK and PD in organ impaired patient populations.

Description of Methods & Materials: A PBPK-PD model was developed for two FDA approved GalNAc-siRNAs, inclisiran and vutrisiran, with nonclinical and clinical data available in literature. The structure of the base model was adapted from the literature. Briefly, the model captures receptor mediated liver uptake and mode of action-based PD target engagement and response time-course. The PBPK-PD model was calibrated to predict PK and PD of inclisiran and vutrisiran in cynomolgus monkeys and translated to humans by capturing physiological differences and allometric principles. Furthermore, the PBPK-PD model for inclisiran and vutrisiran was further developed to include the various pathophysiological changes that occur in hepatic and renal impairment as a function of disease severity (mild, moderate and severe). Specifically for hepatic impairment, changes in the total concentration of hepatic ASGPR receptors and its impact on siRNA PK and PD were evaluated. The predictability of the model is confirmed using both nonclinical and clinical data and those available for the various degrees of organ impairment.

Data & Results: The PBPK-PD model was successfully calibrated for inclisiran and vutrisiran in cynomolgus monkeys and translated to humans. Specifically, the key parameters calibrated to capture sequence related differences in siRNA PK and PD were hepatic endosomal degradation rate, the fractional endosomal escape, the RISC-bound siRNA complex degradation rate and the in vivo potency of mRNA degradation. We noted that the model when calibrated for specific sequences, translated well across species with less than 2-fold difference in fractional bioavailability, in vivo potency, and plasma protein binding between cynomolgus monkeys and humans. For hepatic impairment, applying the intact hepatocyte theory, the model well predicted PD changes within 1SD of the mean percentage change from baseline observed for inclisiran in mild and moderate hepatic impairment and for vutrisiran in mild hepatic impairment population. Overall, we found that a 50% decrease in ASGPR concentration did not result in considerable PD alterations in humans for GalNAc-siRNAs. Similarly in renal impairment, in agreement with observations, the model with altered renal physiologies including changes in GFR, did not predict clinically significant changes in PD for inclisiran in mild, moderate and severe renal impairment and for vutrisiran in mild and moderate impairment.

Interpretation, Conclusion or Significance: Our model-based analysis identified key parameters that determines sequence related PK/PD differences and translation to humans and help inform dosing considerations in organ-impaired subpopulations. The model can serve as a platform-based tool to predict clinical PK/PD, guide dose-optimization, and predict impacts of organ impairment for optimal clinical development of novel siRNA-based therapies.

Disclosures: N/A