Abstract 4349: Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling for VVD-130037, a novel, first-in-class covalent small molecule Kelch-like ECH-associated protein 1 (KEAP1) activator

Introduction: The KEAP1-nuclear factor erythroid 2 (NRF2) pathway provides homeostatic mechanisms for oxidative stress response which can be activated in cancers. Vividion Therapeutics has developed novel allosteric molecular glues of the Keap1-CUL3 E3-ligase complex. Preclinically, these agents covalently target KEAP1-CUL3 E3 ligase and allosterically increase the affinity between KEAP1 and CUL3, promoting the formation of active KEAP1-CUL3 E3 ligase complexes and enhancing NRF2 degradation (Mol Cancer Ther (2023) 22 (12_Suppl): PR011). We established a translational PK/PD model for KEAP1 target engagement (TE) for the clinical candidate, VVD-130037. Methods: VVD-130037 PK/PD modeling leveraged an initially developed framework (Mol Cancer Ther (2023) 22 (12_Suppl): C126). Compartmental PK models are used to describe VVD-130037 plasma and tumor exposure and are coupled to a mechanistic TE model capturing intracellular covalent binding to KEAP1 and KEAP1/NRF2 synthesis, degradation and complex formation. The PK models were parameterized using mouse experiments; the predicted tumor concentration provided the input to the TE model. Predictive accuracy of the TE model was made by comparison to experimental TE. A physiologically-based PK (PBPK) model incorporating human physiology was linked to the TE model for human PK-TE predictions. Results: The PK model captures mouse plasma and tumor PK across dose levels. Similarly, the mechanistic TE model adequately predicts in vitro and in vivo TE profiles at various drug concentrations. Sensitivity analyses reveal KEAP1 turnover as a key parameter influencing VVD-130037 TE. Biologically plausible ranges facilitate predictions of efficacious dose regimens to saturate TE. The VVD-130037 human PBPK model predicted a rapid plasma half-life, however when coupled with the TE model predict sustained peripheral and tumor TE with once and twice daily dosing regimens. Conclusions: A translational PK/PD model is developed for VVD-130037; supporting efficacious doses during clinical development. Citation Format: Conrad Housand, Nil Roy, Tine Wyseure, Christie Eissler, Hauke Ruehs, Christoph Niederalt, Carsten Zieschang, Marielena Mata, Ramin Samadani, John Bothos, Lawrence Lu, Jenna Goldberg, Peter N. Morcos. Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling for VVD-130037, a novel, first-in-class covalent small molecule Kelch-like ECH-associated protein 1 (KEAP1) activator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4349.