Abstract 841: The preclinical pharmacokinetics and pharmacodynamics of AZD0022: A potent, oral KRASG12D-selective agent exhibiting oral bioavailability and KRAS pathway suppression in the GP2D xenograft model

Abstract Objectives: AZD0022 is a small molecule selective inhibitor of KRASG12D. These studies investigate the preclinical PKPD relationships of AZD0022 to inform clinical development. Methods: Measurement of plasma and tumor concentrations were completed using standard extraction techniques with quantitation by LC-MS/MS methods. Target modulation (pRSK inhibition) was assessed in Nude mice implanted with GP2D human tumors by Western blot. Results: The preclinical PK properties of AZD0022 are defined by its physicochemistry (MW 614, extensive lipophilicity with log D(7.4) 2.5, dibasic with pKa values of 8.4 and 7.4). Oral administration studies suggest that AZD0022 is 30 to 70% absorbed from the gastrointestinal tract. AZD0022 exhibits extensive distribution into tissues. It also undergoes time-dependent partitioning into the red blood cell fraction of whole blood, suggesting that whole blood is the matrix that best represents the PK of the molecule. Blood clearance of AZD0022 was 8.2 and 8.6 mL/min/kg in mice and dogs, respectively. The measured Vss values based on blood were 10.8 and 20.4 L/kg, respectively. These characteristics suggest that in human, AZD0022 should be orally absorbed and exhibit a half-life consistent with once daily administration. In the GP2D model, single oral 150 mg/kg doses displayed prolonged plasma and tumour exposure. AZD0022 was estimated to be 18x more bound in tumour tissue than in plasma. Seven days of continuous 150mg/kg BID dosing resulted in up to approx. 75% pRSK inhibition. A dose range of 10, 50 and 150 mg/kg BID over 7 days displayed exposure-dependent pRSK modulation, with maximal of 75% pRSK inhibition. PKPD modelling suggested an unbound IC50 of 1.4 nM for pRSK inhibition. Conclusions: The results presented here support the clinical development of AZD0022 which is currently being tested in a first in human Phase I/IIa study (ALAFOSS-01, NCT06599502) Citation Format: Kevin Beaumont, Sofia Guzzetti, Pablo Morentin-Gutierrez, Rhys D. Jones, Ken Grime, Carla Martins, Alex Koers, Alison Peter, Simon T. Barry, Susan Critchlow, Michele Moschetta, Michael Niedbala. The preclinical pharmacokinetics and pharmacodynamics of AZD0A potent, oral KRASG12D-selective agent exhibiting oral bioavailability and KRAS pathway suppression in the GP2D xenograft model [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 841.