Abstract 2110: Characterization of the correlation between BTK degradation and tumor growth inhibition of the BTK target protein degraders using PK/PD modeling
Authors: Yue Wu, Shuran Li, Fan Wang, Nan Hu, Longbo Yin, Xiaomin Song, Jiye Zhang, Aiying Xu, Shasha Yang
Journal: Cancer Research (2024)

Abstract Introduction: Chimeric degradation activation compound (CDACs) are heterobifunctional molecules causing target protein degradation by simultaneously binding to the target protein as well as an E3-ubiquitin ligase. As an emerging new therapeutic modality, it is critical to understand the contribution of compound-specific parameters (e.g. drug exposure and binding potency to the target protein) and the system-specific parameters (e.g. target protein turnover) of CDACs to its in vivo effect. Method: To identify the key parameters for guiding compound optimization and to find the correlation between BTK degradation and the extent of tumor growth inhibition, a mechanistic PK/PD model was built (Phoenix WinNonlin 8.1) on a dataset generated from a BTK CDAC (Compound A). The PK/PD model was simplified mathematically compared to the full mechanistic models published previously1, since the binding affinity of Compound A to BTK was much higher than the binding affinity of CDAC to E3 ligase. This model can be linked to a tumor growth inhibition (TGI) mathematical model to find the correlation between target degradation and efficacy.Result: In mouse Rec-1 xenograft model, the BTK degradation and TGI was studied. The mice were dosed with Compound A orally at 0.3, 1, or 3 mg/kg, dose-dependent PK and BTK degradation in tumor was observed. After a single dose administration of Compound A, ~50% BTK degradation was observed in tumor at 24 h post dosing and the tumor BTK rebound to baseline at 72 hours post dosing at 3 mg/kg. The tumor BTK degradation was deeper after repeated dosing. A PK/PD model was built based on the data in this PK/PD study. The calculated BTK turnover half-life in Rec-1 model is about 16 h. In the efficacy study, Compound A was dosed orally once a day to the mice at 0.3, 1, or 3 mg/kg. The 3 mg/kg group achieved ~90% tumor growth inhibition in Rec-1 xenograft model. The PK/PD model was then linked with a mathematical model describing TGI2. A threshold level of BTK degradation in tumor to achieve tumor stasis was identified to be 96% for Rec-1 tumor model. At 90% tumor growth inhibition, average of 70% BTK was predicted to be degraded in tumor at steady state. The model was subsequently used to characterize the PK/PD relationship of BGB-16673. The efficacy of BGB-16673 was predicted using the model and it agreed with the observed value.Conclusions: The current model deepened our understanding of the PK/PD relationship of CDACs. The approach can be used to simulate different scenarios, e.g. different BTK turnover, potency or PK exposure. It can also be used in compound selection and optimization to predict repeated dose PD and efficacy from a single dose PK/PD data.1. J Pharmacokinet Pharmacodyn. 2021 Feb;48(1):149-163.2. Cancer Res. 2004 Feb 1;64(3):1094-101. Citation Format: Yue Wu, Shuran Li, Fan Wang, Nan Hu, Longbo Yin, Xiaomin Song, Jiye Zhang, Aiying Xu, Shasha Yang. Characterization of the correlation between BTK degradation and tumor growth inhibition of the BTK target protein degraders using PK/PD modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2110.