Abstract 7575: BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development

Abstract The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations leading to TEAD activation have been reported in many cancers. Inhibiting TEAD function by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Betta Pharma has discovered a selective, covalent and irreversible TEAD inhibitor known as BPI-460372. The discovery of BPI-460372 was first reported in AACR 2023. Here we present additional preclinical and clinical data characterizing BPI-460372 as a promising candidate drug. In the dose-escalating part of the Phase Ι study, the exposure of BPI-460372 increased proportionally over 10 to 80 mg dose range after oral administration and exhibited linear pharmacokinetics, with a clearance rate suitable for once-daily dosing. The compound is generally well tolerated, with no drug-related Grade ≥3 adverse event observed. Remarkably, we have not seen renal toxicities that was perceived as a potential risk associated with certain TEAD inhibitors. Preliminary efficacy was observed in a few subjects. In preclinical studies, we found that intermittent dosing schedule of 3 days on/4 days off, compared with continuous dosing at equivalent weekly exposure, can ameliorate kidney damage and improve early renal injury biomarkers while maintaining anti- tumor activity. Thus, alternative dosing schedule could further improve the therapeutic window and enable combination studies in clinical development. Collectively, these results support further development of BPI-460372 for the treatment of cancers harboring Hippo pathway alterations. Citation Format: Xiaohong Han, Jing Guo, Xiangyu Jin, Lingyin Zhu, Hongling Shen, Xiaofeng Xu, Mengjie Zhang, Xiaoyun Liu, Yanju Liu, Hongke Cheng, Shunna Guo, Lieming Ding, Jiabing Wang, Hong Lan, Mengzhao Wang. BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development [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 7575.