Kymera Therapeutics presents preclinical data on MDM2 degrader activity

Kymera Therapeutics reported preclinical data highlighting the therapeutic potential in liquid and solid tumors of potent and selective heterobifunctional degraders of MDM2, including KT-253. The data was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 11-15, 2023, in Boston, Massachusetts and will also be shared at the 10th International MDM2 Workshop taking place October 15-18, 2023, in Tokyo, Japan. MDM2 is a crucial regulator of the most common tumor suppressor, p53. p53 remains intact in approximately 50% of cancers, meaning that it retains its ability to modulate cancer cell growth. While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they cannot overcome the induced feedback loop that increases MDM2 protein levels, which can repress p53 and thereby limit their efficacy. In preclinical studies, MDM2 degraders have demonstrated the ability to overcome the MDM2 feedback loop observed with MDM2 SMIs and rapidly induce cell death in sensitive p53 wild-type cancer cell lines, even with brief compound exposure. This may enable an improved therapeutic index, which could result in a superior efficacy and safety profile over MDM2 SMIs. The Company previously presented data on KT-253, its lead MDM2 degrader, showing greater than 200-fold higher growth inhibition potency in vitro against p53 wild-type cancer cell lines compared with MDM2 SMI and a favorable pharmacological profile. Results shared at the 10th International MDM2 workshop show potent in vivo activity of a single dose of KT-253 in models of AML and ALL as well as activity in combination with clinical and sub-clinical doses of venetoclax in a venetoclax-resistant AML model. KT-253 is currently being evaluated in a Phase 1 trial in liquid and solid tumors and the Company plans to share data regarding proof-of-mechanism from its Phase 1 trial later this year. Work completed in collaboration with the Dana-Farber Cancer Institute and presented at both congresses support MDM2 degradation as a promising therapeutic approach in Merkel cell carcinoma, a high-grade neuroendocrine carcinoma of the skin. These data demonstrate in vitro efficacy of an MDM2 degrader, KTX-049, against p53 wild-type MCC cell lines that was achieved with brief compound exposure. In two MCC PDX models, KT-253 demonstrated tumor regressions with weekly as well as every three-week dosing whereas an MDM2 SMI only showed modest tumor growth inhibition.