Kymera Therapeutics presents preclinical data demonstrating activity of KT-253

Kymera Therapeutics presented preclinical data showing that KT-253, a novel MDM2 degrader, inhibited tumor growth as single agent and in combination with venetoclax in AML xenograft models. The data was presented at the American Society of Hematology Annual Meeting, taking place from December 10 – 13, 2022 in New Orleans, Louisiana. The murine double minute 2 oncoprotein is the E3 ligase that ubiquitinates and degrades the p53 tumor suppressor. While reversible small molecule inhibitors of the MDM2/p53 interaction have been developed to stabilize p53 in order to induce cancer cell death in wildtype p53 tumors, they induce a feedback loop that upregulates MDM2 protein and thereby reduces p53 protein levels – limiting their biological activity and clinical application. Recent clinical trials with MDM2 inhibitors, especially in relapsed/refractory Acute Myeloid Leukemia, have resulted in suboptimal clinical activity, highlighting the need for novel therapeutic approaches to treat WT p53 hematologic and solid tumor malignancies. MDM2 degraders, because of their catalytic mechanism, can overcome the feedback loop and lead to more efficient p53 stabilization and induction of an acute apoptotic response in tumor cells. Kymera previously showed that KT-253, a novel, highly potent and selective heterobifunctional MDM2 degrader, has superior activity compared to MDM2 SMIs and demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis. Because of the distinct pharmacological profile compared to MDM2/p53 SMIs, a single dose of KT-253 was sufficient to induce rapid apoptosis and sustained tumor regression in the MV4;11 AML and RS4;11 ALL cell line-derived mouse xenograft models. New results in AML now demonstrate that KT-253 administered once every three weeks led to tumor regression in the CTG-2227 AML patient-derived xenograft model and responses in CTG-2240 and CTG-2700 AML PDX models. These data support an intermittent dosing schedule of KT-253 in AML which has the potential for improved efficacy and safety using the degrader approach. In addition, in an AML CDX model resistant to the standard of care BCL-2 inhibitor venetoclax, KT-253 administered once every three weeks in combination with venetoclax achieved durable tumor regression. This suggests a potential benefit of KT-253 combined with AML standard of care agents that could further expand the development possibilities in AML. KT-253 also showed activity in additional hematological malignancies, including both in vitro and in vivo single-agent responses in DLBCL, supporting the development of KT-253 in additional indications such as lymphoma.