Kymera presents clinical data from ongoing Phase 1 trial of MDM2 Degrader KT-253

Kymera Therapeutics shared new clinical data from its ongoing KT-253 Phase 1 trial. KT-253, a potent, selective heterobifunctional small molecule degrader of MDM2, demonstrated preliminary signs of efficacy across tumor types at doses that were generally well-tolerated. The Phase 1 study of KT-253 is evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and clinical activity of KT-253 in patients with relapsed or refractory high grade myeloid malignancies, including acute myeloid leukemia, acute lymphocytic leukemia, lymphomas, and solid tumors. The poster provides a clinical update from the ongoing KT-253 Phase 1 trial from 24 patients including 16 patients in Arm A at dose levels 1-5, and 8 patients in Arm B at DL1-3 as of April 9, 2024. The most common solid tumor types treated were Merkel cell carcinoma in 3 patients, adenoid cystic carcinoma in 2 patients, melanoma in 2 patients, and uveal melanoma in 2 patients. In Arm A, there was one partial response confirmed in a MCC patient in DL1. Additionally, 4 stable diseases were reported for patients with fibromyxoid sarcoma, ACC, and renal cell cancer in DL1-3, respectively. In Arm B, one confirmed complete response in DL2 and one confirmed partial response in DL1, both in patients with post-myeloproliferative neoplasm AML. KT-253 treatment resulted in upregulation of p53 pathway activation biomarkers, including plasma GDF-15 protein and CDKN1A and PHLDA3 mRNA levels in blood, even at the lowest dose levels in solid tumor and AML patients, providing proof of mechanism for MDM2 target engagement. KT-253 demonstrated dose-dependent increase in plasma exposure with levels approximating projected efficacious doses. KT-253 was generally well-tolerated with the most common adverse events considered related to KT-253 including nausea, fatigue, and decreased appetite. There was 1 dose-limiting toxicity of AEs leading to discontinuation that included Grade 2 fatigue and arthralgia in Arm A DL4. There were no neutropenia or thrombocytopenia AEs in either Arm. In Arm A, KT-253 related serious adverse events included Grade 3 hypotension in a patient with decreased oral intake at DL1 and Grade 3 ventricular tachycardia leading to treatment discontinuation in one patient at DL3. No SAEs were observed in Arm B. The Phase 1a trial for KT-253 is currently ongoing. The Company expects to complete the study and share additional clinical data to inform the program’s next development steps in 2024 at an upcoming medical meeting. Kymera is also developing a biomarker-based patient selection strategy for subsequent development beyond Phase 1a and is expected to present data at a medical meeting this year.