A single dose of KT-253 drives tumor regression and demonstrates differentiated pharmacology compared to small molecule inhibitor (SMI) in preclinical models of ALL and AML

WATERTOWN, MA, USA I June 09, 2023 I Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation (TPD) to deliver novel small molecule protein degrader medicines, will present preclinical data on KT-253, a potent and selective heterobifunctional MDM2 degrader. The data will be presented at the European Hematology Association (EHA) Congress, taking place from June 8-15, 2023, in Frankfurt, Germany.

KT-253 targets MDM2, the crucial regulator of the most common tumor suppressor, p53. p53 remains intact (wild type) in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth. While small molecule inhibitors (SMIs) have been developed to stabilize and upregulate p53 expression, they have been found to induce a feedback loop that increases MDM2 protein levels, which can repress p53 and limit their efficacy. In preclinical studies, KT-253 has shown the ability to overcome the MDM2 feedback loop and rapidly induce cancer cell death with brief exposures, providing the opportunity for an improved efficacy and safety profile.

New results show that a single, high dose of KT-253 administered intravenously (IV) in preclinical models of acute lymphoblastic leukemia (RS4;11 ALL) and acute myeloid leukemia (MV4;11 AML) led to >90% MDM2 degradation in tumors within one hour of dosing, strong p53 upregulation and induction of apoptosis within the first 8-24 hours, and sustained tumor regressions. In contrast, lower doses of KT-253 administered IV more frequently or repeat dosing with an oral MDM2 SMI led only to relatively weak p53 activation and apoptosis induction and modest tumor growth inhibition. These results suggest that a pulse IV dosing regimen of KT-253 has the potential for an improved efficacy and safety profile over MDM2 SMIs currently in the clinic.

“KT-253 exemplifies our approach of selecting targets with strong genetic validation where we believe that targeted protein degradation provides the best chance for an effective treatment. These findings in models of AML and ALL demonstrate that acute and potent MDM2 degradation with IV pulse dosing of KT-253 enables the most effective upregulation of the p53 pathway in vulnerable p53 wild-type tumor cells while limiting the duration of pathway modulation in normal cells, thereby potentially improving the therapeutic index for MDM2 targeting,” said Nello Mainolfi, Ph.D., Founder, President and CEO, Kymera Therapeutics. “This hit-and-run approach with our MDM2 degrader has the potential to overcome the inherent limitations of small molecule MDM2 inhibitors against this promising target, and we look forward to investigating the activity of KT-253 in a variety of liquid and solid tumors in our ongoing clinical studies.”

Presentation at EHA:

  • Title: Pulse Dosing of Potent and Selective Heterobifunctional MDM2 Degrader KT-253 Drives Tumor Regression and Demonstrates Differentiated Pharmacology Compared to p53/MDM2 Small Molecule Inhibitors
    • Abstract Number: P464
    • Session Time: 6:00 PM – 7:00 PM CEST, June 9, 2023
    • Presenter: Nancy Dumont, Director, In Vivo Pharmacology‌, Kymera Therapeutics

MDM2 Degrader Program (KT-253)

The KT-253 Phase 1 trial initiated in March 2023 will evaluate 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 (AML), acute lymphocytic leukemia (ALL), lymphoma and solid tumors. Patients in the KT-253 Phase 1 dose escalation study will receive IV doses of KT-253 administered once every 3 weeks. The open-label study is intended to identify the recommended Phase 2 dose for KT-253, and is comprised of two arms, with ascending doses of KT-253 in each arm. The first arm will consist of patients with lymphomas and advanced solid tumors and the second arm will consist of patients with high grade myeloid malignancies and ALL.

More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05775406.

About Kymera Therapeutics

Kymera is a biopharmaceutical company pioneering the field of targeted protein degradation, a transformative approach to address disease targets and pathways inaccessible with conventional therapeutics. Kymera’s Pegasus platform is a powerful drug discovery engine, advancing novel small molecule programs designed to harness the body’s innate protein recycling machinery to degrade dysregulated, disease-causing proteins. With a focus on undrugged nodes in validated pathways, Kymera is advancing a pipeline of novel therapeutic candidates designed to address the most promising targets and provide patients with more effective treatments. Kymera’s initial programs target IRAK4, IRAKIMiD, and STAT3 within the IL-1R/TLR or JAK/STAT pathways, and the MDM2 oncoprotein, providing the opportunity to treat patients with a broad range of immune-inflammatory diseases, hematologic malignancies, and solid tumors.  

Founded in 2016, Kymera is headquartered in Watertown, Mass. Kymera has been named a “Fierce 15” company by Fierce Biotech and has been recognized by both the Boston Globe and the Boston Business Journal as one of Boston’s top workplaces. For more information about our people, science, and pipeline, please visit www.kymeratx.com or follow us on Twitter or LinkedIn.  

SOURCE: Kymera Therapeutics