Preclinical models highlight the potential of KT-253 as a monotherapy and combined with the standard of care agent venetoclax for the treatment of Acute Myeloid Leukemia (AML)
MDM2 degraders shown to be highly active compared to MDM2 small molecule inhibitor in preclinical models of Merkel cell carcinoma (MCC)
WATERTOWN, MA, USA I October 16, 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, 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 (wild type) in approximately 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 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 (MCC), 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 (referred to as KTX-169 in the presentation) demonstrated tumor regressions with weekly as well as every three-week dosing whereas an MDM2 SMI only showed modest tumor growth inhibition.
“These compelling results with MDM2 degraders exemplify our approach of selecting targets with strong genetic validation where we believe that targeted protein degradation provides the best chance for an effective treatment. They also support the potential of MDM2 degradation to overcome the inherent limitations of MDM2 SMIs to more effectively stabilize p53 and thereby induce cancer cell death in sensitive p53 wild type liquid and solid tumors, both alone and in combination with widely used treatments,” said Jared Gollob, M.D., Chief Medical Officer, Kymera Therapeutics. “We aim to drive meaningful improvements in efficacy as well as safety and tolerability over MDM2 small molecule inhibitors through intermittent dosing of our MDM2 degrader, and are currently evaluating KT-253 dosed every three weeks in a variety of liquid and solid tumors in our ongoing Phase 1 trial.”
Presentation at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics:
- Title: The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC).
- Abstract Number: C134
- Session Time: Poster Session C, 12:30 PM – 4:00 PM ET, October 14, 2023
- Presenter: Varsha Ananthapadmanabhan, Ph.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Presentations at the 10th International MDM2 Workshop:
- Title: Development of KT-253, a highly potent and selective heterobifunctional MDM2 degrader, for the treatment of Acute Myeloid Leukemia
- Abstract Number: 5
- Session Time: 1:00 PM – 2:00 PM JST, October 16, 2023
- Presenter: Yogesh Chutake, Ph.D., Principal Scientist, Translational Medicine, Kymera Therapeutics
- Title: Activity of MDM2 degrader KTX-049 in Merkel cell carcinoma
- Abstract Number: ST19
- Session Time: 10:35 AM – 10:50 AM JST, October 18, 2023
- Presenter: James A. DeCaprio, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Copies of the presentations are available online in the Scientific Resources section of Kymera’s website.
About 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
Post Views: 271
Preclinical models highlight the potential of KT-253 as a monotherapy and combined with the standard of care agent venetoclax for the treatment of Acute Myeloid Leukemia (AML)
MDM2 degraders shown to be highly active compared to MDM2 small molecule inhibitor in preclinical models of Merkel cell carcinoma (MCC)
WATERTOWN, MA, USA I October 16, 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, 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 (wild type) in approximately 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 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 (MCC), 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 (referred to as KTX-169 in the presentation) demonstrated tumor regressions with weekly as well as every three-week dosing whereas an MDM2 SMI only showed modest tumor growth inhibition.
“These compelling results with MDM2 degraders exemplify our approach of selecting targets with strong genetic validation where we believe that targeted protein degradation provides the best chance for an effective treatment. They also support the potential of MDM2 degradation to overcome the inherent limitations of MDM2 SMIs to more effectively stabilize p53 and thereby induce cancer cell death in sensitive p53 wild type liquid and solid tumors, both alone and in combination with widely used treatments,” said Jared Gollob, M.D., Chief Medical Officer, Kymera Therapeutics. “We aim to drive meaningful improvements in efficacy as well as safety and tolerability over MDM2 small molecule inhibitors through intermittent dosing of our MDM2 degrader, and are currently evaluating KT-253 dosed every three weeks in a variety of liquid and solid tumors in our ongoing Phase 1 trial.”
Presentation at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics:
- Title: The MDM2 degrader KTX-049 is highly potent in TP53 wild-type (p53 WT) Merkel cell carcinoma (MCC).
- Abstract Number: C134
- Session Time: Poster Session C, 12:30 PM – 4:00 PM ET, October 14, 2023
- Presenter: Varsha Ananthapadmanabhan, Ph.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Presentations at the 10th International MDM2 Workshop:
- Title: Development of KT-253, a highly potent and selective heterobifunctional MDM2 degrader, for the treatment of Acute Myeloid Leukemia
- Abstract Number: 5
- Session Time: 1:00 PM – 2:00 PM JST, October 16, 2023
- Presenter: Yogesh Chutake, Ph.D., Principal Scientist, Translational Medicine, Kymera Therapeutics
- Title: Activity of MDM2 degrader KTX-049 in Merkel cell carcinoma
- Abstract Number: ST19
- Session Time: 10:35 AM – 10:50 AM JST, October 18, 2023
- Presenter: James A. DeCaprio, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Copies of the presentations are available online in the Scientific Resources section of Kymera’s website.
About 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
Post Views: 271
