- A single dose of KT-253 induced rapid apoptosis and sustained tumor regression in AML xenograft models
- KT-253 showed combinatorial benefit with the BCL-2 inhibitor venetoclax in a model of venetoclax-resistant AML
- KT-253 is also active in other hematologic malignancies including DLBCL
WATERTOWN, Massachusetts, Dec. 11, 2022 (GLOBE NEWSWIRE) — Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation to deliver novel small molecule protein degradation drugs, today presented preclinical data showing that KT-253, a novel MDM2 degrader, inhibits tumor growth as a single agent in combined with venetoclax in AML xenograft models. The data were presented at the annual meeting of the American Society of Hematology (ASH), which takes place December 10-13, 2022 in New Orleans, Louisiana.
Mouse double minute 2 (MDM2) oncoprotein is an E3 ligase that ubiquitinates and degrades the tumor suppressor p53. While reversible small molecule inhibitors (SMIs) of the MDM2/p53 interaction were developed to stabilize p53 to induce cancer cell death in wild-type (WT) p53 tumors, they induce a feedback loop that upregulates MDM2 protein and thereby reduces p53 protein levels—limiting their biological activities and clinical applications. Recent clinical trials with MDM2 inhibitors, particularly in relapsed/refractory acute myeloid leukemia (AML), have resulted in suboptimal clinical activity, highlighting the need for new therapeutic approaches to treat WT p53 hematologic and solid malignancies. MDM2 degraders, due to their catalytic mechanism, can overcome the feedback loop and lead to more efficient stabilization of p53 and induction of an acute apoptotic response in tumor cells.
Kymera has previously shown that KT-253, a novel, highly potent and selective heterobifunctional MDM2 degrader, has superior activity compared to MDM2 SMI and has shown more than 200-fold improvement in in vitro inhibition of cell growth and apoptosis. Due to the distinct pharmacological profile compared to MDM2/p53 SMI, a single dose of KT-253 was sufficient to induce rapid apoptosis and sustained tumor regression in MV4;11 AML and RS4;11 ALL cell line-derived mouse xenografts (CDX). models.
New results in AML now show that KT-253 administered once every three weeks led to tumor regression in the patient-derived CTG-2227 AML xenograft (PDX) model and responses in the CTG-2240 and CTG-2700 AML PDX models. These data support an intermittent dosing schedule of KT-253 in AML that has the potential for improved efficacy and safety using a degradation approach. Additionally, in an AML CDX model that is resistant to the standard-of-care BCL-2 inhibitor venetoclax, KT-253 administered once every three weeks in combination with venetoclax achieved sustained tumor regression. This suggests a potential benefit of KT-253 in combination with AML standard of care agents that could further expand development opportunities in AML.
KT-253 has also demonstrated activity in additional hematologic 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.
“Our KT-253 degrader, unlike small molecule inhibitors, has the potential to overcome the feedback loop that enhances MDM2 production and more effectively stabilize the tumor suppressor p53, alone and in combination with widely used treatments,” said Nello Mainolfi, Ph.D. ., Co-Founder, President and CEO, Kymera Therapeutics. “Given that P53 dependence is seen in a wide variety of tumor types, we are excited to advance this compound into clinical trials to evaluate its impact on the treatment of AML and other p53 wild-type cancers.”
Presentation at the annual assembly of ASH:
- Title: Development of KT-253, a highly potent and selective heterobifunctional MDM2 degrader for the treatment of acute myeloid leukemia
- Summary number: 2776
- Session Time: 6:00 PM – 8:00 PM CT, December 11, 2022.
- Location: Ernest N. Morial Convention Center, Hall D
- Presenter: Stefanie Schalm, Senior Director, Oncology, Biology, Kymera Therapeutics
About the MDM2 degrader program, KT-253
KT-253 is a potent and selective MDM2 degrader with the potential to be a best-in-class p53 stabilizer. Degradation of MDM2 overcomes a feedback loop that increases the production of MDM2 and thus more efficiently forces tumor cells to rapidly undergo apoptosis. As wild-type p53 is present in more than 50% of tumors, KT-253 represents another program with broad franchise potential in both liquid and solid tumors. Kymera is targeting indications with specific sensitivity to this mechanism of action, such as AML, lymphomas and solid tumors through a focused biomarker strategy. Kymera expects to resolve the IND for KT-253 by the fourth quarter of 2022.
About Kymera Therapeutics
Kymera Therapeutics (Nasdaq: KYMR) is a biopharmaceutical company pioneering the field of targeted protein degradation, a transformative approach to address disease targets and pathways inaccessible to conventional therapeutics. Kymera’s Pegasus platform is a powerful engine for drug discovery, advancing new small molecule therapies that harness the body’s innate protein recycling machinery to break down dysregulated proteins that cause disease. With a focus on untreated nodes in validated pathways, Kymera is advancing a range of novel therapeutics designed to address the most difficult pathways and provide new treatments for patients. Kymera’s initial programs target IRAK4, IRAKIMiD and STAT3 within the IL-1R/TLR or JAK/STAT pathways, providing an opportunity to treat patients with a broad spectrum of immune inflammatory diseases, hematological malignancies and solid tumors. For more information, visit www.kymeratx.com.
Founded in 2016, Kymera is headquartered in Watertown, Massachusetts. Fierce Biotech named Kymera a “Fierce 15” biotech company, and the Boston Globe and Boston Business Journal recognized it as one of the best places to work in Boston. For more information about our people, science and pipeline, visit www.kymeratx.com or follow us on Twitter or LinkedIn.
Caution regarding forward-looking statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements made by Kymera Therapeutics regarding its: strategy, business plans and goals for IRAK4, IRAKIMiD, STAT3 and MDM2 degrader programs; plans and timelines for the clinical development of its product candidates, including their therapeutic potential, clinical benefits and safety; expectations regarding the timing, success and data announcements of ongoing clinical trials; ability to initiate new clinical programs; and cash position and expected runway. The words “may”, “may”, “will”, “could”, “should”, “expect”, “plan”, “anticipate”, “intend”, “believe”, “expect”, “estimate” , “seek”, “anticipate”, “future”, “project”, “potential”, “continue”, “goal” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identification words. All forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that could cause actual events or results to differ materially from those expressed or implied by any forward-looking statements. contained in this press release, including, without limitation, the risks associated with: the impact of COVID-19 on the countries or regions in which we operate or do business, as well as the timing and expected results of our current and future preclinical studies and clinical trials, supply chain, strategy and future operations; delaying any current and future preclinical studies or clinical trials or development of Kymera Therapeutics’ drug candidates; the risk that the results of current preclinical studies and clinical trials may not be predictive of future results in connection with future clinical trials; Kymera Therapeutics’ ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of Kymera Therapeutics’ planned interactions with regulatory authorities; obtaining, maintaining and protecting its intellectual property; and Kymera Therapeutics’ relationships with its existing and future collaboration partners. These and other risks and uncertainties are described in more detail in the section entitled “Risk Factors” in the Annual Report on Form 10-K for the period ended December 31, 2021 and the most recent Quarterly Report on Form 10-Q, as well as discussions of potential risks, uncertainties and other important factors in Kymera Therapeutics’ subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent the views of Kymera Therapeutics only as of today and should not be deemed to represent its views as of any subsequent date. Kymera Therapeutics expressly disclaims any obligation to update any forward-looking statements. No representations or warranties (express or implied) are made as to the accuracy of any such forward-looking statement.
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