CDKN1A

– Preclinical data demonstrate that inhibiting the p300 KAT domain reactivates p53 in HPV-driven tumors resulting in anti-tumor activity –SAN MATEO, Calif., and CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to developing small molecule therapeutics that address cancers and autoimmune diseases driven by deregulated transcription, today announced preclinical data from its p300 KAT inhibitor program for human papillomavirus (HPV)-driven tumors at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Kronos Bio is exploring the utility of its p300 KAT inhibitor, KB-9558, for HPV-driven tumors. In the presentation, the authors show that the HPV genome preferentially integrates into transcriptionally active regions in the human genome where it becomes dependent on p300 to drive expression of its E6 and E7 oncogenes. It is widely recognized that elevated transcription of HPV E6 and E7 genes promotes degradation of tumor suppressors p53 and Rb. Importantly, inhibition of p300 KAT activity was highly selective in repressing the transcription of E6 and E7, which in turn led to restoration of the p53 and Rb pathways and drove anti-tumor effects through apoptosis and inhibition of uncontrolled tumor cell growth. "Continued expression of certain viral genes, especially E6 and E7, plays a critical role in tumor growth and progression of HPV-driven tumors, including head & neck, cervical, and other anogenital cancers. Importantly, there are no approved targeted therapies that inhibit E6 and E7,” said Charles Lin, Ph.D., chief scientific officer of Kronos Bio. "While this is early-stage research, given the ability of p300 KAT inhibition to target E6 and E7 and restore tumor suppressor pathways, we believe this p300 KAT inhibitor has the potential to be a remarkable and unique approach toward ensuring that fewer people suffer from HPV-driven cancer." In the presentation titled, "Oncogenic human papillomavirus hijacks p300 to drive viral transcription, creating a therapeutic vulnerability that can be exploited with selective p300/CBP catalytic inhibitors", the authors describe the experiments that led to the following key findings: HPV integrates into the human genome at specific locations where p300 regulates transcriptionp300 inhibition demonstrated specific and potent reduction of expression of HPV oncogenes E6 and E7, both at the RNA and protein levelLoss of E6 and E7 led to restoration of p53 and Rb tumor suppressor pathways which led to the upregulation of p53 activated genes (e.g., CDKN1A) and downregulation of Rb repressed genes (e.g., CDK1)Re-expression of E6 and E7 from an exogenous lentiviral vector where viral oncogene transcription is not mediated by p300 KAT activity reversed the effects of p300 KAT inhibition on p53 restoration and anti-tumor effectsThese findings support the potential of KB-9558, a p300 KAT inhibitor, to treat HPV-driven tumors given its potential to suppress E6 and E7 expression and restore the p53 pathway The poster presentation will take place on October 24, 2024, and is currently available under the Publications section of the Kronos Bio website. About Kronos BioKronos Bio is a clinical-stage biopharmaceutical company dedicated to developing small molecule therapeutics that address deregulated transcription, a hallmark of cancer and autoimmune disease. Our proprietary discovery engine decodes complex transcription factor regulatory networks to identify druggable cofactors. We screen for and optimize small molecules that target these cofactors in a disease-specific context. Kronos Bio has a pipeline of three drug candidates. Istisociclib (KB-0742) is currently enrolling ovarian cancer patients in a Phase 1/2 clinical trial. Preclinical candidate KB-9558 is being developed for multiple myeloma and HPV-driven tumors. KB-7898 is Kronos Bio’s first autoimmune development candidate and has a target indication of Sjögren’s disease. Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass. For more information, visit https://www.kronosbio.com or follow the Company on LinkedIn. Forward-Looking StatementsStatements in this press release that are not statements of historical fact are forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release, in some cases, uses terms such as “anticipate,” “believe,” “could,” “expect,” “plan,” “will,” “may,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding Kronos Bio’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, KB-9558’s ability to potentially treat HPV-driven tumors; the potential of Kronos Bio’s product candidates, pipeline and its proprietary discovery engine; and other statements that are not historical fact. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: changes in the macroeconomic environment or competitive landscape that impact Kronos Bio’s business; whether Kronos Bio will be able to progress its preclinical pipeline on the timelines anticipated, including due to risks inherent in the development of novel therapeutics; the risk that results of preclinical studies, early clinical trials (including preliminary results) and pharmacokinetic modeling are not necessarily predictive of future results; and risks associated with the sufficiency of Kronos Bio’s cash resources and need for additional capital. These and other risks are described in greater detail in Kronos Bio’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in its Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, filed with the SEC on August 8, 2024. Any forward-looking statements that are made in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Except as required by law, Kronos Bio assumes no obligation to update the forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

KT-253 demonstrates initial clinical proof of concept in patients with tumor types shown to be sensitive in preclinical models, including responses in MCC and AML Evidence of target engagement and potent upregulation of p53 pathway biomarkers even at the lowest dose levels in solid tumor and AML patients KT-253 was generally well tolerated without hematologic adverse events seen with traditional MDM2 small molecule inhibitors KT-253 Phase 1 study ongoing with additional data expected in the second half of 2024 WATERTOWN, Mass., June 01, 2024 (GLOBE NEWSWIRE) -- Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing a new class of small molecule medicines using targeted protein degradation (TPD), today 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 data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, taking place from May 31 – June 4, 2024. Results released in an ASCO poster today include a data cut-off of April 9, 2024. “We’re encouraged by the data emerging from the KT-253 Phase 1 dose escalation trial, showcasing the potential of TPD to address this clinically proven but inadequately drugged cancer mechanism. We have demonstrated strong proof of mechanism as well as preliminary signs of efficacy in both solid tumors and AML, with translation from our preclinical models to patient populations, without the hematological toxicity typically seen with traditional small molecule inhibitors,” said Jared Gollob, MD, Chief Medical Officer, Kymera Therapeutics. “These findings continue to support our therapeutic hypothesis for MDM2 degradation and the potential to improve the therapeutic index compared to small molecule inhibitors. We look forward to sharing the full Phase 1 data set, as well as our biomarker strategy and guidance on the program’s next development steps, later this year.” “I am pleased to see responses in both liquid and solid tumor patients being treated with KT-253 at doses that do not cause neutropenia or diarrhea,” said Naval Daver, MD, of The University of Texas MD Anderson Cancer Center and clinical investigator of the KT-253 Phase 1 study. “The responses in post-MPN AML are especially encouraging, as these patients are often refractory to multiple different therapies and therefore represent a subset of AML with high unmet medical need.” KT-253 Clinical Update The Phase 1 study of KT-253 is evaluating the safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), 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), 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 (solid tumors and lymphomas) at dose levels (DL) 1-5, and 8 patients in Arm B (high grade myeloid malignancies) at DL1-3 as of April 9, 2024. The most common solid tumor types treated were Merkel cell carcinoma (MCC) in 3 patients, adenoid cystic carcinoma (ACC) in 2 patients, melanoma in 2 patients, and uveal melanoma in 2 patients. Highlights include: Disease Response Assessments: Arm A: 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.Arm B: One confirmed complete response in DL2 and one confirmed partial response in DL1, both in patients with post-myeloproliferative neoplasm (MPN) 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 (AEs) 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 (SAEs) 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. A copy of the ASCO poster presentation is available in the Resource Library section of Kymera's website. About KT-253 MDM2 Degrader 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 unable to show meaningful clinical benefits of p53 stabilization, with acceptable safety margins, likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when p53 is upregulated. 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. The Phase 1 study of KT-253 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), lymphomas, and solid tumors. KT-253 has achieved clinical proof-of-mechanism in the Phase 1 trial and shown early signs of anti-tumor activity and the Phase 1a trial is currently ongoing. More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05775406. About Kymera TherapeuticsKymera is a clinical-stage biotechnology company pioneering the field of targeted protein degradation (TPD) to develop medicines that address critical health problems and have the potential to dramatically improve patients’ lives. Kymera is deploying TPD to address disease targets and pathways inaccessible with conventional therapeutics. Having advanced the first degrader into the clinic for immunological diseases, Kymera is focused on delivering oral small molecule degraders to provide a new generation of convenient, highly effective therapies for patients with these conditions. Kymera is also progressing degrader oncology programs that target undrugged or poorly drugged proteins to create new ways to fight cancer. Founded in 2016, Kymera has been recognized as one of Boston’s top workplaces for the past several years. For more information about our science, pipeline and people, please visit www.kymeratx.com or follow us on X (previously Twitter) or LinkedIn. Cautionary Note Regarding Forward-Looking StatementsThis 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 by Kymera Therapeutics regarding its: strategy, business plans and objectives for its clinical programs; plans and timelines for the preclinical and clinical development of its product candidates, including the therapeutic potential, clinical benefits and safety thereof; expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials; the ability to initiate new clinical programs; and Kymera's financial condition and expected cash runway into the first half of 2027. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any 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 may 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, risks associated with: the timing and anticipated results of our current and future preclinical studies and clinical trials, supply chain, strategy and future operations; the delay of any current and future preclinical studies or clinical trials or the 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 current or future preclinical and clinical trials, including for KT-253; Kymera Therapeutics' ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of the Kymera Therapeutics' planned interactions with regulatory authorities; obtaining, maintaining and protecting its intellectual property; the risks associated with pandemics or epidemics; and Kymera Therapeutics' relationships with its existing and future collaboration partners. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in the Annual Report on Form 10-K for the period ended December 31, 2023, 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 Kymera Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. Kymera Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor and Media Contact: Justine KoenigsbergVice President, Investor Relationsinvestors@kymeratx.commedia@kymeratx.com 857-285-5300

Abstract released today highlights safety, pharmacodynamic and clinical response data with additional data to be presented in a poster session on June 1, 2024 KT-253 Phase 1 study ongoing with additional data expected in the second half of 2024 WATERTOWN, Mass., May 23, 2024 (GLOBE NEWSWIRE) -- Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing a new class of small molecule medicines using targeted protein degradation (TPD), today announced new clinical data for KT-253, a first-in-class MDM2 degrader, from its ongoing Phase 1 dose escalation trial will be presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, taking place from May 31 – June 4, 2024, in Chicago, Illinois. Results released in an ASCO abstract today include a data cut-off of January 26, 2024. “We continue to see encouraging data from the trial’s dose escalation phase demonstrating potent upregulation of p53 biomarkers and signs of antitumor activity in patients. Results have included objective responses in liquid and solid tumors, at doses that are well tolerated without the traditional hematological toxicity seen with small molecule inhibitors,” said Jared Gollob, MD, Chief Medical Officer, Kymera Therapeutics. “We look forward to sharing the full Phase 1 data set, as well as our biomarker-based patient selection strategy and guidance on the program’s next development steps, later this year.” Highlights of the KT-253 Clinical Abstract The abstract reported Phase 1 data from 18 patients including 13 patients in Arm A (solid tumors and lymphomas) at dose levels (DL) 1-4, and 5 patients in Arm B (high grade myeloid malignancies) at DL1-2 as of January 26, 2024. The most common solid tumor types were Merkel cell carcinoma (MCC) in 3 patients, adenoid cystic carcinoma (ACC) in 2 patients, and uveal melanoma in 2 patients. Highlights include: Disease Response Assessments: Arm A: One partial response confirmed in a MCC patient in DL1. Additionally, 3 stable diseases were reported for patients with fibromyxoid sarcoma, ACC, and renal cell cancer in DL1-3, respectively.Arm B: One confirmed complete response in DL2 and one confirmed partial response in DL1, both in patients with post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML). Pharmacodynamic (PD) data from Arm A (DL1-4) and Arm B (DL1-2) demonstrated rapid upregulation of plasma GDF-15 protein and upregulation of CDKN1A and PHLDA3 mRNA levels in blood. 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 (AEs) including nausea, fatigue, headache, and vomiting. There was 1 dose-limiting toxicity (DLT) of AEs leading to discontinuation that included Grade 2 nausea and fatigue in Arm A DL4. There were no neutropenia or thrombocytopenia AEs in either Arm. KT-253 related serious adverse events (SAEs) included Grade 3 hypotension in a patient with decreased oral intake in Arm A DL1. The poster to be presented will include three additional patients in each Arm, as well as pharmacokinetic, pharmacodynamic, and safety data subsequent to the abstract cut-off date. A copy of the poster will be available on June 1, 2024, in the Resource Library section of Kymera’s website. 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. Poster Presentation at ASCO Title: Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Efficacy of KT-253, a Targeted Protein Degrader of MDM2, in Patients with Relapsed/Refractory (R/R) Solid Tumors, Lymphoma, High Grade Myeloid Malignancies and Acute Lymphoblastic Leukemia (ALL)Abstract ID Number: 3084Session Date/Time: June 1, 2024, from 9:00 AM – 12:00 PM CT Presenter: Muhammad R. Khawaja, MD, HonorHealth Research Institute, Scottsdale, AZ About KT-253 MDM2 Degrader 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 unable to show meaningful clinical benefits of p53 stabilization, with acceptable safety margins, likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when p53 is upregulated. 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. The Phase 1 study of KT-253 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), lymphomas, and solid tumors. KT-253 has achieved clinical proof-of-mechanism in the Phase 1 trial and shown early signs of anti-tumor activity and the Phase 1a trial is currently ongoing. About Kymera TherapeuticsKymera is a clinical-stage biotechnology company pioneering the field of targeted protein degradation (TPD) to develop medicines that address critical health problems and have the potential to dramatically improve patients’ lives. Kymera is deploying TPD to address disease targets and pathways inaccessible with conventional therapeutics. Having advanced the first degrader into the clinic for immunological diseases, Kymera is focused on delivering oral small molecule degraders to provide a new generation of convenient, highly effective therapies for patients with these conditions. Kymera is also progressing degrader oncology programs that target undrugged or poorly drugged proteins to create new ways to fight cancer. Founded in 2016, Kymera has been recognized as one of Boston’s top workplaces for the past several years. For more information about our science, pipeline and people, please visit www.kymeratx.com or follow us on X (previously Twitter) or LinkedIn. Cautionary Note Regarding Forward-Looking StatementsThis 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 by Kymera Therapeutics regarding its: strategy, business plans and objectives for its clinical programs; plans and timelines for the preclinical and clinical development of its product candidates, including the therapeutic potential, clinical benefits and safety thereof; expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials; the ability to initiate new clinical programs; and Kymera's financial condition and expected cash runway into the first half of 2027. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any 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 may 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, risks associated with: the timing and anticipated results of our current and future preclinical studies and clinical trials, supply chain, strategy and future operations; the delay of any current and future preclinical studies or clinical trials or the 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 current or future preclinical and clinical trials, including for KT-253; Kymera Therapeutics' ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of the Kymera Therapeutics' planned interactions with regulatory authorities; obtaining, maintaining and protecting its intellectual property; the risks associated with pandemics or epidemics; and Kymera Therapeutics' relationships with its existing and future collaboration partners. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in the Annual Report on Form 10-K for the period ended December 31, 2023, 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 Kymera Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. Kymera Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor and Media Contact: Justine KoenigsbergVice President, Investor Relationsinvestors@kymeratx.commedia@kymeratx.com 857-285-5300