Lown-Ganong-Levine Syndrome

KT-333 demonstrated initial clinical proof of concept across multiple hematological malignancies, including complete responses in two patients with Hodgkin’s lymphoma Robust STAT3 knockdown and positive immunomodulatory effect achieved in blood and tumor KT-333 was well-tolerated with Phase 1 dose escalation ongoing and additional data expected in the second half of 2024 WATERTOWN, Mass., June 14, 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-333 Phase 1 trial. KT-333, a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of STAT3, demonstrated antitumor responses in hematological malignancies with high unmet need, including relapsed/refractory classic Hodgkin’s lymphoma (cHL), cutaneous T-cell lymphoma (CTCL), and NK-cell lymphoma, at doses that were well-tolerated. The data were presented at the European Hematology Association (EHA) Annual Meeting, taking place from June 13-16, 2024, in Madrid, Spain. Results released in an EHA poster today include a data cut-off of June 3, 2024. “The complete responses we’ve shown in Hodgkin’s lymphoma demonstrate the transformative therapeutic potential of STAT3 degradation, with two heavily pretreated cHL patients in the KT-333 trial moving to potentially curative stem cell transplants after treatment,” said Jared Gollob, MD, Chief Medical Officer, Kymera Therapeutics. “We continue to be encouraged by the data generated in the ongoing Phase 1 trial showing clinical translation of our degrader’s profile across multiple hematological malignancies including cHL, CTCL and NK-cell lymphoma and the potential to improve patients’ lives. With dose escalation continuing, we look forward to completing the Phase 1 study and sharing the full data set later this year.” KT-333 Clinical Update The KT-333 Phase 1 clinical trial is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333 dosed weekly on 28-day cycles in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. The poster provides a clinical update as of June 3, 2024, from the ongoing KT-333 Phase 1 trial from 47 patients enrolled through seven dose levels (DLs) with a mean of 9.1 doses. This includes patients with cHL, B-cell non-Hodgkin’s lymphoma, CTCL, peripheral T-cell lymphoma (PTCL), large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), NK-cell lymphoma, as well as solid tumors. Highlights from the poster include: Antitumor activity in patients with hematological malignancies evaluable for response: In cHL, complete responses were achieved in two of three patients at DL4. Both responders, who had received prior treatment with at least one regimen containing a check point inhibitor as well as brentuximab vedotin, have subsequently undergone stem cell transplantation. Additionally, stable disease was observed in a third cHL patient at DL6.In NK-cell lymphoma, one complete response was achieved at DL7 in a patient with STAT3 mutation.Among nine patients with CTCL, partial responses were achieved in four patients at DL2 and DL4-6, and stable disease was observed in one patient at DL4.In solid tumors, stable disease was observed in four of fourteen patients, including two head and neck tumor types as well as patients with cholangiocarcinoma and renal cell cancer, at DL3-4. Strong proof of mechanism with KT-333 achieving up to 95% mean maximum STAT3 degradation in peripheral blood mononuclear cells at DL7 with evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers in whole blood. Notably, KT-333 resulted in robust reduction of STAT3, pSTAT3, and SOCS3 expression in a CTCL tumor biopsy in DL4.Induction of an IFN-γ stimulated gene signature predictive of sensitivity to anti-PD1 was seen in both peripheral blood and tumor as previously shown, suggestive of favorable immunomodulatory response in the tumor microenvironment following KT-333 treatment and supporting a potential novel combination partner with anti-PD-1 drugs in solid tumors.Dose dependent increases in KT-333 plasma exposure were observed, achieving levels predicted to be efficacious.KT-333 was well tolerated with primarily Grade 1 and 2 adverse events, including stomatitis and fatigue. Two dose-limiting toxicities (DLTs), Grade 3 stomatitis and arthralgia, occurred in LGL-L patients at DL5 and one DLT, Grade 3 fatigue, was observed in a lymphoma patient treated at DL7. The Phase 1a trial for KT-333 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. A copy of the EHA poster presentation is available in the Resource Library section of Kymera's website. About KT-333 STAT3 Degrader KT-333 is a potent, highly selective degrader of STAT3 in development for the treatment of multiple STAT3-dependent pathologies, including hematological malignancies and solid tumors. STAT3 is an undrugged transcription factor activated through a variety of different cytokine and growth factor receptors via Janus kinases (JAKs), as well as through oncogenic fusion proteins and mutations in STAT3 itself. In certain malignant cells, STAT3 activation is set into overdrive, leading to a dampened immune response, tumor progression, and metastasis. STAT3’s role as a cancer driver and tumor microenvironment modulator has been validated in a multitude of studies, making it a strong candidate to target in the treatment of cancer. KT-333 was the first degrader against an undrugged transcription factor to enter the clinic and the Phase 1 clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of KT-333 dosed weekly in adult patients with relapsed and/or refractory lymphomas, leukemias, and solid tumors. Clinical data from the KT-333 Phase 1 trial has shown evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting this previously undruggable transcription factor. The Phase 1a trial for KT-333 is currently ongoing. More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05225584. 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-333; 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

STAT3 Degrader KT-333 showed early signs of antitumor activity across liquid and solid tumors, including major responses in cutaneous T-cell lymphoma (CTCL) and Hodgkin’s lymphoma Robust STAT3 knockdown and positive immunomodulatory effect demonstrated in tumor as well as blood KT-333 was generally well-tolerated with dose escalation continuing WATERTOWN, Mass., Dec. 10, 2023 (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 data from its ongoing KT-333 Phase 1 trial. KT-333, a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of STAT3, demonstrated early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor. The data were presented at the American Society of Hematology (ASH) 65th Annual Meeting and Exposition taking place from December 9-12, 2023, in San Diego, California. “We’re encouraged by the data from the Phase 1 trial showing consistent fidelity of translation from preclinical models to patients, including STAT3 degradation in blood and tumor, induction of IFN-γ response signature, and antitumor responses in CTCL and Hodgkin’s lymphoma, which we believe supports the potential of KT-333 to address both hematological malignancies as a single agent and solid tumors as a potential novel combination partner with anti-PD-1 drugs,” said Jared Gollob, M.D., Chief Medical Officer, Kymera Therapeutics. “We look forward to completing the dose escalation portion of the Phase 1 study in 2024 and sharing additional updates on this first-in-class program across a range of indications at future medical meetings.” KT-333 STAT3 Clinical Update KT-333 degrades STAT3, a transcriptional regulator that has been linked to numerous cancers, as well as to inflammatory and autoimmune diseases, and is being developed for the treatment of STAT3-dependent hematological malignancies and solid tumors. The Phase 1 clinical trial is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333 dosed weekly on 28-day cycles in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. The poster provides an interim update with a data cut-off as of October 18, 2023. Twenty-nine patients were treated across five dose levels (DL1-5) with a mean of eight doses, including five with cutaneous T-cell lymphoma (CTCL), two with large granular lymphocytic leukemia (LGL-L), one each with peripheral T-cell lymphoma (PTCL), B-cell and Hodgkins’s lymphoma, and nineteen with a variety of solid tumor malignancies. Dose escalation is ongoing at DL5 in solid tumor/lymphoma patients and at DL3 in leukemia patients. Dr. Aditi Shastri from Montefiore Medical Center and Albert Einstein College of Medicine, a lead investigator in the study, presented the interim Phase 1 findings. Highlights from the poster presentation include: A partial response (PR) was observed in one patient with Hodgkin’s lymphoma, and two PRs and one stable disease were reported among the five CTCL patients treated. Stable disease was observed in four patients with advanced solid tumors, including two head and neck cancer patients as well as patients with cholangiocarcinoma and renal cell cancer.KT-333 was generally well tolerated with primarily Grade 1 and 2 adverse events which included constipation, fatigue, nausea and anemia. The only KT-333 related adverse events that were Grade 3 or higher were stomatitis, arthralgia, and decreased weight in one patient each. Two dose-limiting toxicities (DLTs), stomatitis and arthralgia, occurred in LGL-L patients at DL5 and no DLTs were observed in solid tumor/lymphoma patients. Based on these findings, the study protocol was revised to continue dose escalation in solid tumor and lymphoma patients separately from patients with leukemia, including LGL-L and T-cell prolymphocytic leukemia (T-PLL) patients. The study continues to enroll solid tumor/lymphoma patients at DL5 and LGL-L/T-PLL patients at DL3.KT-333 achieved maximum degradation up to 96% in peripheral blood mononuclear cells at DL4-5 and with evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers in peripheral blood.A critical cytokine involved in anti-tumor immunity, IFNγ, as well as IFNγ-stimulated genes, were induced in peripheral blood showing functional engagement of the JAK/STAT pathway, similar to preclinical studies.KT-333 resulted in substantial reduction of STAT3, pSTAT3 and SOCS3 in a CTCL patient tumor with concomitant induction of IFNγ-stimulated genes, suggestive of positive immunomodulatory response in the tumor microenvironment that both clinically and preclinically has been shown to enhance the activity of anti-PD-1 drugs, supporting potential expansion into combinations of KT-333 and anti-PD-1 agents. Preclinical data demonstrating the potential of STAT3 protein degraders as a therapeutic approach in venetoclax-resistant Acute Myeloid Leukemia was also presented at the meeting. A copy of the poster presentation, entitled “Preliminary Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Lymphomas, Large Granular Lymphocytic Leukemia, and Solid Tumors” is available in the Scientific Resources section of Kymera's website. More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05225584. About Kymera TherapeuticsKymera 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 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 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, including those for KT-333; expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials, including those for KT-333; the ability to initiate new clinical programs; and Kymera’s financial condition and expected cash runway into the second half of 2025. 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 those for KT-333; 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, 2022, and 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 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 Contact: Justine KoenigsbergVice President, Investor Relationsinvestors@kymeratx.com857-285-5300Media Contact: Todd Cooper Senior Vice President, Corporate Affairs media@kymeratx.com 857-285-5300

The latest clinical findings of KT-333 will be unveiled at the 2023 ASH Congress, setting the stage for subsequent investigations. KT-333's R&D ProgressKT-333 is a drug classified as PROTACs, which stands for Proteolysis Targeting Chimeras. This type of drug works by harnessing the body's own protein degradation system to selectively remove disease-causing proteins. The specific target of KT-333 is STAT3, a protein that plays a crucial role in various cellular processes and has been implicated in the development and progression of several diseases. The therapeutic areas in which KT-333 is being investigated include neoplasms (abnormal growth of cells), immune system diseases, and hemic and lymphatic diseases. According to the Patsnap Synapse, KT-333 has reached the highest phase of clinical development, which is Phase 1. And the clinical trial area for KT-333 is primarily in the United States. The key indication is Peripheral T-Cell Lymphoma. Detailed Clinical Result of KT-333This ongoing open-label, Phase 1a/1b study is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical activity of KT-333 administered as a QW IV infusion on Day 1, 8, 15 and 22 (28-day cycle) in patients (pts) with B- and T-cell lymphomas, Hodgkin’s lymphoma and advanced solid tumors (ST) relapsed/refractory (R/R) to at least two prior systemic therapies and LGL-L and T-cell prolymphocytic leukemia R/R to at least one prior therapy. In this study, cycle 1 and 2 blood samples are collected for KT-333 plasma concentrations and to measure changes in STAT3 protein expression in peripheral blood mononuclear cells (PBMCs) using targeted mass spectrometry. Whole blood RNA sequencing measures mRNA levels of STAT3 regulated targets. Plasma levels of inflammatory biomarkers are measured with Luminex. STAT3 degradation and other related biomarker changes in tumor are assessed in patients with accessible tumors.  The result showed that as of July 10, 2023, 21 pts were treated at five dose levels (DL) in Phase 1a with a mean number of 5.8 doses. Pts included B-cell non-Hodgkin’s lymphoma (n=1: DL5), Hodgkin’s lymphoma (HL) (n=1: DL4), CTCL (n=3: DL1, 2 and 4), PTCL (n=1: DL2), LGL-L (n=2: DL5) and ST (n=13: DL1-4) with median age of 61 years (range 30,77) and ECOG performance status of 0 (n=7) or 1 (n=14). No DLTs and no KT-333 related serious adverse events (SAE) were reported. The most common AEs were Grade 1 and 2 and included constipation, fatigue, nausea and anemia. Best response among pts evaluable for response at data cut-off (not including CTCL or HL pts at DL4 or any DL5 pts) included one partial response after two cycles in a CTCL pt at DL2 and SD after two cycles in three ST pts treated at DL3 and DL4. PD data in blood available for DL1-4 demonstrated robust, dose-dependent, and sustained STAT3 degradation in PBMC. The mean maximum degradation of STAT3 by targeted mass spectrometry over the first two weeks in Cycle 1 by DL was (% (range; n)): DL1: 69.9% (52.6% to 84.1%; n=4), DL2: 73.5% (65.5% to 80.7%; n=3), DL3: 79.9% (72.3% to 90.4 %; n=3) and DL4: 86.6% (78.9% to 95.9 %; n=4) with absolute quantification of STAT3 peptides falling below lower limit of quantification of the assay for one pt in DL3 and two in DL4. STAT3 pathway inhibition in blood was demonstrated via transcriptional downregulation of a canonical JAK/STAT3 target, SOCS3, which correlated with changes in STAT3 protein levels. KT-333 also resulted in dose-dependent downregulation of STAT3-regulated inflammatory biomarkers C-reactive protein and serum amyloid A protein in plasma. KT-333 demonstrated linear PK with plasma exposure increasing with dose and reaching levels close to those predicted to be efficacious. It can be concluded that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with potential early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting previously undruggable transcription factors implicated in diseases. Based on non-clinical data and PK/PD modeling, the high levels of degradation achieved so far are expected to be clinically efficacious in STAT3-dependent malignancies. Accrual is ongoing, and analyses from additional patients will be presented at the meeting. 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