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) 65^th 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 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 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.

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