Kymera Therapeutics Shares Phase 1 STAT3 Degrader KT-333 Data at EHA Meeting

Kymera Therapeutics, Inc., a clinical-stage biopharmaceutical company known for pioneering targeted protein degradation (TPD) treatments, has shared promising data from its ongoing Phase 1 trial of KT-333. This small molecule degrader targets the STAT3 protein and has shown encouraging antitumor responses across various hematological malignancies, including Hodgkin’s lymphoma, cutaneous T-cell lymphoma (CTCL), and NK-cell lymphoma. The data were unveiled at the European Hematology Association (EHA) Annual Meeting in Madrid, Spain.

KT-333 has demonstrated significant clinical potential, particularly in patients with relapsed or refractory classic Hodgkin’s lymphoma (cHL), cutaneous T-cell lymphoma, and NK-cell lymphoma. In the trial, two patients with heavily pretreated Hodgkin’s lymphoma experienced complete responses and subsequently moved to potentially curative stem cell transplants. The trial’s success also includes robust STAT3 knockdown and positive immunomodulatory effects in both blood and tumor samples.

Dr. Jared Gollob, Chief Medical Officer of Kymera Therapeutics, remarked on the transformative potential of STAT3 degradation, highlighted by the complete responses observed in Hodgkin’s lymphoma patients. He emphasized that ongoing data from the Phase 1 trial indicate clinical translation of KT-333’s profile across multiple hematological malignancies, with the aim of improving patient outcomes. The dose escalation phase of the trial continues, with additional data expected in the latter half of 2024.

The Phase 1 trial of KT-333 is assessing its safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy. As of June 3, 2024, 47 patients have been enrolled across seven dose levels. These participants include those with cHL, B-cell non-Hodgkin’s lymphoma, CTCL, peripheral T-cell lymphoma, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, NK-cell lymphoma, and various solid tumors.

Highlights from the trial data include:
- Complete responses in two of three Hodgkin’s lymphoma patients at dose level four, both of whom underwent stem cell transplants after treatment.
- A complete response in one NK-cell lymphoma patient with a STAT3 mutation at dose level seven.
- Partial responses in four out of nine CTCL patients across dose levels two to six, and one patient maintaining stable disease at dose level four.
- Stable disease in four out of fourteen patients with solid tumors, including head and neck cancers, cholangiocarcinoma, and renal cell cancer.

The trial also demonstrated a strong proof of mechanism, with up to 95% mean maximum STAT3 degradation in peripheral blood mononuclear cells at dose level seven. This was coupled with evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers. Notably, a robust reduction of STAT3-related proteins was seen in a CTCL tumor biopsy at dose level four. Additionally, KT-333 treatment induced an IFN-γ stimulated gene signature predictive of sensitivity to anti-PD1 therapies, suggesting potential combination opportunities with these drugs.

The treatment showed dose-dependent increases in plasma exposure, achieving predicted efficacious levels. KT-333 was generally well-tolerated, with most adverse events being mild to moderate. Only a few dose-limiting toxicities were observed, including Grade 3 stomatitis and arthralgia, and Grade 3 fatigue in higher dose levels.

Kymera Therapeutics plans to complete the Phase 1a trial and present additional clinical data later in 2024. The company continues to explore the potential of KT-333 for treating various cancers by targeting the STAT3 protein, offering hope for advancements in cancer therapy.