Kymera Therapeutics, Inc. announced that new Phase 1 data for KT-333, a first-in-class degrader of STAT3, highlighting safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical responses will be presented at the European Hematology Association (EHA) Annual Meeting, taking place from June 13-16, 2024, in Madrid, Spain. Results released in an EHA abstract, which include a data cut-off as of February 6, 2024, demonstrate that KT-333 is a potent and selective STAT3 degrader that has demonstrated clinically significant responses in specific patient populations. The poster presentation is expected to include additional data, including PK/PD, safety and results of disease response assessments from additional patients subsequent to the abstract cut-off date.

The abstract reported Phase 1 data from 39 patients enrolled through six dose levels (DL) with a mean of 8.7 doses, including patients with classic Hodgkin?s lymphoma (cHL), B-cell non-Hodgkin?s lymphoma, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL) as well as solid tumors. Highlights include: Two complete responses in two cHL patients at DL4, three partial responses in CTCL patients at DL2, 4 and 5, and stable disease in four solid tumor patients at DL3-4. KT-333 achieved maximum degradation up to 97.5% in peripheral blood mononuclear cells at DL1-5 in Cycle 1 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-? stimulated gene signature predictive of sensitivity to anti-PD1 was seen in both peripheral blood and tumor, suggestive of favorable immunomodulatory response in the tumor microenvironment following KT-333 treatment. Dose dependent increases in KT-333 plasma exposure were observed, achieving levels predicted to be efficacious.

KT-333 was generally well-tolerated with the most common adverse events being stomatitis, nausea, ALT increase, constipation and fatigue. Two dose-limiting toxicities (DLTs) were observed at DL5 including Grade 3 stomatitis and arthralgia in two separate LGL-L patients. No DLTs were observed in lymphoma or solid tumor patients at the time of the cut-off.

Grade 3 stomatitis was also the only KT-333 related serious adverse event. 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.

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.