Kymera Therapeutics presents on potential of STAT3 degraders

Kymera Therapeutics announced that preclinical data from collaborations for its STAT3 and IRAKIMiD degraders was presented at the American Society of Hematology Annual Meeting, taking place from December 10 – 13, 2022 in New Orleans, Louisiana. The first presentation, "Leveraging Pre-Clinical Animal Model of CTCL to Explore Therapeutic Potential of a Novel STAT3 Degrader," conveys the results of a study conducted in collaboration with the NYU School of Medicine using a STAT3-dependent model of CTCL that shares many key features of human disease. Cutaneous T cell lymphoma is a type of mature T cell lymphoma characterized by the accumulation of malignant T cells in the skin with upregulation of the STAT3 signaling pathway as a key driver of disease pathogenesis. The model was used to evaluate the therapeutic potential of one of Kymera’s potent and selective STAT3 heterobifunctional degraders for targeting this difficult-to-treat hematologic malignancy. A single intravenous infusion of a STAT3 degrader led to substantial reduction in STAT3 levels in lymph node T cells, circulating T cells, and skin-resident T cells. Chronic weekly dosing on a 4 weeks on/1 week off schedule resulted in the dramatic amelioration of disease and prevented development of characteristic skin pathology. These data provide a rationale for selective STAT3 degradation as a therapeutic strategy for T cell malignancies such as CTCL that are associated with constitutive activation of STAT3 signaling. Kymera’s lead STAT3 degrader, KT-333, is currently being evaluated in a Phase 1 clinical trial in liquid and solid tumors, including CTCL. The second presentation, "Precision Targeting of MYD88 Mutant DLBCL Using the Novel Combination of IRAKIMiDs and BCL2 Inhibition," was a research collaboration with the Department of Medicine, Lymphoma Service, at Memorial Sloan Kettering Cancer Center. Kymera has previously shown that IRAKIMiD degraders targeting IRAK4 and the IMiD substrates Ikaros and Aiolos have profound antitumor activity in CDX and PDX mouse models of MYD88-mutant DLBCL, where both the NF-kB and IRF4 pathways are upregulated by oncogenic MYD88 mutations. As BCL-2 upregulation has been seen in conjunction with NF-kB activation, the activity of BCL-2 inhibition combined with IRAKIMiDs was assessed in MYD88-mutant and -wild type DLBCL. Strong synergistic inhibition of cell growth and induction of apoptosis in vitro was seen with nanomolar concentrations of an IRAKIMiD combined with the BCL-2 inhibitor venetoclax in MYD88-mutant DLBCL cell lines. Weaker synergy with the combination was seen in wild-type MYD88 DLBCL. These data show the potential for IRAKIMiD/BCL-2 inhibitor combinations in MYD88-mutant DLBCL. Kymera’s lead IRAKIMiD compound, KT-413, is currently being evaluated in a Phase 1 clinical trial in B cell lymphoma, including MYD88-mutant DLBCL.