Kymera Therapeutics Presents Late-Breaking Preclinical Data Highlighting Superiority of Dual-Targeting Activity of IRAKIMiD Degrader KT-413 at AACR Annual Meeting 2021
- Category: Small Molecules
- Published on Monday, 12 April 2021 09:25
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KT-413-mediated degradation of IRAK4 and IMiD substrates has synergistic effect on MYD88-NFkB and IRF4-Type 1 Interferon pathways resulting in superior antitumor activity in MYD88-mutant DLBCL models compared to IMiDs or selective IRAK4 targeting alone
Company anticipates IND submission and, if cleared, initiation of Phase 1 trial of KT-413 in relapsed/refractory B cell lymphomas, including MYD88-mutant DLBCL, in 2H 2021
WATERTOWN, MA, USA I April 10, 2021 I Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation to deliver novel small molecule protein degrader medicines, today presented late-breaking preclinical data showing how the dual targeting of IRAK4 and IMiD substrates by KT-413, its IRAKIMiD degrader currently in preclinical development, synergizes to impact signaling and cell killing in MYD88-mutant diffuse large B cell lymphoma (DLBCL) in a manner that is distinct from IMiDs or selective IRAK4 targeting alone. The data were presented today in a poster session at the American Association of Cancer Research (AACR) Annual Meeting 2021 (LB118: Mechanisms underlying synergistic activity in MYD88MT DLBCL of KT-413, a targeted degrader of IRAK4 and IMiD substrates).
IRAKIMiDs are novel heterobifunctional degraders designed to degrade both IRAK4 and IMiD substrates, including Ikaros and Aiolos, with a single small molecule. IRAKIMiDs synergistically target both the MYD88-NFkB and IRF4-Type 1 interferon pathways to enhance and broaden anti-tumor activity in MYD88-mutant DLBCL. KT-413 is being developed initially for the treatment of relapsed/refractory MYD88-mutant DLBCL, with the potential to expand into other MYD88-mutant indications and IL-1R/NFkB-driven malignancies. KT-413 is currently in preclinical development and Kymera plans to submit an Investigational New Drug Application (IND) to the U.S. Food and Drug Administration (FDA) and, if cleared, initiate a Phase 1 clinical trial in relapsed/refractory B cell lymphomas, including MYD88-mutant DLBCL, in the second half of 2021.
“KT-413 combines IRAK4 degradation with potent IMiD activity in a single agent in order to simultaneously target two signaling pathways central to the malignant phenotype of aggressive, poor prognosis MYD88-mutant DLBCL,” said Jared Gollob, MD, Chief Medical Officer at Kymera Therapeutics. “KT-413 has demonstrated broad activity against MYD88-mutant lymphomas in vitro and in mouse xenograft models, leading to rapid, complete and sustained tumor regressions, even when dosed intermittently. Our understanding of the molecular mechanism driving this remarkable antitumor activity allows us to further differentiate this dual-degrader approach from either IMiDs or selective IRAK4 targeting alone.”
Data highlights include:
- KT-413 showed superior cell killing compared to the potent IMiD CC-220 or the IRAK4-selective degrader KTX-545 across MYD88-mutant DLBCL cell lines.
- In an in vivo MYD88-mutant mouse xenograft model, intermittent dosing of KT-413 induced deep and sustained tumor regressions, whereas the IMiDs pomalidomide or CC-220 showed only tumor stasis or slight regressions.
- KT-413 uniquely inhibited both IRAK4-dependent MYD88-NFkB signaling and IMiD substrate-dependent IRF4 upregulation and Type 1 interferon response suppression, whereas CC-220 and KTX-545 affected only IRF4-Type 1 interferon or MYD88-NFkB signaling, respectively.
- Global transcriptomics analysis showed KT-413 induced significantly greater downregulation of NFkB, cell cycle and DNA replication pathways, as well as greater activation of interferon and apoptosis pathway signaling, compared to CC-220 or KTX-545.
“We believe this will be the first precision medicine in DLBCL to target a genetically defined population, which accounts for at least 25% of DLBCL patients, and we are excited to begin clinical development of this compound with Phase 1 initiation planned for the second half of this year,” said Nello Mainolfi, PhD, Co-Founder, President and CEO, Kymera Therapeutics. “We are also excited about the potential of this dual mechanism in areas where IMiDs and IRAK4 targeting alone are insufficient to drive profound clinical benefits.”
The AACR poster presentation is available for download at: https://www.kymeratx.com/scientific-resources/?cat=13&tag=all.
About Kymera Therapeutics
Kymera Therapeutics is a clinical-stage biopharmaceutical company focused on advancing the field of targeted protein degradation, a transformative new approach to address previously intractable disease targets. Kymera’s Pegasus™ targeted protein degradation platform harnesses the body’s natural protein recycling machinery to degrade disease-causing proteins, with a focus on undrugged nodes in validated pathways currently inaccessible with conventional therapeutics. Kymera is accelerating drug discovery with an unmatched ability to target and degrade the most intractable of proteins, and advance new treatment options for patients. Kymera’s initial programs are IRAK4, IRAKIMiD, and STAT3, which each address high impact targets within the IL-1R/TLR or JAK/STAT pathways, providing the opportunity to treat a broad range of immune-inflammatory diseases, hematologic malignancies, and solid tumors. For more information, visit www.kymeratx.com.
SOURCE: Kymera Therapeutics