Kymera Therapeutics (KYMR) Presents At AACR Virtual Meeting 2021 - Slideshow

KT-413 Activity and Selectivity - KT-413 selectively degrades both IRAK4 and IMiD substrates, while CC220 only degrades IMiD substrates and KTX-545 only degrades IRAK4[8] - KT-413 substrate degradation is hierarchical: IRAK4 degradation is slower than Ikaros and Aiolos[8] - KT-413 inhibits MYD88-dependent NF-kB transcription, unlike CC220[13] - KT-413 and CC220 activate Type1 IFN signaling in MYD88MT OCI-Ly10 cells, unlike KTX-545[13] Efficacy in MYD88MT Lymphoma - KT-413 is more active in MYD88MT cells than CC220 and KTX-545, both in potency and in the maximal level of CGI achieved[10] - In both OCI-Ly10 and SUDHL2 cell lines, KT-413 showed >98% maximal cell growth inhibition, whereas maximum cell growth inhibition by CC220 was <70% in both lines[10] - In the OCI-Ly10 MYD88MT xenograft model, KT-413 dosed at 9 mg/kg on D1,2 every 3 weeks induced strong regressions[12] Mechanism of Action - Global transcriptomics analysis showed preferential downregulation of NF-kB, DNA replication and cell cycle genes and activated apoptosis pathway signaling compared to the IMiD CC220 or IRAK4-selective degraders[19] - KT-413 preferentially downregulates NF-kB, cell cycle, and upregulates apoptosis pathways compared to IMiDs or IRAK4-selective degradation[15] - The pro-apoptotic regulator BNIP3L and the anti-proliferative regulator CDKN2A are exclusively activated by KT-413[17] Future Plans - IND filing and initiation of Phase 1 studies in MYD88MT lymphoma followed by other indications are planned in 2H 2021[19]