KYM‐001, A FIRST‐IN‐CLASS ORAL IRAK4 PROTEIN DEGRADER, INDUCES TUMOR REGRESSION IN XENOGRAFT MODELS OF MYD88‐MUTANT ABC DLBCL ALONE AND IN COMBINATION WITH BTK INHIBITION

Introduction: ABC DLBCL comprises approximately 45% of DLBCL and has a worse outcome with R-CHOP chemotherapy compared to GCB DLBCL. Activating mutations in MYD88 occur in 30-40% of ABC DLBCL; L265P, the most prevalent MYD88 mutation, causes constitutive assembly and activation of the Myddosome. IRAK4 kinase and scaffolding functions are essential for full signaling through the Myddosome to NFκB and MAPK pathways. Kymera Therapeutics is using a chemical knockdown strategy to develop heterobifunctional small molecule IRAK4 degraders, exemplified by KYM-001, for the treatment of MYD88-driven B cell malignancies. Methods: IRAK4 in human PBMC, ABC DLBCL cell lines and tumor xenografts was quantified by immunoassays or targeted mass spectrometry. Cell viability and cell cycle were monitored by flow cytometry. Tumor xenograft studies were conducted by implanting human ABC DLBCL lines into immunocompromised mouse strains. Results: KYM-001 led to potent E3 ligase-dependent degradation of IRAK4. Notably, KYM-001 more effectively inhibited TLR-activated Myddosome signaling compared to IRAK4 kinase inhibitors in human whole blood. Degradation was highly selective for IRAK4 vs >10,000 other detected proteins in the MYD88 L265P mutant ABC DLBCL line OCI-LY10. IRAK4 degradation by KYM-001 resulted in cell cycle inhibition and apoptosis within 72 h in MYD88-mutant ABC DLBCL. Since mutations in MYD88 frequently co-occur with CD79 mutations in B-cell malignancies, we investigated the potential for combined activity of IRAK4 degradation with BTK or PI3Kδ inhibition. In the OCI-LY10 and TMD8 cell lines, which have activating mutations in both MYD88 and CD79B, BTK inhibition with ibrutinib or PI3Kδ inhibition with umbralisib both synergized with KYM-001 to induce cell death in vitro. Oral dosing of KYM-001 showed dose-dependent antitumor activity in several mouse xenograft models of human MYD88-mutant ABC DLBCL at tolerated doses and schedules. In the OCI-LY10 model, tumor regression was associated with >80% degradation of IRAK4, establishing the pharmacodynamic effect required for maximal efficacy. Combination of KYM-001 with ibrutinib drove tumor regression in both OCI-LY10 and TMD8 at suboptimal doses of each agent. Hypothesis-driven combination studies with umbralisib and other drugs with activity in DLBCL, including lenalidomide, are in progress in MYD88-mutant DLBCL xenograft models. Conclusions: KYM-001 is a first-in-class, potent, selective and orally active IRAK4 degrader that causes tumor regression in MYD88-mutant ABC-DLBCL models. Degradation of IRAK4 removes both the kinase and scaffolding functions of IRAK4, and may be superior to kinase inhibition alone. These data support clinical development of IRAK4 degraders as a promising new therapeutic opportunity for MYD88-driven lymphoma, both alone and in combination with inhibitors of complementary pathways. Keywords: B-cell lymphoma; MYD88. Disclosures: Kelleher, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Campbell, V: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Chen, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Gollob, J: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Ji, N: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Kamadurai, H: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Klaus, C: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Li, H: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Loh, C: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. McDonald, A: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Rong, H: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Rusin, S: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Sharma, K: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Vigil, D: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Walker, D: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Weiss, M: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Yuan, K: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Zhang, Y: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics. Mainolfi, N: Employment Leadership Position: Kymera Therapeutics; Stock Ownership: Kymera Therapeutics.