KT‐413, A NOVEL IRAKIMID DEGRADER OF IRAK4 AND IMID SUBSTRATES, HAS A DIFFERENTIATED MOA THAT LEADS TO SINGLE‐AGENT AND COMBINATION REGRESSIONS IN MYD88 MT LYMPHOMA MODELS

Abstract

An important goal of cancer therapy is to improve patient outcomes by driving to deep and durable tumor responses. The activity of single-agent targeted therapies, such as BTK inhibitors or IMiDs alone, has been modest in relapsed and refractory DLBCL, necessitating the use of combination therapy. IRAKIMiDs are novel IRAK4 degraders that simultaneously degrade IMiD substrates and show synergistic antitumor activity over either mechanism alone, enabling a therapeutically relevant biological combination within a single small molecule. Here we describe KT-413, a novel IRAKIMiD development candidate. KT-413 is a potent and selective degrader of IRAK4 (DC50 6nM) and IMiD substrates (Ikaros/Aiolos DC50 2nM), that induces rapid and potent cell killing in MYD88MT DLBCL cell lines in vitro. This activity is superior to both IRAK4-selective degraders and inhibitors (such as CA-4948) and the IMiD CC220, which has similar potency against IMiD substrates (Ikaros/Aiolos DC50 1 nM). The combined activity of these two mechanisms drives a synergistic effect on NFkB and IRF4 signaling with greater downstream effect on NFkB, type 1 interferon (IFN) signaling, apoptosis pathways and cell cycle gene expression than can be achieved with either CC220 or IRAK4 degraders and inhibitors alone. These data support the hypothesis that simultaneous targeting of both NFkB and type 1 IFN signaling leads to the rapid antiproliferative and cell killing activity of KT-413 in MYD88MT cells. In MYD88MT DLBCL xenograft models, a single IV dose of KT-413 showed significant and sustained degradation of both IRAK4 and the IMiD substrates, Ikaros/Aiolos, supporting the potential for intermittent dosing to drive cell kill and tumor regressions. To assess this, we have explored the antitumor efficacy of KT-413 in intermittent dosing schedules in MYD88WT and MYD88MT cell line models in vivo. KT-413 was well tolerated and showed potent antitumor activity in multiple models of MYD88MT DLBCL irrespective of the presence of comutations in CD79B, TNFAIP3, or IRF4, but substantially lower activity in MYD88WT models. Regressions were observed on intermittent dosing schedules ranging from QW to Q3W, supporting the clinical investigation of KT-413 as monotherapy in patients with MYD88MT DLBCL. KT-413 also showed strongly additive activity in combination with rituximab or BTK inhibitors in MYD88MT OCI-Ly10 xenografts in vivo, suggesting the potential for therapeutically relevant drug combinations in MYD88MT DLBCL. Collectively, these data demonstrate the synergistic activity of combined IRAK4 degradation and IMiD activity with KT-413 that is superior to either mechanism alone. Based on these results, we propose KT-413 has the potential to be effective both as a single agent and in combination with other agents in patients with MYD88MT lymphomas.