IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies

Abstract

Several studies have identified mutations in the MYD88L265P gene as a key driver mutation in several B-cell lymphomas. B-cell lymphomas that harbor the MYD88L265P mutation form a complex with phosphorylated Bruton’s tyrosine kinase (BTK) and are responsive to BTK inhibition. However, BTK inhibition in B-cell lymphomas rarely results in a complete response and most patients experience eventual disease relapse. Persistent survival signaling though downstream molecules such as interleukin 1 receptor-associated kinase 4 (IRAK-4), an integral part of the “myddosome” complex, has been shown to be constitutively active in B-cell lymphoma patients treated with BTK inhibitors. Emerging evidence is demonstrating the therapeutic benefit of IRAK-4 inhibition in B-cell lymphomas, along with possibly reversing BTK inhibitor resistance. While MYD88 gene mutations are not present in myeloid malignancies, downstream overexpression of the oncogenic long form of IRAK-4 has been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), particularly in AML and MDS that harbor mutations in splicing factors U2AF1 and SF3B1. These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia

“…The in vitro concentrations of the tested inhibitors were in the range of physiologically relevant concentrations for all compounds. Emavusertib plasma concentrations of 1-5 µg/mL (2-10 µM) were detected in patients receiving 50 to 400 mg BID [18]. Venetoclax plasma concentrations of 1-3 µg/mL (1.2-3.5 µM) were observed in patients receiving 400 mg/day [36].…”

“…Mutations in the spliceosome genes U2AF1 and SF3B1 have been linked to the expression of oncogenic IRAK4 isoforms in myeloid malignancies [18,29,30], and may impose sensitivity to IRAK4 inhibition [31]. Mutations in epigenetic modifiers may also be linked to treatment responses to targeted therapies, e.g., enhanced sensitivity to venetoclax and azacitidine [47,48], venetoclax and bimiralisib [35], or AC-4-130 and S63845 [49].…”

“…Pacritinib, a multi-kinase inhibitor of IRAK1, JAK2, and FLT3, demonstrated anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations [16,17]. Emavusertib (CA4948), a multi-kinase inhibitor of IRAK4 and FLT3, has been proposed for the treatment of B-cell lymphoma and myeloid malignancies [10,18]. Emavusertib is currently being evaluated in a phase 1/2 clinical trial in R/R AML as a monotherapy and in combination with azacitidine or venetoclax (NCT04278768) [19].…”

Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies

“…IL-1 receptor-associated kinase 4 (IRAK-4) is a key mediator of the TLR signaling processes [237], while TLR4 signaling induces the NLRP3 inflammasome priming step via NF-κB. Emavusertib, a selective IRAK-4 inhibitor, is under clinical investigation to overcome the persistent survival signaling through IRAK-4 in B-cell lymphomas [238]. Multiple therapeutic modalities were explored in terms of NF-κB inhibition for lymphoid neoplasms by directly targeting NF-κB components or indirectly by inhibiting upstream signaling pathways' components (reviewed in [239]).…”

Monogenic lupus: insights into disease pathogenesis and therapeutic opportunities

“…For example, patients identified to carry GoF TLR7 variants ( 45 ), or LoF UNC93B1 variants ( 52 , 53 ) that disrupt degradative sorting of TLR7, may benefit from TLR7 inhibitors currently in phase II clinical trials. Additionally, mouse models of TLR7-driven lupus are dependent on IRAK4 ( 112 ), and several IRAK4 inhibitors are currently in phase I/II clinical trials ( 113 ), thus treatment with IRAK4 inhibitors may also be successful. Patients with pathogenic variants in specific DNases may benefit from administration of recombinant human DNase1 and DNase1L3 therapies.…”