Development of HPB-092: A novel dual kinase inhibitor targeting FLT3 and IRAK4 for the treatment of relapsed/refractory Acute Myeloid Leukemia (RR-AML)

Abstract Fms-like tyrosine kinase 3 (FLT3) is a clinically validated oncogene in acute myeloid leukemia (AML), while interleukin-1 receptor-associated kinase 4 (IRAK4) is a newly identified oncogene in AML that is currently undergoing clinical validation. Mutations in the FLT3 and IRAK4 genes are closely related to the mechanisms of resistance to FLT3 inhibitors and significantly impact overall efficacy in relapsed and refractory AML (RR-AML). HPB-092 is a novel, highly selective dual-target kinase inhibitor developed to target both FLT3 and IRAK4 mutations in RR-AML patients. Given the high frequency of FLT3 mutations identified in RR-AML, second-generation FLT3 inhibitors that selectively disrupt the oncogenic signaling initiated by these mutations have the potential to significantly improve clinical outcomes in patients with FLT3-mutated RR-AML, demonstrating substantial clinical benefits. Meanwhile, the long isoform of IRAK4 (IRAK4-L), which retains full exon 6 and encodes the full-length protein, has been associated with resistance mechanisms to FLT3 inhibitors in both preclinical models and clinical patients. IRAK4-L, which is highly expressed in most AML cases, activates NF-κB and contributes to this resistance, leading to a poor prognosis. Preclinical studies indicate that FLT3/IRAK4 dual kinase inhibition can effectively counteract IRAK4-mediated resistance to FLT3 inhibitors in leukemia cells. Consequently, the development of highly selective and effective dual inhibitors that target both FLT3 and IRAK4 mutations could enhance treatment efficacy and durability for patients with RR-AML, thereby further improving clinical outcomes in this FLT3-mutated RR-AML population. HPB-092, a highly selective dual kinase inhibitor of FLT3 and IRAK4, demonstrated potent inhibition of FLT3-ITD (IC50 = 0.24 nM), FLT3-D835Y (IC50 = 0.18 nM), and IRAK4 (IC50 = 3.1 nM). Additionally, HPB-092 effectively inhibited the proliferation of the FLT3-ITD mutant cell line MV4-11 (IC50 = 6.5 nM). In mouse models of FLT3 mutant leukemia, treatment with HPB-092 induced dose-dependent tumor regression. The 28-day GLP-compliant toxicity studies indicated a favorable safety profile, with NOAELs of 75 mg/kg/day for rats and 24 mg/kg/day for dogs (both at the highest doses tested), and no adverse findings were observed in GLP-compliant genotoxicity or safety pharmacology studies. Compared to the approved FLT3 inhibitors gilteritinib and quizartinib, as well as the clinical-stage dual inhibitor CA-4948, HPB-092 displayed comparable or superior potency against mutant FLT3 and IRAK4, improved kinome selectivity (selectivity score < 0.1), minimal CYP inhibition (IC50 > 50 μM), and no hERG inhibition (IC50 > 10 μM), along with an excellent overall safety profile in nonclinical species. HPB-092 received FDA and NMPA approvals for a Phase 1 clinical study, an open-label trial designed to assess its monotherapy through dose escalation and cohort expansion. The trial will begin with a dose of 30 mg BID, escalating to 60 mg, 100 mg, 150 mg, and 200 mg BID, with each treatment cycle lasting 28 days. The objectives are to evaluate safety and tolerability, pharmacokinetic (PK) profiles, clinical activity, as well as to determine the Recommended Phase 2 Dose (RP2D) in patients with RR-AML. The dose expansion will focus on patients with RR-AML harboring FLT3 mutations, as well as those with U2AF1 or SF3B1 mutations that induce IRAK4 mutations in RR-AML patients. The study has been approved by the Institutional Review Board (IRB) and has also been submitted to ClinicalTrials.gov, currently pending final approval. The first patient is anticipated to be enrolled in the fourth quarter of 2025.