FDA Greenlights IND of KME-0584 for AML and MDS Therapy

• The FDA has cleared an investigational new drug application (IND) for KME-0584 for relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) treatment.

• KME-0584 is a first-in-class, investigational interleukin 1 (IL-1) receptor associated kinases (IRAK)1/IRAK4/pan FMS-like receptor tyrosine kinase-3 (FLT3) inhibitor.

• With this clearance, a phase 1 trial of KME-0584 in AML and MDS will begin.

The FDA has granted clearance to the IND for KME-0584 for the treatment of patients with R/R AML and high-risk MDS, and a phase 1 trial evaluating the agent in this patient population will begin in the later portion of 2024.¹

KME-0584, a first-in-class, investigational potent and specifically targeted small molecule inhibitor, effectively blocks IRAK1, IRAK4, and all variants of FLT3. This shows promise for a new option in the treatment of R/R AML or high-risk MDS.

Acute myeloid leukemia (AML) cells in blood flow - isometric view 3d illustration: © LASZLO - stock.adobe.com

Designed for oral delivery, KME-0584 is intended both as a standalone treatment and in conjunction with azacitidine or venetoclax (Venclexta) as a combination therapy.

According to data presented at the 2023 American Society of Hematology Annual Meeting, KME-0584 showed remarkable selectivity and potency, with >100-fold selectivity vs 89% of the Kinome, improving IC50 values of 23, <1.29, and <0.5nM at IRAK1, IRAK4, and FLT3 respectively.² In cell-based assays, KME-0584 demonstrated high potency kinase antagonist activity against various targets, including PHKg1, PDGFRβ, RET, CLK1, and CLK4.

KME-0584 also inhibits NF-κB signaling through the TLR and IL1-receptor pathways. This indicates comprehensive inhibition of multiple receptor pathways necessitates both IRAK1 and IRAK4 antagonism. Notably, KME-0584 also led to superior potency in leukemia stem cell progenitor function inhibition. This potency was seen irrespective of mutational status, suggesting its potential efficacy across a broader patient population than IRAK4 inhibitors.

Moreover, the inhibitor can reverse the IRAK1/4 gene signature associated with myelomonocytic AML subtypes, hinting at its effectiveness against venetoclax and azacitidine-resistant AML subtypes. In FLT3-ITD xenograft models, KME-0584 also outperformed gilteritinib (Xospata) after oral dosing and showed favorable pharmacokinetics as well as oral bioavailability.

Based on these promising data, in the phase 1 study, investigators will assess the safety, tolerability, pharmacokinetics, and antitumor activity of KME-0584 given as a monotherapy or combined with venetoclax or azacitidine for the treatment of patients with R/R AML and high-risk MDS.¹

Dose-escalation and dose-expansion phases will be used in the study. Investigators plan to enroll up to 100 patients with the goal of initiating the study in 2024 across multiple investigative sites in the United States.

REFERENCES:

1. CORRECTING and REPLACING Kurome Therapeutics announces FDA clearance of investigational new drug (IND) application for KME-0584 for the treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). News release. Kurome Therapeutics Inc. February 15, 2024. Accessed February 16, 2024. http://tinyurl.com/mrbayxyf

2. Rosenbaum JS, Kolt AS, Hoyt SB, et al. KME-0584, a highly potent IRAK1/IRAK4/panFLT3 inhibitor, is a promising clinical candidate for hypomethylating agent plus venetoclax resistant AML/MDS patients. Blood. 2023;142(Suppl 1):4152. doi:10.1182/blood-2023-189899