An investigational drug, KME-0584, developed by Kurome Therapeutics, is poised to enter clinical trials in early 2025, offering a potential breakthrough for patients with relapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS). This milestone marks nearly two decades of research led by Daniel Starczynowski, PhD, at Cincinnati Children’s Hospital, highlighting the institution's growing capacity for drug discovery. The dual inhibition of IRAK1 and IRAK4 by KME-0584 represents a novel therapeutic strategy for these challenging hematologic malignancies.
Targeting IRAK1 and IRAK4 in AML and HR-MDS
KME-0584 is a small-molecule compound designed to inhibit both IRAK1 and IRAK4, two kinases implicated in the inflammatory signaling pathways that drive the progression of AML and HR-MDS. AML affects over 20,000 people annually in the US, with a similar number diagnosed with MDS. While treatments exist, a significant portion of patients either do not achieve remission or relapse, underscoring the need for new therapeutic options. HR-MDS, in particular, has limited treatment options, making KME-0584 a potentially valuable addition to the treatment landscape.
Starczynowski's research demonstrated that inhibiting both IRAK1 and IRAK4 is essential to effectively disrupt the critical signaling pathway in AML. "These two kinases are basically partners in crime," Starczynowski noted. "We had implicated both individually in these diseases, but the idea had always been that if you target one, it would effectively block signaling involving the other. In recent studies, we established that inhibiting both was required to disrupt the critical pathway in AML. In fact, we have recently published that there is functional compensation occurring when either one is blocked alone. This was never appreciated in the past."
From Discovery to Clinical Candidate
The journey to KME-0584 began in 2009 with the identification of miR-146a's role in bone marrow disorders. Further research at Cincinnati Children’s, in collaboration with Craig Thomas, PhD, at the National Center for Advancing Translational Sciences (NCATS), led to the identification of an initial “hit” compound. Kurome Therapeutics, formed in 2020, then licensed the technology and further optimized the molecule, synthesizing over 1,600 derivatives to arrive at the clinical candidate, KME-0584. This involved extensive testing to understand the drug's properties, including its circulation, processing, target binding, and potential toxicities.
Clinical Trial and Future Prospects
The upcoming clinical trial aims to enroll up to 100 patients with relapsed AML and HR-MDS. While the trial's specific design and endpoints were not detailed, the focus will likely be on assessing the safety and efficacy of KME-0584 in this patient population. The development of KME-0584 highlights the importance of long-term investment in basic science and the collaborative efforts of researchers, institutions, and companies in translating discoveries into potential therapies. As Starczynowski notes, "This is one of only a very few therapeutics to ever be developed at Cincinnati Children’s from the initial concept all the way to a clinical candidate..."
