On July 7, 2020 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that the first patient has been dosed in its Phase 1 trial evaluating CA-4948, a novel, small molecule IRAK4 kinase inhibitor, in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with spliceosome mutations, such as SF3B1 and U2AF1, that drive expression of the long isoform of IRAK4 (IRAK4-L) (Press release, Curis, JUL 7, 2020, View Source [SID1234561717]). IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, and these pathways are frequently dysregulated in patients with AML and MDS.
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"When Drs. Daniel Starczynowski, Professor, Cincinnati Children’s Hospital and Amit Verma, Director of the Division of Hematologic Malignancies at the Albert Einstein College of Medicine, demonstrated the important pathogenic role of IRAK4 in MDS/AML in their seminal publication in Nature Cell Biology and presentation at ASH (Free ASH Whitepaper) last December, everyone in the AML/MDS community paid attention, including our team at Curis," said James Dentzer, President and Chief Executive Officer of Curis. "Dr. Starczynowski, Dr. Verma, and their colleagues showed that IRAK4-L, the oncogenic long isoform of IRAK-4, is expressed as a result of specific spliceosome mutations common in AML and MDS. Further, they demonstrated that it potentially impacts over 50% of the AML/MDS population. We quickly worked with our clinical investigators and the U.S. Food and Drug Administration (FDA) to design a study of CA-4948, our first-in-class IRAK4 inhibitor, in this population. We are pleased to announce today, just six months later, that we have initiated this new study and successfully dosed our first patient. The initial dose in this study is 200mg twice-daily (BID) which, based on our preclinical models, we believe may be a therapeutic dose level. As a result, we expect to report initial efficacy data by the end of the year."
"Historically, no single oncogenic driver of AML and MDS has been known to impact the majority of patients," said Dr. Guillermo Garcia-Manero, Chief, Section of Myelodysplastic Syndromes at the University of Texas MD Anderson Cancer Center. "Recent studies have changed this understanding. The long isoform of IRAK4, itself the result of specific genetic mutations, was recently discovered to be a driver of disease in over half the population of patients with AML and MDS. With CA-4948, we may now have a single drug that can directly target a key driver of disease in these patients. We are delighted to be a lead clinical site in the study of this novel new drug."
About the CA-4948 Phase 1 Clinical Trial
The Phase 1 trial is an open-label, dose escalation study designed to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of CA-4948 in patients with AML and high-risk MDS. The primary objective of the study is to determine the maximum tolerated dose and recommended Phase 2 dose of CA-4948 based on safety and tolerability, dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic findings. A minimum of three patients will be enrolled at each dose level, starting with 200 mg BID, which was determined to be safe, capable of achieving relevant levels of drug exposure, and demonstrated signs of biologic activity and clinical efficacy in a separate, ongoing Phase 1 study. Each treatment cycle will be 28 days in length and repeated in the absence of toxicity. Initial data from the study is expected in the fourth quarter of 2020.