FDA Grants Orphan Drug Status to Novel IRAK4 Inhibitor in AML and MDS


The FDA has granted an orphan drug designation to CA-4948, a first-in-class, small-molecule inhibitor of IRAK4, for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome.

The FDA has granted an orphan drug designation to CA-4948, a first-in-class, small-molecule inhibitor of IRAK4, for the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), announced Curis, Inc., in a press release.

The novel agent is under investigation as treatment of both AML and MDS in a phase 1 clinical trial (NCT04278768).

"We are pleased to take this important next step in unlocking the potential of CA-4948 to offer a safe and transformative, disease-modifying alternative treatment for patients on the AML/MDS spectrum," said James Dentzer, chief executive officer of Curis, in a statement. "Receiving orphan drug designation for CA-4948 in AML and MDS represents a significant milestone in our mission of slowing or preventing the progression of disease in patients with these rare hematological malignancies.”

In the study, investigators are exploring the maximum tolerated dose (MTD) and recommended phase 2 dose of CA-4948 as co-primary end points. As secondary end points, the study will explore several pharmacokinetic and pharmacodynamic parameters. 

Patients enrolled will receive CA-4948 in tablet form starting at a dose of 200 mg twice daily for up to 28 days. At the start of the study, 3 patients with either AML or MDS will be dosed with the agent and will continue treatment at the next dose level if no dose-limiting toxicities (DLTs) are observed. In the event that 2 or 3 patients experience a DLT at that level, the DLT rate will be considered above 33%, which is above the MTD of the agent, and the dose will be lowered.

To be eligible for enrollment, patients must be 18 years or older, with a life expectancy of at least 3 months, and an ECOG performance status of 2 or lower. Patients with AML are required to have relapsed or refractory disease, and those with MDS are required to have high or very high risk relapsed/refractory disease following at least 6 cycles of therapy with hypomethylating agents or evidence of early progression. At the time of screening in the study, patients must have adequate organ function, a negative serum pregnancy test if they are a female of childbearing age, and be able to undergo serial bone marrow sampling and peripheral blood sampling.

The study excludes patients with acute promyelocytic leukemia, blast phase of chronic myeloid leukemia, active central nervous system leukemia, acute or chronic toxicity resulting from prior anti-cancer therapy, human immunodeficiency virus, hepatitis B or C virus, severe cardiovascular disease, as well as a history of other invasive malignancy, gastrointestinal disease or disorder, other invasive malignancy, uncontrolled fungal, bacterial, viral, or other infection or allergy or hypersensitivity to any component of the formulation of CA-4948.

In terms of prior therapy, patients are not considered eligible for treatment with CA-4948 in the study if they had an allogeneic hematopoietic stem cell transplant within 60 days of the first dose of CA-4948, systemic anti-cancer treatment such as chemotherapy or immunomodulatory drug therapy within 14 days of CA-4948 dosing, or an investigational agent within 28 days of the start of CA-4948 in the study.

Currently, patients with AML and MDS are being recruited throughout the United States at Moffitt Cancer Center, Dana-Farber Cancer Institute, Oncology Hematology West, PC dba Nebraska Cancer Specialists, Albert Einstein Medical College, Novant Health Hematology – Forsyth, and the University of Texas MD Anderson Cancer Center.

IRAK4 kinase plays a roll in the Toll-like receptor and interleukin-1 receptor signaling pathways, both of which are often dysregulated in AML, MDS, and non-Hodgkin lymphomas. The agent is also being explored in combination with ibrutinib (Imbruvica) as treatment of patients with non-Hodgkin lymphoma.

Curis receives FDA orphan drug designation for CA-4948 for the Treatment of AML and MDS. News release. Curis Inc. April 19, 2021. Accessed April 19, 2021. https://bit.ly/32uqz7k

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