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CA-4948, an IRAK4 inhibitor, attained orphan drug designation by the FDA for the treatment of relapsed/refractory MDS and AML

Apr 22, 2021

CA-4948 is a first-in-class, small-molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which plays a role in toll-like receptor (TLR) and interleukin-1 receptor signaling pathways. These pathways are known to be dysregulated in non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS).1,2 IRAK4 was identified as the most dominant, alternatively-spliced isoform, and the long form of IRAK-4 (IRAK4-L), which encodes a mutant IRAK4 protein with an additional exon, was found to be associated with maximum pathway activation through interaction with the Myddosome protein complex. Inhibiting IRAK4-L activity with CA-4948 resulted in eradicating leukemic activity in AML cells.3

CA-4948 is currently under evaluation as an orally administered monotherapy in a phase I study (NCT04278768) in adults with AML or high-risk MDS. The preliminary results presented during the 62nd American Society of Hematology (ASH) Annual Meeting showed marrow blast reductions and marrow complete responses with no dose-limiting toxicity. More information can be found here.

Initial success in the phase I trial led to the orphan drug designation of CA-4948 by the U.S. Food and Drug Administration (FDA) to treat patients with relapsed or refractory (R/R) AML and MDS.4−6

CA-4948 is also under investigation in a phase I trial (NCT03328078) as a monotherapy or in combination with ibrutinib for adults with R/R NHL.4

  1. Smith MA, Choudhary GS, Pellagatti A, et al. U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat Cell Biol. 2019;21(5):640-650. DOI: 1038/s41556-019-0314-5
  2. Choudhary GS, Smith MA, Pellagatti A, et al. SF3B1 mutations induce oncogenic IRAK4 isoforms and activate targetable innate immune pathways in MDS and AML. Blood. 2019;134(Supplement_1):4224. DOI: 1182/blood-2019-124458
  3. Curis. CA-4948: First-in-class suppressor of the TLR pathway. Accessed Apr 8, 2021.
  4. A study of CA-4948 in patients with relapsed or refractory hematologic malignancies. Published, Mar 19, 2021. Accessed Apr 21, 2021.
  5. U.S. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Published Apr 16, 2021. Accessed Apr 21, 2021.
  6. Curis. Curis receives FDA orphan drug designation for CA-4948 for the treatment of AML and MDS. Published Apr 19, 2021. Accessed Apr 21, 2021.