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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
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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. https://www.curis.com/pipeline/ca-4948/. Accessed Apr 8, 2021.
  4. Clinicaltrials.gov. A study of CA-4948 in patients with relapsed or refractory hematologic malignancies. https://clinicaltrials.gov/ct2/show/NCT03328078. Published, Mar 19, 2021. Accessed Apr 21, 2021.
  5. U.S. Food and Drug Administration. Search Orphan Drug Designations and Approvals. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=810221. 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. http://investors.curis.com/2021-04-19-Curis-Receives-FDA-Orphan-Drug-Designation-for-CA-4948-for-the-Treatment-of-AML-and-MDS. Published Apr 19, 2021. Accessed Apr 21, 2021.

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