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

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