Guillermo Garcia-Manero, MD, on IRAK4, Emavusertib

Guillermo Garcia-Manero, MD, of the Department of Leukemia at MD Anderson Cancer Center, says the novel drug emavusertib, an IRAK4 inhibitor, is a potential treatment option for patients with hematologic malignancies.

IRAK4 is “becoming a really important target in leukemia, myelodysplastic syndromes, lymphoma and potentially other diseases,” Dr. Garcia-Manero said, noting this is because “alterations in innate immunity signaling are common in these diseases, and IRAK4 is a central molecule in this pathway.”

Due to this, inhibiting IRAK4 downstream signaling “may exert anti-leukemia or [anti]-lymphoma activity,” he said.

“It has been shown that perhaps specific subsets of patients with MDS and AML that have splicing mutations may have different isoforms of this IRAK4 molecule,” Dr. Garcia-Manero said. “And this could actually lead toward targeting of these agents, let’s say IRAK4 inhibitors, for particular molecular subsets of patients that have a splicing mutation.”

There are multiple compounds under development that target the IRAK4 pathway. Data from a phase I trial of emavusertib, also known as CA-4948, showed “significant anti-leukemia activity,” he said.

“A large majority of the patients had a decrease in blasts,” Dr. Garcia-Manero said. “This is unusual actually, for a phase I study, where we are looking for safety signals, and here, all of a sudden, we’re seeing actually quite a significant reduction in blasts … we think that for a phase I trial to see that level of activity is quite significant. And some of these patients actually went on to achieve complete remission.”

With these results, Dr. Garcia-Manero looks forward to the next steps.

“This is early in development, but what we saw is very significant clinical activity for an asset that is very early on its clinical development, so we’re excited,” he said. “And this [research] is now moving pretty soon into combinations of this IRAK4 inhibitor, perhaps with BCL inhibitors, hypomethylating agents, and a number of other initiatives are being discussed.”