Study Investigates Mechanism Behind Anemia Benefit of Pacritinib

By Cecilia Brown - August 17, 2023

The anemia benefit associated with pacritinib, a JAK2/IRAK1 inhibitor, “may be a function of potent ACVR1 inhibition,” according to a recent study.

Stephen Oh, MD, PhD, of Washington University School of Medicine in St. Louis and colleagues conducted the research because the “impact of pacritinib on transfusion independence has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated.”

They assessed the relative inhibitory potency of pacritinib against ACVR1 and compared it with other JAK2 inhibitors.

Study Compares ACVR1 Inhibition Potency Among JAK2 Inhibitors

Pacritinib inhibited ACVR1 with “greater potency” than momelotinib, fedratinib, and ruxolitinib, Dr. Oh and colleagues wrote. Pacritinib showed a half-maximal inhibitory concentration (IC50) of 16.7 nM and a maximum serum concentration (Cmax):IC50 of 12.7. Momelotinib showed an IC50 of 52.5 nM, a Cmax:IC50 of 3.2. Fedratinib showed an IC50 of 273 nM and a Cmax:IC50 of 1.0, while ruxolitinib showed an IC50 >1,000 and a Cmax:IC50 of <0.01.

“Pacritinib’s inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production,” Dr. Oh and colleagues wrote.

In the PERSIST-2 trial, among patients who were not transfusion independent at baseline, a significantly greater proportion achieved transfusion independence on pacritinib (37%) compared with the best available therapy (7%; P=.001). Furthermore, 49% of patients receiving pacritinib had at least a 50% reduction in transfusion burden, significantly higher than the patients receiving the best available therapy (9%; P<.0001).

“These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition,” Dr. Oh and colleagues concluded.


Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023. doi:10.1182/bloodadvances.2023010151

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