BACKGROUND: Fibrotic diseases result from an exuberant response to chronic 
inflammation. Myelofibrosis is the end result of inflammation in bone, caused by 
an inflammatory process triggered by production of abnormal myeloid cells driven 
by mutations affecting the JAK-STAT pathway. Inflammatory cytokine 
overproduction leads to increased mesenchymal cell proliferation, culminating in 
fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and 
the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion 
in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow 
fibrosis in most patients. In two Phase III clinical trials, pacritinib, 
however, demonstrated improvements in platelet counts and hemoglobin and 
reductions in transfusion burden in some patients with baseline cytopenias, 
suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib 
suppresses signaling through IRAK1, a key control point for inflammatory and 
fibrotic signaling.
PURPOSE: To investigate potential antifibrotic effects of pacritinib in an 
animal model of liver fibrosis relevant to the observed course of human disease.
METHODS: Pacritinib, negative control (vehicle), and positive control (the 
angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were 
assessed in the murine Stelic animal model, which mimics the clinically observed 
progression from hepatic steatosis to nonalcoholic steatohepatitis, liver 
fibrosis, and hepatocellular carcinoma. Histopathological analysis used 
hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic 
fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels 
(a biomarker of hepatic necrosis) were measured.
RESULTS: Pacritinib-treated mice had significantly (P<0.01) reduced fibrotic 
areas in liver compared to vehicle control and significantly (P<0.05) lower 
levels of CK18. The antifibrotic effect of pacritinib was comparable to that of 
telmisartan, but without significant effects on fat accumulation.
CONCLUSION: These results, the first to demonstrate hepatic antifibrotic effects 
for pacritinib in an animal model of liver disease, provide preliminary support 
for potential clinical applications of pacritinib in fibrotic diseases other 
than myelofibrosis.