Treatment with pacritinib led to an improvement in transfusion independence and hemoglobin in patients with myelofibrosis according to findings from a retrospective analysis of the phase 3 PERSIST-2 trial.
Treatment with pacritinib led to an improvement in transfusion independence and hemoglobin in patients with myelofibrosis according to findings from a retrospective analysis of the phase 3 PERSIST-2 trial (NCT02055781) that were presented at the 2022 SOHO Annual Meeting. Accompanying pharmacodynamic data implicated the ACVR1 pathway in the mechanism of action for pacritinib.
Pharmacodynamic data demonstrated that on duplicate assays, pacritinib inhibited ACVR1 with an IC50 of 22.6 and 10.8 nM, with a mean IC50 of 16.7 nM. Notably, the positive control had an IC50 of 20.4 and 32.4 nM, respectively, with a mean IC50 of 36.6 nM. Additionally, momelotinib, the sole JAK2/ACVR1 inhibitor in development for myelofibrosis, had an IC50 of 34.9 and 70.2 nM. Fedratinib had limited activity, and ruxolitinib had none.
“Pacritinib is a highly potent inhibitor of ACVR1 with greater potency than other JAK2 inhibitors. In evaluable, non–transfusion independent patients, pacritinib therapy improved transfusion independence and symptoms of myelofibrosis. Therefore, the anemia benefit of pacritinib may be related to inhibition of ACVR1 and IRAK1,” said lead study author Stephen Oh, MD, PhD, a hematologist at Siteman Cancer Center in St Louis, Missouri. “Taken together, these data suggest an important role for pacritinib in addressing anemia in patients with myelofibrosis.”
Pacritinib is an oral JAK2/IRAK1 inhibitor approved at a dose of 200 mg twice daily for the treatment of patients with myelofibrosis who have severe thrombocytopenia. Investigators in this trial evaluated the approved dose and a once-daily 400 mg dose.
Primary findings from the PERSIST-2 trial demonstrated improvements in spleen volume, symptom scores, and anemia, as well as a reduction in transfusion burden.
ACVR1 is responsible for hepcidin regulation, and its inhibition could result in improved anemia in myelofibrosis. Although, the anemia benefit of pacritinib has been tied in part to IRAK1 inhibition, the role of ACVR1 inhibition is not clear. As such, investigators conducted an in vitro analysis to evaluate the effect of ACVR1 inhibition on pacritinib’s efficacy.
In the analysis, the activity of pacritinib was evaluated against momelotinib, fedratinib (Inrebic), ruxolitinib (Jakafi), and a positive control: LDN193189. With the HotSpot assay from Reaction Biology Corporation, a 10-dose IC50 assessment with 3-fold serial dilution starting at 10 μM was performed.
The analysis included patients with an available 24-week visit with a platelet count at or below 100 x 109/L who had been randomly assigned to pacritinib at a dose of 200 mg twice daily or 400 mg once daily, or best available therapy.
Evaluable patients who were non–transfusion independent, defined as having had any transfusions or hemoglobin below 8 g/dL, or those with hemoglobin below 10 g/dL at baseline were analyzed.
Additional results showed that the percentage of non–transfusion independent patients who achieved transfusion independence over any 12-week period through week 24 was higher with the 200-mg and 400-mg doses of pacritinib compared with best available therapy, at 27% and 25% vs 5%, respectively. Moreover, the cumulative probability thereof was higher at both doses of pacritinib compared with best available therapy.
Regarding symptom improvement in this population, a greater percentage of patients reported “much improved” or “very much improved” symptoms with 200 mg of pacritinib vs best available therapy, at 50% and 16%, respectively (P = .027). Additionally, more patients who received pacritinib had at least a 50% decrease in modified total symptom score vs those who received best available therapy, at 46% and 16%, respectively (P = .054).
In patients with baseline hemoglobin less than 10 g/dL, the percentage who attained an improvement at any time through week 24 of at least 1g/dL or at least 2 g/dL was higher with both the 200-mg and 400-mg doses of pacritinib compared with best available therapy, at 15% and 23% vs 7%, and 9% and 7% vs 4%, respectively.
Oh S, Mesa R, Harrison C, et al. Retrospective analysis of anemia benefit of pacritinib from the PERSIST-2 trial. Presented at: the 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Abstract MPN-145.