MPN-145 Retrospective Analysis of Anemia Benefit of Pacritinib From the PERSIST-2 Trial

Background: Pacritinib (PAC) is a novel JAK2/IRAK1 inhibitor approved for patients with myelofibrosis (MF) and platelets <50×10^9/L. Previous publications have characterized PAC's unique advantage of reduced myelosuppression. We conducted a retrospective analysis of the phase 3 PERSIST-2 trial to assess PAC's impact on anemia and performed in vitro analysis to explore PAC inhibition of ACVR1 (ALK2). Methods: This analysis included PERSIST-2 patients with platelet count ≤100×10⁹/L randomized to PAC 200mg BID, PAC 400mg QD, or best available therapy BAT. Transfusion independence (TI) was defined as no RBC transfusions and no hemoglobin level <8g/dL. PAC's activity against ACVR1 was assessed using the HotSpot assay from Reaction Biology Corporation. The activity of the JAK1/JAK2/ACVR1 inhibitor momelotinib was also assessed. IC50 was calculated using 3-fold serial dilutions starting at 10µM. Results: The analysis included 106 patients on PAC 200mg BID, 104 on 400mg QD and 98 on BAT. Patients at baseline, were severely cytopenic, with a median platelet count of 55×10⁹/L. Among patients with baseline hemoglobin <10g/dL, the percentage who achieved ≥1g/dL improvement at any time through week 24 was higher on PAC than BAT (PAC 200mg BID: 15% (5/33); PAC 400mg QD: 23% (7/30); BAT: 7% (2/28). The percentage who achieved an increase of ≥2g/dL trended similarly: PAC 200mg BID: 9% (3/33), PAC 400mg QD: 7% (2/30), BAT: 4% (1/28)). Among patients receiving transfusions or with Hb <8 at baseline, the percentage who achieved TI at any point (evaluated at 12-week intervals) through week 24 was greater on PAC 200mg BID (7/26, 27%) and PAC 400mg QD (6/24, 25%) than BAT (1/19, 5%). On duplicate assays, pacritinib was shown to inhibit ACVR1 with an IC₅₀ of 23 and 11nM. Momelotinib's IC₅₀ was 70 and 35nM in the same assay. Conclusions: Improvement in hemoglobin levels and transfusion requirements was greater on PAC than BAT, in PERSIST-2. This anemia benefit could be due to PAC's ability to inhibit the iron regulator ACVR1, which has been linked to hepcidin reduction and anemia benefit. These data suggest an important role for PAC in anemic patients with myelofibrosis. This study was supported by CTI BioPharma.