A randomized, double-blind, phase 3 study of jaktinib versus hydroxyurea (HU) in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF).

7015 Background: Ruxolitinib and HU are recommended by Chinese MF guideline for splenomegaly. There is an unmet need for new treatments. Jaktinib, a novel JAK and AVCR1 inhibitor, showed promising activity on splenomegaly, anemia, and MF symptoms in a phase 2 study (NCT03886415). Here we present the interim results of a phase 3 study, which assessed the efficacy and safety of jaktinib compared to HU. Methods: Pts aged ≥ 18 with primary or post-ET/PV MF, DIPSS Int-2 or high risk, and no prior or ≤10 days’ treatment with a JAK inhibitor were enrolled and randomly assigned (2:1) to receive jaktinib 100 mg bid plus HU placebo or HU 0.5g bid plus jaktinib placebo, stratified by DIPSS risk status (Int-2 or high risk). One interim analysis was pre-specified to be conducted when 70 pts completed the week (wk) 24 visit or met the criteria for treatment termination before wk 24. The primary endpoint was the proportion of pts with a spleen volume reduction of ≥ 35% from baseline (SVR35) at wk 24, measured by MRI/CT images and assessed centrally. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with a ≥ 50% reduction in Total Symptom Score (TSS50), improvement of anemia, safety, etc. Results: This interim analysis (cut-off: April 8, 2022) included 47 pts receiving jaktinib and 23 receiving HU. 66.0% (jaktinib) and 69.6% (HU) had a baseline hemoglobin (Hb) < 100 g/L. 59.6% (jaktinib) and 69.6% (HU) were JAK2V617F positive. The SVR35 rates at wk 24 were 72.3% for jaktinib vs. 17.4% for HU ( p≤0.0001). The best spleen response rates were 80.9% of jaktinib-treat pts vs. 26.1% of HU-treated pts ( p≤0.0001). The median maximum percentage change from baseline in spleen volume were -46.59% vs. -18.50%. The TSS50 rates at wk 24 were 63.8% for jaktinib vs. 43.5% for HU ( p = 0.1163). 5 of 7 jaktinib-treated and two of 5 HU-treated pts who required RBC transfusion at baseline achieved a ≥50% decrease in RBC transfusion by wk 24. In transfusion-independent pts with baseline Hb ≤100 g/L, 39.3% for jaktinib and 15.4% for HU had a ≥20 g/L Hb increase. The most common grade ≥3 hematological treatment emergent adverse events (TEAEs) (jaktinib vs. HU) were anemia (25.5% vs. 43.5%), thrombocytopenia (17.0% vs. 39.1%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). Most common non-hematological TEAEs were upper respiratory tract infection (21.3% vs. 21.7%), elevated bilirubin (12.8% vs. 26.1%), fever (12.8% vs. 21.7%) and diarrhea (10.6% vs. 21.7%), predominantly of grade 1 or 2. TEAEs leading to treatment discontinuation occurred in 8.5% of jaktinib and 17.4% of HU. Conclusions: Jaktinib demonstrated significant clinical benefits over HU in MF pts for spleen response with improved symptom response and less cytopenias. Jaktinib may be a new treatment option for MF pts, especially for those with anemia. Clinical trial information: NCT04617028 .