Preliminary analysis of a phase 2b, randomized, active-control study of flonoltinib maleate (FM) vs. ruxolitinib in intermediate-2 or high-risk myelofibrosis patients Free

Background Myelofibrosis (MF) is characterized by abnormal clonal expansion of hematopoietic stem cells driven by mutations JAK2, CALR and MPL genes and resultant bone marrow fibrosis. Thrombocytopenia is a poor prognostic feature and limits the use of JAK1/JAK2 inhibitor ruxolitinib (Rux). Flonoltinib Maleate (FM), a new generation of JAK2 /FLT3/CDK6 inhibitor, can stabilize platelet level and improve bone marrow fibrosis via suppressing the TGF-β signal passway. In FIH trial (NCT05153343), FM achieved SVR35, best SVR35, and TSS50 of 81.8%, 93.3% and 73.3%, respectively at week-24 in MF patients. Bone marrow fibrosis improvement was also observed in 36.4% MF patients. To further explore the efficacy and safety of FM compared with Rux, a multicenter randomized, open-label, phase IIb trial were conducted in JAKi-naïve MF patients (pts) (NCT06457425).

Methods 75 pts aged ≥18 years with primary MF, post-PV MF or post-ET MF, DIPSS with int-2 or high risk MF were randomized 1:1:1 to FM 50 mg low dose (FM L), 100 mg high dose (FM H) once daily or Rux BID (dosage per label) for 28-day as a cycle for core 24 weeks treatment. Key eligible criteria included platelet count ≥50 x 10⁹/L, ANC ≥1.0 x 10⁹/L, palpable ≥5 cm below LCM or spleen volume ≥450 cm³ by MRI/CT, PB blasts <10%. Primary endpoint was rate achieving 35% (SVR35%) by MRI or CT at week 24 by IRC. Key secondary endpoint was 50% or more reduction in total symptom score (TSS50) at week 24.

Results As of Jul 29 2025, 75 MF Pts (median age was 63.0, 52% were male) have been enrolled across 24 centers, with 25 patients allocated to FM L, 26 to FM H and 24 to Rux. Baseline characteristics were generally similar across three arms, exception of the higher proportions grade 3 bone marrow fibrosis (60.0%,76.9% vs 50.0%), high risk MF by IPSS (68.0%,73.1% vs. 50.0%) and CALR mutations (32.0%, 34.6% vs. 12.5%) in FM L and FM H arms compared with RUX arm. 6 severe myelodepletive phenotype pts with PLT < 100×10⁹/L and HGB < 100g/L at baseline enrolled in FM arms. 51 pts completed 12-week and 32 pts completed core 24-week evaluation (CT/MRI by IRC), respectively. At 12 weeks, the SVR35 were superior and achieved respective 80.0% of pts on FM L (12/15) and 100% on FM H (18/18) compared to 50.0% on Rux. The TSS50 rates were 66.7% for FM L, 83.3% for FM H vs.61.1% for Rux treated patients. Notably, CARL mutations pts achieved significantly high SVR35% response in FM L and FM H groups than Rux [66.7% (4/6), 100% (6/6) and 0% (0/2)]. At 24 weeks, pts with FM L and FM H remained significantly benefits versus Rux in SVR 35% [90.0%(9/10), 100.0% (11/11) vs, 54.5%(6/11)] and TSS 50% (80.0%,100% vs.63.6%). 87.5% (7/8) patients with CALR mutation in FM arms achieved SVR35 or CI. Pts with PLT< 100×10⁹/L or PLT> 100×10⁹/L treated with FM arms had higher mean platelet count and greater increase from baseline versus Rux, particularly in early treatment cycles. However, pts with baseline PLT> 100×10⁹/L Rux experienced a rapid decline in PLT, leading to an early dose adjustment. Furthermore, in FM treated group, the proportion of patients with an improvement in bone marrow fibrosis (> 1 grade) and remained stable condition were higher than Rux treated group with 93.8% (15/16) and 60% (6/10), respectively. For FM L, FM H, and Rux arms, the most >10% common Grade ≥3 hematological TEAEs were anemia (37.5%, 52% vs. 34.8%), No Grade ≥3 non-hematological TEAEs were reported in 3 arms. Relatively high incidence of grade ≥3 anemia in both FM arms was partly related to 6 severe myelodepletive phenotype pts at baseline. The incidence of Grade ≥3 anemia in FM L, FM H and Rux for patients with baseline platelet count >100×10⁹/L were respectively 30.0%, 47.8% and 34.8%. Dose reduction occurred in 6 pts (30%) in FM L, 17 pts (73.9%) in FM H and 16 pts (69.6%) in Rux. Only one discontinuation occurred in Rux arms due to disease progression.

Conclusions FM demonstrated excellent clinical benefits in MF pts for spleen response and improved symptom compared with RUX and manageable toxicities, suggesting FM as a potential profound innovation in treating MF through a novel mechanism of JAK2 inhibition. The updated results for the phase 2b of 75 MF patients will be completed in December 2025. A pivotal phase III multicenter, randomized, positive control, double blind clinical trial in China is currently in discussion with regulatory authority.