XPO1 inhibitor WJ01024 monotherapy or in combination with ruxolitinib in myelofibrosis

Abstract

Abstract Introduction Ruxolitinib is a common first-line therapy in myelofibrosis (MF), reducing spleen size and alleviating symptoms. However, only 41.9% and 45.9% patients achieved ³ 35% spleen volume reduction (SVR35) and total symptom score reduction (TSS50), respectively by 24 weeks, highlighting the need for novel agents targeting mechanisms beyond the JAK-STAT pathway to broaden therapeutic strategies. WJ01024 is an XPO1 inhibitor targeting nuclear export with a differentiated pharmacokinetic profile. Here we report the preliminary result from an investigator-initiated Phase I study aimed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of WJ01024, either alone or combined with ruxolitinib, in MF. Methods This trial comprised the dose-escalation and expansion phases for monotherapy (Phase IA) or combination therapies with ruxolitinib (Phase IB). The key inclusion criteria included diagnosis of primary myelofibrosis (PMF) per WHO 2016 criteria, post-polycythemia vera MF (post-PV MF) and post-essential thrombocythemia MF (post-ET MF) per IWG-MRT, irrespective of JAK2 mutation status; intermediate-1, intermediate-2, or high-risk according to DIPSS; palpable splenomegaly (≥ 5 cm below left costal margin) or radiologically confirmed spleen volume ≥ 450 cm³. Patients, who were refractory, intolerant to JAKi, or had disease relapse, after at least 6 months of JAKi treatment, were eligible for the Phase IA. The Phase IA employed accelerated titration and a 3+3 design for dose escalation across 4 cohorts (20, 40, 60, and 80 mg). In 60 and 80 mg cohorts, patients were divided into two groups to receive monotherapy or the combination therapy with ≥ 5 mg ruxolitinib, twice daily. WJ01024 was administered orally once a week in 4-week cycles. The study utilized a two-dose titration scheme, where an initial reduced dose was given on Day 1 and was increased by 20 mg on Day 8 to reach a steady dose. The objectives included safety and preliminary efficacy, e.g., response rate of SVR35 and TSS50. Results As of April 22, 2025, a total of 14 patients (12 PMF, 1 post-PV MF, and 1 post-ET MF) were enrolled in Phase IA. Half of the patients were male with the median age of all patients being 63.5 (range 36-78) years. The median baseline spleen volume was 1540.02 (range 833.53-3046.11) cm3 and the median baseline TSS was 18.5 (range 2-32). No DLT was observed in all patients. All patients reported treatment-emergent adverse events (TEAEs), all of which were considered as related to treatment with the most frequent ones (≥ 50%) being nausea (N=11, 78.6%), anemia (N=8, 57.1%), weight loss (N=7, 50%), and platelet count decreased (N=7, 50%). Five (35.7%) patients reported grade ≥ 3 TEAEs with the most common ones (≥ 10%) being anemia (N=3, 21.4%) and platelet count decreased (N=2, 14.3%). WJ01024 is well tolerated with mild gastrointestinal toxicity. Notably, no grade ≥ 3 TEAEs or vomiting of any grade occurred in the combination therapy group. SVR35 occurred in 3 patients, including 1 of 2 (50%) in 40 mg monotherapy group and 2 of 3 (66.7%) in 60 mg combination therapy group. Five patients achieved TSS50, including 1 of 1 (100%) in 20 mg monotherapy group, 1 of 2 (50%) in 40 mg monotherapy group, and 3 of 3 (100%) in 60 mg combination therapy group. Conclusions WJ01024, as monotherapy or combined with ruxolitinib, was well tolerated, and significantly reduced spleen volume and relieved core symptoms of MF. Our study suggests that WJ01024 plus ruxolitinib warrants further development in MF.