First in-Class JAK2 Inhibitor OB756 Therapy for Patients with Polycythemia Vera : A Phase 2, Open-Label, Multicenter Study

Introduction: OB756, is a first-in-class, oral, small molecule Janus kinase2（JAK2）inhibitor, was shown to have a clinical benefit in patients with myeloproliferative neoplasm (MPN) in phase 1 study. Here we conducted a phase 2 multicenter study to evaluate the safety and efficacy of OB756 in patients with polycythemia vera.

Methods: A multicenter, phase 2 trial (CTR20201950) was conducted at 11 sites in China. Eligible patients aged ≥ 18 years with polycythemia vera (PV) were enrolled in this study. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Patients were treated with OB756 16 mg or 20 mg twice daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression. The primary endpoint was complete haematologic response (CHR) rate at 24 week. Secondary endpoints included haematologic response (HR), duration of response (DOR), symptom, molecular response, and safety.

Results: Between November 3, 2020 and November 15, 2023, 296 patients were assessed for eligibility, 66 patients of PV were enrolled and treated with either OB756 16 mg BID or 20 mg BID. Median treatment duration was 508 (range, 29~1066) days. At baseline, median age was 57 (range, 44-79) years, and 28/66 (42.2%) patients were men. 34/66 (51.5%) patients were intolerant to hydroxycarbamide (HU). Baseline median spleen volume was 614.5 (rang, 356.2~1742.6)ml. Patients identified JAK2 V617F, and JAK2 exon12 mutation were 95.3% (61/66), 0% (0/28), respectively (Figure 1A). A total of 46/66 (69.7%) evaluable patients met the primary endpoint of CHR at week 24. 11/46 (23.9%) patients in the 16 mg BID group and 4/12 (33.3%) in the 20 mg BID group achieved CHR at week 24 (p = 0.507). In addition, 23/62 (37.1%), 18/43 (41.9%), and 10/26 (38.5%) patients achieved CHR at EOC3, EOC9, and EOC12, respectively (Figure 1B). In secondary endpoints, 55/61(90.2%), 42/52(80.7%), and 24/26 (92.3%) evaluable patients showed HR at EOC3, EOC6, and EOC12, respectively (Figure 1C). The median time from baseline to achieve the first HR was 1.4 months (95% CI: 0.9–1.8) in the 16 mg BID group and 1.2 months (95% CI: 0.3 to 1.3) in the 20 mg BID group. All patients (30/30, 100.0%) achieved spleen response at EOC12. The median spleen reduction was -38.9% (-63.8% to 21.3%), -44.1% (-66.1% to -9.8%) at EOC6, and EOC12, respectively. For molecular response, 15/19(78.9%) patients achieved JAK2V617F allele burden reduction at ECO6, and 7/19(36.8%) patients achieved ≥ 10% JAK2V617F allele burden reduction at ECO6. OB756 had a significant efficacy in CHR and HR, high spleen response and allele burden reduction in JAK2V617F. The most common treatment-emergent adverse events (TEAEs) were 1~2 grade, and only 3/66 (4.5%) patients were observed with thrombocytopenia. Grade≥3 TEAEs were reported in 14/66 (21.2%) patients. The most common grade≥3 hematological TEAE (≥5%) only included anemia (4/66, 6.1%). Occurrence of other grade≥3 non-hematologic TEAEs was very low (Figure 1D). Only three patients (3/66, 4.5%) were reported thrombosis during treatment, and no death was reported with related to disease progression of PV or OB756. TEAEs were generally manageable.

Conclusion: OB756 is well tolerated and showed meaningful clinical benefits in patients with PV, especially for quick spleen reduction and high JAK2V617F allele burden reduction. OB756 also showed durable CHR and few non-hematological TEAEs, and may be a new treatment option for PV patients. Furthermore, a randomized double-blind phase 3 study is ongoing, aiming to assess the efficacy and safety of OB756 compared to hydroxyurea in patients with PV in China (CTR20240873).

This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137) and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09). *Correspondence to: Prof * Jie Jin, email: jiej0503@zju.edu.cn.