Background: OB756 is a novel, orally administered, selective JAK2 inhibitor that targets the JAK–STAT signaling pathway. It has been reported to produce significant therapeutic effects with an acceptable safety profile in Janus-kinase-inhibitor-naïve patients with essential thrombocythemia. In this study, we aimed to evaluate the safety and efficacy of OB756 in patients with essential thrombocythemia (ET) who were resistant to, or intolerant of, hydroxyurea or interferon.

Methods:This multicentre, phase 2 trial enrolled patients with ET who were resistant to or intolerant of hydroxyurea or interferon at 12 centres in China. Participants (aged ≥18 years; ECOG performance status ≤2) received OB756 at 16 mg (exploratory subgroup, n=5) or 20 mg (n=45) twice daily in 28-day cycles until disease progression or intolerance. The primary endpoint was complete haematologic response (CHR) at week 24. CHR is characterized by a platelet count of ≤400×10⁹/L and a white blood cell count of <10×10⁹/L, in the absence of disease-related symptoms and with normalization of spleen size (confirmed by imaging). Secondary endpoints include the composite hematologic response (HR) rate, which is achieved if any of the following criteria are met: a platelet count of ≤400×10⁹/L and a white blood cell count of ≤10×10⁹/L (Criterion A), or a platelet count of ≤600×10⁹/L, or a reduction of >50% from baseline (Criterion B); safety and tolerability assessed using the NCI-CTCAE v5.0 grading system from the first dose until 28 days after the last dose; molecular response rate, defined as a reduction in the burden of driver gene mutations. Molecular response assessment is conducted in accordance with the criteria established by the ELN and IWG-MRT consensus project. For molecular response evaluation, patients are required to have a baseline JAK2 mutation allele burden of at least 20%. Complete molecular response (CMR) is defined as reducing specific molecular abnormalities to undetectable levels, while partial molecular response (PMR) is defined as a reduction in allele burden of ≥50%. The proportion of patients achieving a ≥35% reduction in spleen volume from baseline at Week 24 (SVR35) is also measured. ET-related symptoms are assessed using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). The MPN-related symptom response rate is defined as the proportion of patients who achieve ≥50% reduction in MPN-SAF TSS from baseline (MPN-SAF TSS 50). All endpoints are quantitatively analyzed using prespecified statistical methods.

Results: Between 3 November 2020 and 16 May 2024, 50 patients were enrolled—5 in the 16 mg cohort and 45 in the 20 mg twice-daily (BID) cohort (Figure A-B). Complete haematologic response (CHR) was achieved in 23.4 % (9/38) of evaluable patients at week 24 and rose to 40 % (4/10) by week 48. High overall haematologic response (HR) rates were observed: 56.6 % (26/46) at week 12, 65.6 % (25/38) at week 24, 76 % (19/25) at week 36 and 90 % (9/10) at week 48. At week 24, 94.7 % (36/38) of patients had any reduction in spleen volume, with 50.0 % (19/38) achieving ≥35 % reduction; 74.2 % (23/31) of patients experienced ≥50 % reduction in MPN-SAF TSS. Among evaluable patients, 85.7 % (12/14) showed a decrease in JAK2-V617F allele burden, 57.1 % by ≥10 %, with two partial and one complete molecular response (Figure C-D). Most treatment-emergent adverse events (TEAEs) were grade 1–2; grade ≥3 haematologic TEAEs were anaemia (10%, 5/50) and neutropenia (6%, 3/50). Grade ≥3 non-haematologic toxicities included infections in 16% (8/50) and thrombotic events in 2% (1/50), none considered drug-related (Figure E).

Conclusion: In summary, OB756 demonstrated favourable tolerability and marked clinical efficacy in patients with ET who were resistant to or intolerant of hydroxyurea or interferon. The agent rapidly induced haematologic responses, reduced spleen volume, and lowered JAK2 V617F allelic burden. Sustained complete haematologic responses were maintained, and non-haematologic toxicities were infrequent, positioning OB756 as a highly promising new therapeutic option for ET patients who are resistant to or intolerant of hydroxyurea or interferon.

Acknowledgement: This research was funded by the Zhejiang Provincial Health High-level Innovative Talent Project (2022-2026).

*Correspondence to: Prof Jian Huang, E-mail:househuang@zju.edu.cn

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2025
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