Introduction:JAK inhibitors (JAKi) are crucial in managing polycythaemia vera (PV) by improving symptoms and reducing spleen volume, but their efficacy and hematologic toxicity vary significantly. OB756 ,a novel oral JAK2 inhibitor, has shown promising efficacy and safety in recent studies.

Methods: We assessed the relative efficacy and safety of OB756 compared to ruxolitinib in PV patients with splenomegaly using a matching-adjusted indirect comparison (MAIC). This analysis was based on data from the RESPONSE-1 clinical trials. Key endpoints included hematocrit control (HC), spleen volume reduction ≥35% (SVR35), complete hematological response (CHR), and total symptom score reduction ≥50% (TSS50) at Week 32, and adverse events (AEs) over 32 weeks. Due to limitations in published aggregate data, not all outcomes were feasible for comparison. The MAIC process involved reweighting the OB756 patient data to match baseline characteristics (including age, sex, spleen volume, hematocrit level, white blood cell count, and platelet counts) prioritized by clinical experts. Odds ratios (ORs) were then calculated for the balanced populations. Confidence intervals (CIs) for the quantiles were estimated using the Brookmeyer-Crowley method.

Results: The main results were presented in Table 1. At Week 32, the ORs for hematocrit control, SVR35, and TSS50 with OB756 were numerically higher than those of ruxolitinib in RESPONSE-1 study. Specifically, for hematocrit control, the OR was 24.53 (95% CI, 6.94-92.73; P = 0.0000024) compared to RESPONSE-1 (ruxolitinib). Additionally, a statistically significant advantage in SVR35 for OB756 was observed only when compared to the ruxolitinib arm of RESPONSE-1(OR = 3.33, 95% CI, 1.06-10.49; P = 0.0396).

For TSS50, the MAIC-estimated weighted OR values at Week 32 were statistically significant and favored OB756 therapy compared to RESPONSE-1 (ruxolitinib) arms. The ORs for TSS50 was 4.54 (95% CI, 1.49-13.84; P = 0.0077) compared to RESPONSE-1 (ruxolitinib). CHR at week 32 were similarly in OB756 compared to RESPONSE-1 (ruxolitinib). The OR of CHR was 2.35 (95% CI, 0.93-5.92; P = 0.0695) compared to RESPONSE-1 (ruxolitinib).

In terms of safety, for hematological AEs, the risk of any grade anemia, thrombocytopenia, and lymphopenia were statistically lower with OB756 compared to ruxolitinib in RESPONSE-1 study (P = 2.90x10^-110 in anemia; P = 0.024 in thrombocytopenia; P = 0.014 in lymphopenia ). For the risk of hematological grade 3/4 leukopenia and neutropenia were statistically lower with OB756 compared to ruxolitinib in RESPONSE-1 study (P = 2.62x10^-60both in leukopenia and neutropenia). For non-hematological AEs, the risk of any grade headache, fatigue, dizzniess, muscle spasms, and dyspnea were statistically lower with OB756 compared to ruxolitinib in RESPONSE-1 study.

Conclusion: Overall, OB756 appears to show potential benefits in efficacy and safety in PV patients with splenomegaly compared to ruxolitinib in preliminary analyses of RESPONSE-1 study. These findings suggest that OB756 may offer advantages in reducing both hematological AEs such as anemia, thrombocytopenia, lymphopenia, neutropenia, and non-hematological AEs in JAK inhibitor-naïve PV patients with splenomegaly. However, these observations require confirmation through direct head-to-head studies.

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

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2025
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