Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

中文翻译：

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SIMPLIFY-1：莫莫替尼与鲁索替尼在 Janus 激酶抑制剂-初治骨髓纤维化患者中的 III 期随机试验

目的 我们评估了莫洛替尼（一种有效的选择性 Janus 激酶 1 和 2 抑制剂 (JAKi) 与鲁索替尼相比）在 JAKi 初治的骨髓纤维化患者中的疗效和安全性。患者和方法 具有高风险或中 2 风险或有症状的中 1 风险骨髓纤维化的患者 (N = 432) 被随机分配接受 24 周的治疗，接受 24 周的莫洛替尼 200 mg 每天一次或鲁索替尼 20 mg 每天两次（或按标签） )，之后所有患者都可以接受开放标签莫罗替尼。主要终点是治疗 24 周时脾脏体积减少 ≥ 35%。次要终点是症状反应率和对红细胞输血需求的影响。结果 在第 24 周时，两个治疗组的患者比例相似：26 例患者的脾脏体积减少 ≥ 35%。莫罗替尼组的 5% 和鲁索替尼组的 29%（非劣效性；P = .011）。在接受莫罗替尼和鲁索替尼治疗的患者中，分别观察到 28.4% 和 42.2% 的总症状评分降低 ≥ 50%，表明未达到非劣效性 (P = .98)。莫罗替尼改善了输血率、输血独立性和输血依赖性（所有标称 P ≤ .019）。两组中最常见的≥ 3 级血液学异常是血小板减少症和贫血。接受莫罗替尼治疗的患者中有 7% 的患者发生了≥3 级感染，而接受鲁索替尼治疗的患者中有 3% 的患者发生了 3 级感染。接受莫罗替尼治疗的患者中有 10%（所有级别 ≤ 2）和 5% 接受鲁索替尼治疗的患者（所有等级 ≤ 3）发生治疗后出现的周围神经病变。结论 在 JAKi 初治的骨髓纤维化患者中，24 周莫莫替尼治疗在脾反应方面不劣于鲁索替尼，但在症状反应方面不劣于鲁索替尼。莫罗替尼治疗与输血需求减少有关。