Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia
Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia
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DOI：
10.1182/bloodadvances.2020002003
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发表时间：
2020-09-08
期刊：
影响因子：
7.5
通讯作者：
Jolles, Stephen
中科院分区：
文献类型：
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作者：
Robak, Tadeusz;Kazmierczak, Maciej;Jolles, Stephen
原发性免疫性血小板减少症(ITP)是一种主要由免疫球蛋白G(Ig G)自身抗体介导的疾病，以孤立性血小板减少为特征。皮下注射人源化抗新生儿Fc受体(FcRN)单抗Rozanolixizumab可降低健康志愿者的血清免疫球蛋白G水平。在这项第二阶段的多中心开放研究中，持续性/慢性原发ITP患者每周皮下注射1-5次罗扎诺昔单抗(累积剂量为15-21毫克/公斤)。主要目标是安全性和耐受性，次要目标是临床疗效(血小板计数的变化)和药效学效应(免疫球蛋白的变化)。总体而言，66名患者中有51名(77.3%)报告了1次或1次以上的不良事件(AEs)，均为轻至中度，最常见的头痛(26例[39.4%])，其中15例与治疗有关。有4名患者有严重的不良反应，但没有一例与治疗有关。没有不良反应导致研究药物停用。没有发生严重的感染。在多次输注(5×4、3×7、2×3~10 mg/kg分别为35.7%、35.7%、45.5%)或单次输注(15、20 mg/kg，分别为66.7%、54.5%)后，血小板计数均至少达到1次。在高剂量组(15 mg/kg和20 mg/kg)，最低平均免疫球蛋白水平和最大平均血小板计数均出现在第8天，而在多剂量队列中，最大平均血小板计数出现在第11天。免疫球蛋白A、免疫球蛋白M、免疫球蛋白E或白蛋白水平无临床意义变化。在持续性/慢性原发ITP患者中，罗扎诺利昔单抗表现出良好的安全性和快速、显著的血小板升高，与大量的免疫球蛋白降低相一致，特别是单剂。到第8天，在15和20 mg/kg单次剂量组中，50%的患者获得了临床相关的血小板反应(>；=50×10(9)/L)，与平均免疫球蛋白水平的最低水平一致。这些数据支持罗扎诺利昔单抗在持续性/慢性原发ITP中的第三阶段发展。
Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of >= 50 x 10(9)/L were achieved at least once at any time after multiple infusions (5 x 4, 3 x 7, or 2 x 3 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (>= 50 x 10(9)/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP.