佩格司他单抗与依库珠单抗治疗阵发性睡眠性血红蛋白尿症的疗效比较。
Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.
机构信息
From the Department of Haematology, St. James's University Hospital, Leeds (P.H., M.G.), and Lisa Tan Pharma Consulting, Cambridge (L.T.) - both in the United Kingdom; the Department of Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, VIC, Australia (J.S.); Jane Anne Nohl Division of Hematology, Keck School of Medicine of USC, Los Angeles (I.W.); the Department of Hematology, West German Cancer Center University Hospital Essen, University of Duisburg-Essen, Essen (A. Röth), the Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service and University Hospital Ulm, Ulm (B.H.), and the Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen (J.P.) - all in Germany; the Department of Hematology, NTT Medical Center Tokyo, Tokyo (K.U.), and the Department of Hematology and Oncology, Okayama University Hospital, Okayama (H.N.) - both in Japan; Centre d'Investigations Cliniques (J.-J.K.) and the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria (R.P.T.), Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris; the Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC (C.C.); Apellis Pharmaceuticals, Waltham, MA (M.H., P.D., C.F., F.G., T.A.); and the Hematology and BMT Unit, AORN San Giuseppe Moscati, Avellino, Italy (A. Risitano).
出版信息
N Engl J Med. 2021 Mar 18;384(11):1028-1037. doi: 10.1056/NEJMoa2029073.
BACKGROUND
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis.
METHODS
We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed.
RESULTS
Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group.
CONCLUSIONS
Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).
背景
阵发性夜间血红蛋白尿症（PNH）是一种罕见的后天获得性疾病，其特征为慢性补体介导的溶血。未治疗的 PNH 中，C5 抑制可控制血管内溶血，但不能解决血管外溶血。聚乙二醇化肽靶向近端补体蛋白 C3 的 pegcetacoplan，可能抑制血管内和血管外溶血。
方法
我们进行了一项 3 期、开放性、对照试验，评估 pegcetacoplan 与依库珠单抗在血红蛋白水平低于 10.5 g/dL 的 PNH 成人患者中的疗效和安全性，这些患者尽管接受了依库珠单抗治疗，但仍存在贫血。在为期 4 周的导入期，所有患者均接受 pegcetacoplan 联合依库珠单抗治疗后，我们将患者随机分配至皮下 pegcetacoplan 单药治疗（41 例）或静脉内依库珠单抗治疗（39 例）。主要终点为从基线至第 16 周时血红蛋白水平的平均变化。评估了其他临床和血液学的溶血标志物以及安全性。
结果
与依库珠单抗相比，pegcetacoplan 改善血红蛋白水平的效果更优，调整后的（最小二乘）平均差异为 3.84 g/dL（P<0.001）。接受 pegcetacoplan 治疗的 35 例患者（85%）不再需要输血，而接受依库珠单抗治疗的患者中仅有 6 例（15%）。pegcetacoplan 与依库珠单抗相比，绝对网织红细胞计数的变化具有非劣效性，但乳酸脱氢酶水平的变化不具有非劣效性。pegcetacoplan 组的慢性疾病治疗功能评估-疲劳评分从基线开始改善。pegcetacoplan 组和依库珠单抗组在治疗期间最常见的不良反应为注射部位反应（37% vs. 3%）、腹泻（22% vs. 3%）、突破性溶血（10% vs. 23%）、头痛（7% vs. 23%）和疲劳（5% vs. 15%）。两组均未发生脑膜炎。
结论
pegcetacoplan 通过提供广泛的溶血控制（包括血管内和血管外溶血的控制），在改善 PNH 患者的血红蛋白水平和临床及血液学结局方面优于依库珠单抗。（由 Apellis 制药公司资助；PEGASUS ClinicalTrials.gov，NCT03500549。）
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