阵发性睡眠性血红蛋白尿症的口服依帕司他单药治疗。
Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.
机构信息
From the Hematology and Transplant Unit, French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint-Louis Hospital (R.P.L., F.S.F.), and Université de Paris (R.P.L.), Paris, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse (S.T.), and CHU Lille, Université de Lille, Lille (L.T.) - all in France; the Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen (A.R., F.A.), the Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, University Hospital RWTH Aachen, and the Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen (J.P.), the University of Ulm, the Institute of Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen, and University Hospital Ulm, Ulm (H.S., B. Höchsmann), the Department of Oncology, Hematology, and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg (P. Schafhausen), and Elblandklinikum Riesa, Riesa (J.S.) - all in Germany; King's College Hospital NHS Foundation Trust (A.G.K., S.G., R.T.), the National Institute for Health and Care Research and Wellcome King's Clinical Research Facility (A.G.K.), King's College London (A.G.K.), and Novartis Pharmaceuticals (C.T.), London, and St. James's University Hospital, Leeds (M.G., R.J.K.) - all in the United Kingdom; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing (B. Han, C.Y.), the Department of Hematology, Tianjin Medical University General Hospital (R.F., H.L.), and the Department of Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (L.Z.), Tianjin, and China Novartis Institutes for BioMedical Research, Shanghai (Z.W., S.L.) - all in China; the Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo (P. Scheinberg), and ABC Medical School, Santo André (V.A.Q.M.) - both in Brazil; the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (J.P.M.); Osaka University Graduate School of Medicine, Suita (Y.U.), Kyoto University Hospital, Kyoto (T.K.), and Japanese Red Cross Society Suwa Hospital, Suwa (M.U.) - all in Japan; Duke University School of Medicine and Duke Cancer Institute, Durham, NC (C.M.C.); Unità Operativa Complessa Oncoematologia, AULSS7 Pedemontana, Bassano del Grappa (E.D.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.), Division of Hematology, University of Turin, Città della Salute e della Scienza, Turin (E.B.), Instituto per lo Studio, la Prevenzione e la Rete Oncologica, and Azienda Ospedaliero-Universitaria Careggi, Florence (R.N.), AORN Moscati, Avellino (L.M., A.M.R.), and University of Naples Federico II, Naples (A.M.R.) - all in Italy; Radboud University Medical Center, Nijmegen, the Netherlands (S.M.C.L.); the Hematology Unit, Department of Medicine, Hospital Umum Sarawak, Kuching (L.P.C.), and the Hematology Unit, Queen Elizabeth Hospital, Kota Kinabalu (L.W.L.L.) - both in Malaysia; Hospital Clinic of Barcelona (A.G.) and the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (R.P.L., A.G.K., M.G., W.B., S.T., L.T., F.S.F., L.M., A.M.R.) - both in Barcelona; the Department of Hematology and Oncology and the Department of Clinical Pathology, Hualien Tzu Chi Hospital, the Buddhist Tzu Chi Medical Foundation, and the Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan (W.-H.H.); the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (J.H.J.); Medical College of Georgia, Augusta (A.K.); City of Hope Medical Center, Duarte, CA (V.P.); the Department of Laboratory Medicine, National University Hospital, Singapore (E.-S.Y.); Novartis Pharma (C.K., R.L., M.D.) and Novartis BioMedical Research (A.V.) - both in Basel, Switzerland; and Novartis Healthcare Private, Hyderabad, India (P.B., R.K., S.M.).
出版信息
N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695.
BACKGROUND
Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients.
METHODS
In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.
RESULTS
In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.
CONCLUSIONS
Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
背景
接受过抗 C5 治疗或未接受补体抑制剂治疗的阵发性睡眠性血红蛋白尿症患者存在持续性溶血性贫血和缺乏口服治疗方法的问题。Iptacopan 是一种首创的口服因子 B 抑制剂，已被证明可提高这些患者的血红蛋白水平。
方法
在两项 3 期临床试验中，我们评估了 Iptacopan 在 24 周内的单药治疗，纳入血红蛋白水平低于 10g/dL 的患者。在第一项试验中，接受过抗 C5 治疗的患者被随机分配转为接受 Iptacopan 治疗或继续接受抗 C5 治疗。在第二项单组试验中，未接受补体抑制剂且乳酸脱氢酶（LDH）水平高于正常上限 1.5 倍的患者接受 Iptacopan 治疗。第一项试验的两个主要终点为血红蛋白水平自基线至少增加 2g/dL，且无需输血；第二项试验的主要终点为血红蛋白水平自基线至少增加 2g/dL，且无需输血。
结果
在第一项试验中，接受 Iptacopan 治疗的 60 例患者中有 51 例血红蛋白水平自基线至少增加了 2g/dL，且 42 例患者血红蛋白水平至少达到了 12g/dL，均无需输血；而 35 例接受抗 C5 治疗的患者均未达到终点水平。在第二项试验中，33 例患者血红蛋白水平自基线至少增加了 2g/dL，且无需输血。在第一项试验中，接受 Iptacopan 治疗的 62 例患者中有 59 例无需或接受输血，接受抗 C5 治疗的 35 例患者中有 14 例无需或接受输血；在第二项试验中，没有患者需要或接受输血。Iptacopan 治疗可提高血红蛋白水平，减轻疲劳，降低网织红细胞和胆红素水平，并使平均 LDH 水平低于正常上限的 1.5 倍。Iptacopan 最常见的不良反应是头痛。
结论
Iptacopan 治疗改善了接受过抗 C5 治疗且持续性贫血的患者（Iptacopan 治疗组优于抗 C5 治疗组）和未接受补体抑制剂治疗的患者的血液学和临床结局。（由诺华公司资助；APPLY-PNH 临床试验.gov 编号，NCT04558918；APPOINT-PNH 临床试验.gov 编号，NCT04820530。）
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