4月 27, 2023

关于PNH

阵发性夜间血红蛋白尿症（PNH）是一种获得性克隆性造血干细胞疾病，全球发病率约为1~2/百万, 亚洲地区发病率相较西方更高[1-3]。PNH患者体内PIG-A基因突变，导致血细胞表面上重要的补体调节蛋白CD55和CD59缺失。因此，细胞更易被补体激活[4]。临床主要表现为溶血、骨髓造血功能衰竭和血栓形成等[5]。抗补体C5疗法是既往国际公认的PNH标准治疗，但抗C5治疗后，仍有大部分患者有残留贫血、疲乏和输血依赖，生活质量受到严重影响[5-9]。

Iptacopan是由诺华研发的首个靶向补体旁路途径B因子的口服抑制剂[10-12]。本届欧洲血液与骨髓移植学会（EBMT）年会上，首次公布iptacopan关键性III期APPOINT-PNH研究达到主要终点[13]。

iptacopan关键性III期APPOINT-PNH研究主要终点和重要次要终点

Iptacopan作为特异性补体B因子抑制剂，作用于C5末端通路上游，能够同时控制血管内溶血和血管外溶血，弥补了抗C5抗体的不足，同时为患者提供了口服单药的治疗新选择[10-12]。Iptacopan还获得了国家药品监督管理局药品审评中心（CDE）“突破性治疗药物”认定[14]。

除PNH治疗外，iptacopan目前也处于其他许多补体介导疾病（CMD）的关键研究阶段，包括肾脏疾病C3肾小球病（C3G）、IgA肾病（IgAN）、非典型溶血性尿毒症综合征（aHUS）、膜性肾病（MN）、狼疮性肾炎（LN）以及免疫性血小板减少性紫癜（ITP）和冷凝集素病（CAD）[15-17]。

基于作用机制和临床疗效的显著优势，iptacopan有望打破现有治疗格局，重新定义PNH治疗标准。

关于APPOINT研究

APPOINT-PNH（NCT04820530）是一项单臂、开放标签、多中心、III期临床试验，评估iptacopan单药治疗未接受过补体抑制剂（包括抗C5抗体）治疗的PNH成人患者的疗效和安全性[13]。

该研究入组40例，平均血红蛋白（Hb）＜10g/dL、乳酸脱氢酶（LDH)＞1.5x正常值上限且未接受过补体抑制剂治疗的成人PNH患者，给予iptacopan单药200mg每日两次治疗[13]。

该研究的主要终点是24周以内在不输注红细胞（RBCT）情况下达到血红蛋白水平较基线升高≥2g/dl的患者比例。次要终点包括血红蛋白水平≥12g/dL（无RBCT）、避免输血患者比例、血红蛋白水平较基线变化、FACIT-疲乏评分较基线变化、网织红细胞绝对计数（ARC）较基线变化、LDH水平较基线百分比变化、临床突破性溶血发生率、主要不良血管事件发生率[13]。

声明
1. Iptacopan目前尚未在中国大陆获批。
2. 本资料目的在于提供疾病领域的相关知识、提高疾病认知的水平、非广告用途。
3. 本资料中涉及的信息仅供参考，请遵从医生或其他医疗卫生专业人士的意见或指导。

参考文献
[1]Korkama E-S et al. EHA Learning Center. Kjellander C. 2018;214791; PF314.

[2]Morado M et al. Clin Cytom. 2017;92:361-370.

[3]PNH Registry (2013) PNH National Service- Leeds and London

[4]Hill A, et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017;3:17028.

[5]Risitano AM and Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics 2008;2(2):205–222.

[6]Risitano AM. Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol. 2013;735:155–72.

[7]Hill A, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010;95(4):567–573.

[8]Risitano AM. Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. Transl Med UniSa. 2014;8:43–52.

[9]Debureaux P, et al. Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals. Blood. 2019;134(Suppl 1):3517.

[10]Jang JH, et al. Iptacopan Effectively Controls Intra- And Extravascular Hemolysis And Leads To Durable Hemoglobin Increase In Patients With Treatment-Naïve PNH. Abstract presented at the 26th Annual Congress of the European Hematology Association (EHA) 2021. 

[11]Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A. 2019;116(16):7926-7931. doi:10.1073/pnas.1820892116.

[12]Novartis. Data on file.

[13]A.M. Risitano, et al. Oral complement factor B inhibitor iptacopan monotherapy improves hemoglobin to normal/near-normal levels in paroxysmal nocturnal hemoglobinuria patients naÏve to complement inhibitors: Phase III APPOINT-PNH trial. OS12-06; 2023 EBMT.

[14]Available at https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f01…. Accessed April 2023.

[15]Clinicaltrials.gov. Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. (APPEAR-C3G). Available at https://clinicaltrials.gov/ct2/show/NCT04817618. Accessed September 2022.

[16]Clinicaltrials.gov. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). Available at https://clinicaltrials.gov/ct2/show/NCT04578834. Accessed September 2022.

[17]Clinicaltrials.gov. Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy (APPELHUS). Available at https://clinicaltrials.gov/ct2/show/NCT04889430. Accessed September 2022.