近日，英国皇家维多利亚医院David Kavanagh团队研究了口服iptacopan治疗C3肾小球病变的疗效与安全性。2025年9月25日出版的《柳叶刀》杂志发表了这项成果。

肾小球病变是一种极为罕见、严重的肾小球肾炎，由替代补体通路过度激活引起。该研究旨在评估iptacopan （LNP023）的有效性和安全性，iptacopan是一种口服补体近端抑制剂，靶向因子B选择性地抑制补体级联的替代途径。

APPEAR-C3G是一项多中心、随机、双盲、安慰剂对照的iptacopan与安慰剂的3期研究（除了支持治疗[肾素-血管紧张素-醛固酮系统（RAAS）抑制剂]和免疫抑制外）。研究组从18个国家的35家医院或医疗中心招募了活检证实的C3肾小球病变的成年参与者（18 - 60岁）。纳入标准包括血清C3浓度降低(即：77 mg/dL[定义为：0.85 ×随机化前第75天和第15天的尿蛋白-肌酐比值（UPCR）为1.0 g/g或更高，筛查和第15天的肾小球滤过率（eGFR）估计为每1.73 m² 30 mL/min或更高，接种脑膜炎奈瑟菌和肺炎链球菌疫苗。所有符合条件的参与者通过互动反应技术被1:1随机分配到iptacopan组或安慰剂组，按皮质类固醇、霉酚酸或两者同时治疗进行分层（是或否）。在6个月的双盲期间，参与者口服iptacopan 200毫克，每日两次或安慰剂；随后是6个月的开放标签期，所有参与者每天两次接受200毫克iptacopan治疗。主要终点是6个月时蛋白尿的相对减少（通过从24小时尿液收集中采样的UPCR与基线的对数转化比来测量）。主要分析是在完整的分析集中进行的（即，随机分配研究治疗的所有参与者）；所有接受至少一剂研究治疗的参与者都被纳入安全性分析。

在2021年7月28日至2023年2月15日期间，对132名参与者进行了筛查，其中58名未完成筛查期，74名（64%男性，69%白人）被1:1随机分配，接受iptacopan （n=38）或安慰剂（n=36）。安慰剂组的一名参与者在开放标签期间停止了治疗。6个月时iptacopan组24小时UPCR相对于基线的百分比变化为- 30.2% (95% CI - 42.8至- 14.8)，安慰剂组为7.6%（- 11.9至31.3）。在iptacopan组，基线时24小时UPCR的几何平均值为3.33 g/g (95% CI 2.79 ~ 3.97)， 6个月时为2.17 g/g (1.62 ~ 2.91)；在安慰剂组，基线时为2.58 g/g(2.18至3.05)，6个月时为2.80 g/g（2.37至3.30）。主要终点是iptacopan与安慰剂相比，6个月时24小时UPCR相对降低35.1%（13.8至51.1;p= 0.0014）。iptacopan组38名参与者中有30人（79%）出现治疗后出现的不良事件，而安慰剂组36名参与者中有24人（67%）出现治疗后出现的不良事件；其中大多数是轻度或中度的严重程度。没有死亡，没有因治疗出现的不良事件而中断治疗，也没有脑膜炎球菌感染。伊他科泮组中有3名（8%）参与者报告了严重不良事件，安慰剂组中有1名（3%）参与者报告了严重不良事件。

研究结果表明，在6个月时，Iptacopan除了RAAS抑制剂和免疫抑制外，还显示有统计学意义的临床意义的蛋白尿减少。Iptacopan在C3肾小球病变患者中耐受性良好，具有可接受的安全性。

附：英文原文

Title: Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study

Author: David Kavanagh, Andrew S Bomback, Marina Vivarelli, Carla M Nester, Giuseppe Remuzzi, Ming-Hui Zhao, Edwin K S Wong, Yaqin Wang, Induja Krishnan, Imelda Schuhmann, Angelo J Trapani, Nicholas J A Webb, Matthias Meier, Rubeen K Israni, Richard J H Smith, Alejandra Ines Espinosa, Rita Marcela Fortunato, Magali Freijo Freijo, Nadia Fretes, Pablo Miguel Raffaele, Gianna Mastroianni Kirsztajn, Juliana Mansur Siliano, Laila Almeida Viana, Dervla Connaughton, Susan Huang, Faisal Rehman, Pavel Roshanav, Matthew A. Weir, Dong-Yuan Chang, Pei Chen, Bixia Gao, Ying Tan, Li Yang, Xiao-Juan Yu, Xin Zhang, Ming-Hui Zhao, Chuan-Ming Hao, Ling-Yun Lai, Shao-Jun Liu, Eva Jancova, Vladimir Tesar, Anne Blanchard, Sophie Chauvet, Nathalie Chavarot, Roxane Gaisset, Franois Provt, Myriam Dao, Hamza Sakhi, Aude Servais, Julia Weinmann-Menke, Ute Eisenberger, Anja Gckler, Benjamin Wilde, Anne Dieterle, Michael Wiesener, Tobias Huber, Malte Andreas Kluger, Eleftheria-Kleio Dermitzaki, Charikleia Gakiopoulou, Konstantinos Stylianou, Narayan Prasad, Dharmendra Singh Bhadauria, Dinesh Khullar, Soumita Bagchi, Naomi Ben-Dor, Valeria Morduhovich, Benaya Rozen-Zvi, Yael Borovitz, Daniel Landau, Camillo Carrara, Erica Daina, Amantia Imeraj, Maddalena Marasà, Piero Luigi Ruggenenti, Giuseppe Remuzzi, Luca Antonucci, Marcello Chinali, Antonio Gargiulo, Marina Vivarelli, Federica Zotta, Sosuke Fukui, Hangsoo Kim, Masashi Mizuno, Yasuhiro Suzuki, Shin Goto, Michihiro Hosojima, Hideyuki Kabasawa, Yoshikatsu Kaneko, Ryohie Kaseda, Ichiei Narita Narita, Tadashi Otsuka, Hirofumi Watanabe, Suguru Yamamoto, Motoki Matsuki, Naoki Nagakawa, Wataru Ohwada, Arata Osanami, Hidemichi Kouzu, Tomohisa Yamashita, Toshiyuki Yano, Hanneke Bouwsma, Aiko Popke Jan de Vries, Soufiane Meziyerh, Wouter Moest, Dennis A.J. Van den Broek, Y.K. Onno Teng, Teresa Cavero Escribano, Wenceslao Adrian Aguilera Morales, Francisco Jose de la Prada Alvarez, Fabiola Alonso Garcia, Mercedes Salgueira Lazo, Katarina Benackova, Uyen Huynh-Do, Laila-Yasmin Mani, Sibylle Tschumi, Asil Demirezen, zant Helvaci, Betul Ogut, Saliha Yildirim, David Kavanagh, Edwin K.S. Wong, Tom Cairns, Stephen Paul McAdoo, Liz Lightstone, Nicholas Medjeral-Thomas, Matthew Pickering, Wooin Ahn, Gerald B. Appel, Andrew S. Bomback, Pietro Canetta, Elizabeth Hendren, Allyson Medina

Issue&Volume: 2025-09-25

Abstract:

Background

C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway. We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.

Methods

APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin–angiotensin–aldosterone system (RAAS) inhibitors] and immunosuppression). Adult participants (aged 18–60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries. Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <0·85×lower limit of the central laboratory normal range]) at screening, urine protein–creatinine ratio (UPCR) of 1·0 g/g or higher at day –75 and day –15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 1·73 m2 or higher at screening and day –15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae. All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no). During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily. The primary endpoint was relative reduction in proteinuria (measured by log-transformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months. The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis. This trial was registered with ClinicalTrials.gov (NCT04817618) and the adult cohort has been completed.

Findings

Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36). One participant in the placebo group discontinued treatment during the open-label period. The 24-h UPCR percentage change relative to baseline at 6 months was –30·2% (95% CI –42·8 to –14·8) in the iptacopan group and 7·6% (–11·9 to 31·3) in the placebo group. In the iptacopan group, the geometric mean of 24-h UPCR was 3·33 g/g (95% CI 2·79 to 3·97) at baseline and 2·17 g/g (1·62 to 2·91) at 6 months; in the placebo group, this was 2·58 g/g (2·18 to 3·05) at baseline and 2·80 g/g (2·37 to 3·30) at 6 months. The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 35·1% (13·8 to 51·1; p=0·0014). 30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity. There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections. Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group.

Interpretation

Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months. Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy.

DOI: 10.1016/S0140-6736(25)01148-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01148-1/abstract