美国Regeneron制药公司Olivier A Harari团队研究了帕泽利单抗治疗CD55缺乏症伴补体过度激活、血管性血栓形成和蛋白质丢失肠病的疗效和安全性。2024年1月23日出版的《柳叶刀》杂志发表了这项最新研究成果。

CD55缺乏症伴补体过度激活、血管性血栓形成和蛋白质丢失肠病（CHAPLE）是一种极为罕见的遗传性疾病，其特征是补体系统过度激活引起的肠道淋巴损伤、淋巴管扩张和蛋白质丢失性肠病。研究组评估了帕泽利单抗的有效性和安全性，它是一种阻断补体成分5的抗体。

这项开放标签、单臂、历史对照、多中心2期和3期研究在泰国、土耳其和美国的三家医院进行，评估了10名CHAPLE疾病患者。招募年龄在1岁及以上的患者，临床诊断为CHAPLE病，通过基因分析鉴定出CD55功能缺失变体，并通过流式细胞术或外周血细胞CD55蛋白印迹证实，符合该研究条件。患者接受单次静脉注射30 mg/kg体重的帕泽利单抗，然后在治疗期内根据体重每周皮下注射一次，浓度为200 mg/mL，单次注射（<40 kg体重）或两次注射（≥40 kg重量）。主要终点是与基线相比，在完整分析集中评估的第24周血清白蛋白正常化的患者比例，活跃临床结局有所改善，而非活跃临床结局（有问题的腹痛频率、排便频率、面部水肿严重程度和外周水肿严重程度）没有恶化。

研究组在2020年1月27日至2021年5月12日期间招募了11名患者，其中10人被纳入研究并纳入分析人群。疗效数据对应于完成第48周评估并至少接受52周治疗的所有患者，安全性数据包括额外的90天随访，对应于至少接受72周治疗的全部患者。患者主要来自儿科（中位年龄8.5岁），来自土耳其、叙利亚、泰国和玻利维亚。患者的年龄体重和身高在基线时明显较低，基线时的平均白蛋白为2.2 g/dL，远低于当地实验室参考范围。帕泽利单抗治疗后，所有10名患者的血清白蛋白均正常化和改善，临床结局没有恶化。总补体活性完全受到抑制。9名患者出现不良事件；两例为严重事件，一例患者出现与帕泽利单抗有关的不良事件。

研究结果表明，帕泽利单抗可抑制补体过度激活，并改善CHAPLE疾病的临床和实验室表现。帕泽利单抗是目前唯一获批的治疗这种危及生命、极为罕见的疾病的药物。在排除了已知病因的蛋白质丢失肠病患者中，应考虑检测CD55缺乏症。诊断为CHAPLE病应尽早考虑使用帕泽利单抗进行治疗。

附：英文原文

Title: Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study

Author: Ahmet Ozen, Voranush Chongsrisawat, Asena Pinar Sefer, Burcu Kolukisa, Jessica J Jalbert, Karoline A Meagher, Taylor Brackin, Hagit Baris Feldman, Safa Baris, Elif Karakoc-Aydiner, Rabia Ergelen, Ivan J Fuss, Heather Moorman, Narissara Suratannon, Kanya Suphapeetiporn, Lorah Perlee, Olivier A Harari, George D Yancopoulos, Michael J Lenardo, Jutta L. Miller, Orly Eshach Adiv, Sevgi Bilgic Eltan, Melek Yorgun Altunbas, Mary Magliocco, Helen Matthews, Beatriz E. Marciano, Pantipa Chatchatee, Caryn F. Trbovic, Michael E. Burczynski, Umesh Chaudhari, Yusuf Usta, Cansu Altunta, Sibel Yavuz, Ahmet Batürk, Fatma Demirba Ar, Erdem Topal, Ayhan Gazi Kalayc, Wanlapa Weerapakorn, Ana Andrea Calabi Martínez, Adriana Bottero

Issue&Volume: 2024-01-23

Abstract:

Background

CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5.

Methods

This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting.

Findings

11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab.

Interpretation

Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab.

DOI: 10.1016/S0140-6736(23)02358-9

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02358-9/abstract