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. 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 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 () and is active but not recruiting. 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. 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. Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

中文翻译：

---

评估 pozelimab 对 CD55 缺乏伴补体过度激活、血管性血栓形成和蛋白丢失性肠病患者的疗效和安全性：一项开放标签 2 期和 3 期研究

CD55 缺乏伴补体过度激活、血管性血栓形成和蛋白质丢失性肠病 (CHAPLE) 是一种极其罕见的遗传性疾病，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。我们评估了 pozelimab（一种阻断补体成分 5 的抗体）的有效性和安全性。这项开放标签、单臂、历史对照、多中心 2 期和 3 期研究评估了 10 名患有 CHAPLE 疾病的患者。这项研究是在泰国、土耳其和美国的三家医院进行的。临床诊断为 CHAPLE 病且通过遗传分析鉴定并通过流式细胞术或外周血细胞 CD55 免疫印迹证实的功能丧失变异的 1 岁或以上患者有资格参加本研究。患者接受单次静脉注射泊泽利单抗负荷剂量 30 mg/kg 体重，然后在治疗期间根据体重每周一次皮下注射，浓度为 200 mg/mL，单次注射（<40 kg）体重）或两次注射（≥40公斤体重）。主要终点是与第 24 周相比，血清白蛋白正常化且活动临床结果有所改善且非活动临床结果（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）没有恶化的患者比例基线，在完整的分析集中进行评估。这项研究已在 () 注册，并且正在进行中，但尚未招募。 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名患者参加了研究并纳入分析人群。功效数据对应于完成第 48 周评估并接受至少 52 周治疗的所有患者，安全性数据包括额外 90 天的随访，对应于所有接受至少 72 周治疗的患者。患者主要是儿童（中位年龄为 8·5 岁），来自土耳其、叙利亚、泰国和玻利维亚。患者基线时的年龄别体重和年龄别身材明显较低，基线时的平均白蛋白为 2·2 g/dL，大大低于当地实验室参考范围。波泽利单抗治疗后，所有 10 名患者的血清白蛋白均恢复正常并有所改善，临床结果没有恶化。总补体活性完全受到抑制。九名患者出现不良事件；两名患者为严重事件，一名患者发生了被认为与波泽利玛相关的不良事件。 Pozelimab 可抑制补体过度激活并解决 CHAPLE 病的临床和实验室表现。 Pozelimab 是目前唯一批准用于治疗这种危及生命的极其罕见疾病的患者的治疗药物。在排除已知原因的蛋白质丢失性肠病患者中，应考虑检测 CD55 缺陷。 CHAPLE 病的诊断应导致及早考虑使用波泽利单抗治疗。再生元制药公司和美国国立卫生研究院国家过敏和传染病研究所校内研究部。