背景:CD55缺乏与补体过度激活,血管病性血栓形成,和蛋白质丢失性肠病(CHAPLE)是一种罕见的遗传性疾病,其特征是肠淋巴损伤,淋巴管扩张症,和补体系统过度激活引起的蛋白质丢失性肠病。我们评估了pozelimab的疗效和安全性,阻断补体成分的抗体5.
方法:这个开放标签,单臂,历史控制,多中心2期和3期研究评估了10例CHAPLE疾病患者。这项研究是在泰国的三家医院进行的,蒂尔基耶,和美国。1岁或以上的患者具有CHAPLE疾病的临床诊断和通过遗传分析鉴定的CD55功能丧失变体,并通过流式细胞术或来自外周血细胞的CD55的蛋白质印迹证实,符合本研究的条件。患者接受了单次静脉内负荷剂量的pozelimab30mg/kg体重,然后在治疗期间,以200mg/mL的体重为基础,每周一次皮下给药,单次注射(<40kg体重)或两次注射(≥40kg体重)。主要终点是血清白蛋白正常化患者的比例,活跃的临床结局有所改善,不活跃的临床结局没有恶化(问题性腹痛的频率,排便频率,面部水肿严重程度,和外周水肿严重程度)在第24周与基线相比,在完整的分析集中评估。这项研究已在ClinicalTrials.gov(NCT04209634)注册,并且是活跃的,但没有招募。
结果:在2020年1月27日至2021年5月12日之间招募了11名患者,其中10名纳入研究并纳入分析人群。疗效数据对应于所有完成第48周评估并有至少52周治疗暴露的患者。安全性数据包括额外的90天随访,并对应于所有接受至少72周治疗的患者.患者主要为儿科(中位年龄为8·5岁),起源于蒂尔基耶,叙利亚,泰国,玻利维亚。基线时,患者的年龄体重和年龄身高明显较低,基线时平均白蛋白为2·2g/dL,远低于当地实验室参考范围。在Pozelimab治疗后,所有10例患者的血清白蛋白均恢复正常,且临床结局无恶化.存在对总补体活性的完全抑制。9例患者出现不良事件,2例为严重事件,1例患者出现与pozelimab相关的不良事件.
结论:Pozelimab抑制补体过度激活并解决CHAPLE疾病的临床和实验室表现。Pozelimab是目前唯一被批准用于这种危及生命的患者的治疗药物,非常罕见的情况。在已知原因已被排除的蛋白丢失性肠病患者中,应考虑检测CD55缺乏。CHAPLE疾病的诊断应导致早期考虑使用pozelimab治疗。
背景:再生时代制药和内部研究部门,国家过敏和传染病研究所,美国国立卫生研究院。
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.