Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study
Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study
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DOI：
10.1016/s0140-6736(21)01256-3
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发表时间：
2021-10-30
期刊：
影响因子：
168.9
通讯作者：
Jacquemin, Emmanuel
中科院分区：
文献类型：
--
作者：
Gonzales, Emmanuel;Hardikar, Winita;Jacquemin, Emmanuel
背景Alagille综合征是一种罕见的遗传性疾病，常表现为严重的胆汁淤积和瘙痒。没有批准的药物用于管理。Maralixibat是一种顶端钠依赖性胆汁酸转运抑制剂，可防止肝肠胆汁酸再循环。我们评估了maralixibat的安全性和有效性为儿童胆汁淤积在Alagille syndrome.Methods ICONIC是一个安慰剂对照，随机停药期（RWD），2b期研究与开放标签扩展的儿童（1-18岁）与Alagille综合征（NCT 02160782）。合格的参与者血清胆汁酸（sBA）水平超过正常值的三倍，并且存在顽固性瘙痒。maralixibat 380 μ g/kg，每天一次，18周后，参与者被随机分配（1：1）继续maralixibat或接受安慰剂4周。随后，所有参与者接受开放标签maralixibat直至第48周。在长期扩展期间（报告204周），剂量增加至380 μ g/kg，每天两次。主要终点是第18周sBA降低至少50%的受试者在RWD期间的平均sBA变化。使用患者评定、患者评定和临床医师评定的0-4级量表评估胆汁淤积性瘙痒。安全性人群定义为至少接受过一剂maralixibat的所有受试者。结果2014年10月28日至2015年8月14日期间，31名受试者（平均年龄5.4岁[SD 4.25]）入组，28名受试者在第48周进行了分析。ClinicalTrials.gov在进入随机停药期的29名参与者中，10名（34%）为女性，19名（66%）为男性。在RWD中，转换为安慰剂的受试者的sBA（94 μ mol/L，95% CI 23 - 164）和瘙痒（1.7分，95% CI 1.2 - 2.2）显著增加，而继续接受maralixibat的受试者维持了治疗效果。本研究符合主要终点（最小二乘均值差-117 μ mol/L，95% CI-232至-2）。从基线至第48周，sBA（-96 μ mol/L，-162至-31）和瘙痒（-1.6例患者，-2.1至-1.1）改善。在持续至第204周的参与者中（n=15），所有改善均得以维持。Maralixibat总体上是安全的，并且耐受性良好。最常见的不良事件与胃肠道相关。大多数不良事件是自限性的性质和轻度至中度的severity.Interpretation在Alagille综合征的儿童，maralixibat是，据我们所知，第一个代理显示持久的和临床上有意义的改善胆汁淤积。Maralixibat可能代表Alagille综合征慢性胆汁淤积的新治疗模式。版权所有（C）2021爱思唯尔有限公司保留所有权利。
Background Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.Methods ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 mu g/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 mu g/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.Findings Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5.4 years [SD 4.25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 mu mol/L, 95% CI 23 to 164) and pruritus (1.7 points, 95% CI 1.2 to 2.2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 mu mol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 mu mol/L, -162 to -31) and pruritus (-1.6 pts, -2.1 to -1.1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.Interpretation In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Copyright (C) 2021 Elsevier Ltd. All rights reserved.