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 μg/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 μg/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 μmol/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 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/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.

Funding

Mirum Pharmaceuticals.

中文翻译：

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马拉利昔布治疗 Alagille 综合征和胆汁淤积性瘙痒症 (ICONIC) 患者的疗效和安全性：一项随机 2 期研究

背景

Alagille 综合征是一种罕见的遗传性疾病，通常表现为严重的胆汁淤积和瘙痒。没有批准的管理药物。Maralixibat 是一种顶端的钠依赖性胆汁酸转运抑制剂，可防止肠肝胆汁酸再循环。我们评估了马拉利昔布治疗 Alagille 综合征胆汁淤积儿童的安全性和有效性。

方法

ICONIC 是一项安慰剂对照、随机停药期 (RWD) 的 2b 期研究，对患有 Alagille 综合征的儿童（1-18 岁）进行开放标签扩展 (NCT02160782)。符合条件的参与者的血清胆汁酸 (sBA) 水平是正常的三倍以上，并且有顽固性瘙痒。在 18 周的 maralixibat 380 μg/kg 每天一次后，参与者被随机分配 (1:1) 继续使用 maralixibat 或接受安慰剂 4 周。随后，所有参与者在第 48 周之前都接受了开放标签的马拉利昔单抗。在长期延长期间（报告为 204 周），剂量增加至 380 μg/kg，每天两次。主要终点是参与者在 RWD 期间的平均 sBA 变化，到第 18 周时 sBA 降低至少 50%。胆汁淤积性瘙痒症使用观察者评定、患者评定和临床医生评定的 0-4 级量表进行评估。安全人群定义为所有接受过至少一剂马拉利昔布的参与者。该试验已在 ClinicalTrials.gov 注册，NCT02160782，目前已停止招募。

发现

2014 年 10 月 28 日至 2015 年 8 月 14 日期间，31 名参与者（平均年龄 5·4 岁 [SD 4·25]）入组，其中 28 名在第 48 周进行了分析。在进入随机停药期的 29 名参与者中，10 (34%) 为女性，19 人 (66%) 为男性。在 RWD 中，改用安慰剂的参与者 sBA（94 μmol/L，95% CI 23 至 164）和瘙痒（1·7 分，95% CI 1·2 至 2·2）显着增加，而继续使用安慰剂的参与者maralixibat 保持治疗效果。该研究达到了主要终点（最小均方差 –117 μmol/L，95% CI –232 至 –2）。从基线到第 48 周，sBA（–96 μmol/L，–162 到 –31）和瘙痒（–1·6 分，–2·1 到 –1·1）有所改善。在持续到第 204 周（n=15）的参与者中，所有的改善都得以维持。Maralixibat 在整个过程中通常是安全的并且耐受性良好。最常见的不良事件与胃肠道有关。大多数不良事件本质上是自限性的，严重程度为轻度至中度。

解释

据我们所知，在患有 Alagille 综合征的儿童中，maralixibat 是第一个在胆汁淤积方面表现出持久且具有临床意义的改善的药物。Maralixibat 可能代表了 Alagille 综合征中慢性胆汁淤积的新治疗模式。

资金

米鲁姆制药。