背景:进行性家族性肝内胆汁淤积(PFIC)是一组常染色体隐性遗传疾病,最普遍的是BSEP缺乏症,导致胆汁形成中断,胆汁淤积,还有瘙痒.在先前的第二阶段研究的基础上,我们旨在评估回肠胆汁酸转运体抑制剂maralixibat在所有类型PFIC参与者中的疗效和安全性.
方法:MARCH-PFIC是多中心,随机化,双盲,安慰剂对照,在欧洲16个国家的29个社区和医院中心进行的第3阶段研究,美洲,和亚洲。我们招募了年龄为1-17岁的PFIC持续瘙痒的参与者(>6个月;在过去4周的筛查中,早晨瘙痒报告的结果[观察者;ItchRO(Obs)]平均≥1·5)和进行性肝病的生化异常或病理证据,或者两者兼而有之。我们定义了三个分析队列。BSEP(或主要)队列仅包括双等位基因,非截短的BSEP缺乏症,没有低或波动的血清胆汁酸或以前的胆道手术。全PFIC队列将BSEP队列与患有双等位基因FIC1,MDR3,TJP2或MYO5B缺陷的参与者相结合,没有先前手术但不考虑胆汁酸。整个队列没有排除。参与者被随机分配(1:1)接受口服maralixibat(起始剂量142·5μg/kg,然后升级到570μg/kg)或安慰剂,每天两次,持续26周。主要终点是BSEP队列中基线和15-26周之间的平均早晨ItchRO(Obs)严重程度评分的平均变化。关键次要疗效终点是BSEP队列中基线与第18、22和26周平均值之间总血清胆汁酸的平均变化。在意向治疗人群(所有随机分配的人群)中进行疗效分析,并在接受至少一剂研究药物的所有参与者中进行安全性分析。这项已完成的试验已在ClinicalTrials.gov注册,NCT03905330和EudraCT,2019-001211-22。
结果:在2019年7月9日至2022年3月4日之间,对125名患者进行了筛查,其中93人被随机分配到maralixibat(n=47;BSEP队列14人,全PFIC队列33人)或安慰剂(n=46;BSEP队列17人,全PFIC队列31人),至少接受了一剂研究药物,并纳入意向治疗和安全性人群.中位年龄为3·0岁(IQR2·0-7·0),93名参与者中有51名(55%)为女性,42名(45%)为男性。在BSEP队列中,maralixibat早晨ItchRO(Obs)从基线的最小二乘平均变化为-1·7(95%CI-2·3至-1·2),安慰剂为-0·6(-1至-0·1),组间差异为-1·1(95%CI-1·8至-0·3;p=0·0063)。血清总胆汁酸从基线的最小二乘平均变化为-176μmol/L(95%CI-257至-94),安慰剂为11μmol/L(-58至80),也代表-187μmol/L的显着差异(95%CI-293至-80;p=0·0013)。最常见的不良事件是腹泻(服用maralixibat的47例患者中有27[57%],服用安慰剂的46例患者中有9例[20%];均为轻度或中度,且大部分为短暂性)。maralixibat组中有5名(11%)参与者出现严重的因治疗引起的不良事件,而安慰剂组中有3名(7%)。无治疗相关死亡发生。
结论:Maralixibat改善了PFIC中瘙痒和天然肝脏存活的预测因子(例如,血清胆汁酸)。Maralixibat代表非手术,药物选择中断肝肠循环和改善PFIC患者的护理标准。
背景:Mirum制药。
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC.
METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22.
RESULTS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred.
CONCLUSIONS: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC.
BACKGROUND: Mirum Pharmaceuticals.