Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA.
Aspen Woods Clinic, Calgary, Alberta, Canada.
Hepatol Commun. 2023 May 15;7(6). doi: 10.1097/HC9.0000000000000153. eCollection 2023 Jun 1.
Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.
This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.
Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.
Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.
原发性硬化性胆管炎（PSC）常伴有瘙痒，显著降低生活质量。马拉利昔巴特是一种选择性回肠胆汁酸转运蛋白（IBAT）抑制剂，可降低循环胆汁酸（BA）水平并减少胆汁淤积性肝病的瘙痒。这是在 PSC 中首次进行的 IBAT 抑制作用的概念验证研究。
这项开放标签研究评估了马拉利昔巴特在 PSC 成人患者中每天≤10mg 治疗 14 周的安全性和耐受性。还评估了瘙痒、BA 合成、胆汁淤积和肝功能的生物标志物。
27 名入组的参与者中，85.2%完成了治疗。81.5%的患者出现胃肠道治疗相关不良事件（TEAE），其中 51.9%为腹泻。TEAE 多为轻中度（63.0%）；1 例严重 TEAE（胆管炎）被认为与治疗相关。治疗 14 周/早期终止（ET）时，平均血清 BA（sBA）水平下降 16.7%（-14.84µmol/L；95%CI，-27.25 至-2.43；p=0.0043）。在基线 sBA 水平高于正常的参与者（n=18）中，平均 sBA 下降 40.0%（-22.3µmol/L，95%CI，-40.38 至-4.3；p=0.004），治疗 14 周/ET。肝酶升高不显著；然而，观察到结合胆红素水平升高，但其临床意义未知。瘙痒 RO 每周总和评分从基线到 ET 第 14 周下降 8.4%（p=0.0495），在基线时有瘙痒的 18 名参与者中下降 12.6%（p=0.0275），在基线时瘙痒 RO 平均每日评分≥3 的 8 名参与者中下降 70%（p=0.0078）。
马拉利昔巴特与 PSC 成人患者 sBA 水平降低有关。在基线瘙痒更严重的参与者中，瘙痒从基线显著改善。TEAE 多与胃肠道相关。这些结果支持进一步研究 IBAT 抑制剂治疗 PSC 相关瘙痒。ClinicalTrials.gov：NCT02061540。
