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The nonsteroidal FXR agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with PSC
Hepatology ( IF 13.5 ) Pub Date : 2019-03-10 , DOI: 10.1002/hep.30509
Michael Trauner 1 , Aliya Gulamhusein 2 , Bilal Hameed 3 , Stephen Caldwell 4 , Mitchell L Shiffman 5 , Charles Landis 6 , Bertus Eksteen 7 , Kosh Agarwal 8 , Andrew Muir 9 , Simon Rushbrook 10 , Xiaomin Lu 11 , Jun Xu 11 , Jen-Chieh Chuang 11 , Andrew N Billin 11 , Georgia Li 11 , Chuhan Chung 11 , G Mani Subramanian 11 , Robert P Myers 11 , Christopher L Bowlus 12 , Kris V Kowdley 13
Affiliation  

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double‐blind, placebo‐controlled study, we tested the safety and efficacy of cilofexor (formerly GS‐9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large‐duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α‐hydroxy‐4‐cholesten‐3‐one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288‐439) and 0.7 mg/dL (0.5‐1.0), respectively. Dose‐dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction −21%; P = 0.029 versus placebo), gamma‐glutamyl transferase (−30%; P < 0.001), alanine aminotransferase (ALT) (−49%; P = 0.009), and aspartate aminotransferase (−42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid–treated and untreated patients. At week 12, cilofexor‐treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, tissue inhibitor of metalloproteinase 1, C‐reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo‐treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12‐week, randomized, placebo‐controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.

中文翻译:

非甾体 FXR 激动剂 cilofexor (GS-9674) 可改善 PSC 患者的胆汁淤积和肝损伤标志物

原发性硬化性胆管炎 (PSC) 代表了主要的未满足的医疗需求。在一项 II 期双盲、安慰剂对照研究中,我们测试了非甾体法尼醇 X 受体激动剂 cilofexor(前身为 GS-9674)在患有大导管 PSC 的无肝硬化患者中的安全性和有效性。患者随机接受 cilofexor 100 mg (n = 22)、30 mg (n = 20) 或安慰剂 (n = 10) 口服,每天一次,持续 12 周。所有患者的基线血清碱性磷酸酶 (ALP) > 1.67 × 正常上限和总胆红素 ≤ 2 mg/dL。对cilofexor(血清C4 [7α-羟基-4-胆甾醇-3-one] 和胆汁酸)的安全性、耐受性、药效学作用以及肝脏生化和血清纤维化标志物的变化进行了评估。总体而言,52 名患者被随机分组​​(中位年龄 43 岁,58% 为男性,60% 患有炎症性肠病,46% 的熊去氧胆酸)。基线血清 ALP 和胆红素中位数分别为 348 U/L(四分位距 288-439)和 0.7 mg/dL(0.5-1.0)。观察到肝脏生化的剂量依赖性降低。在第 12 周,cilofexor 100 mg 导致血清 ALP 显着降低(中位数降低 -21%;与安慰剂相比,P = 0.029)、γ-谷氨酰转移酶(-30%;P < 0.001)、丙氨酸氨基转移酶(ALT)(-49 %;P = 0.009)和天冬氨酸转氨酶(-42%;P = 0.019)。与安慰剂相比,Cilofexor 降低了血清 C4;胆汁酸的减少量最大,为 100 毫克。熊去氧胆酸治疗和未治疗患者的 ALP 相对降低相似。在第 12 周,ALP 相对降低 25% 或更多的 cilofexor 治疗患者血清丙氨酸转氨酶、天冬氨酸转氨酶、γ-谷氨酰转移酶、金属蛋白酶 1、C 反应蛋白和胆汁酸的组织抑制剂比无反应者多。cilofexor 和安慰剂治疗的患者之间的不良事件相似。100mg 组 2 或 3 级瘙痒的发生率为 14%,30mg 组为 20%,安慰剂组为 40%。结论:在这项为期 12 周的随机安慰剂对照研究中,cilofexor 具有良好的耐受性,并显着改善了 PSC 患者的肝脏生化指标和胆汁淤积标志物。
更新日期:2019-03-10
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