The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis

被引：219

作者：

Trauner, Michael ^{[1
]}

Gulamhusein, Aliya ^{[2
]}

Hameed, Bilal ^{[3
]}

Caldwell, Stephen ^{[4
]}

Shiffman, Mitchell L. ^{[5
]}

Landis, Charles ^{[6
]}

Eksteen, Bertus ^{[7
]}

Agarwal, Kosh ^{[8
]}

Muir, Andrew ^{[9
]}

Rushbrook, Simon ^{[10
]}

Lu, Xiaomin ^{[11
]}

Xu, Jun ^{[11
]}

Chuang, Jen-Chieh ^{[11
]}

Billin, Andrew N. ^{[11
]}

Li, Georgia ^{[11
]}

Chung, Chuhan ^{[11
]}

Subramanian, G. Mani ^{[11
]}

Myers, Robert P. ^{[11
]}

Bowlus, Christopher L. ^{[12
]}

Kowdley, Kris V. ^{[13
]}

机构：

[1] Med Univ Vienna, Vienna, Austria

[2] Univ Toronto, Toronto, ON, Canada

[3] Univ Calif San Francisco, Sch Med, San Francisco, CA USA

[4] Univ Virginia, Charlottesville, VA USA

[5] Bon Secours Liver Inst, Richmond, VA USA

[6] Univ Washington, Sch Med, Seattle, WA USA

[7] Aspen Woods Clin, Calgary, AB, Canada

[8] Kings Coll London, London, England

[9] Duke Univ, Sch Med, Durham, NC USA

[10] Norfolk & Norwich Univ Hosp, Norwich, Norfolk, England

[11] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA

[12] Univ Calif Davis, Davis, CA 95616 USA

[13] Swedish Med Ctr, Liver Care Network & Organ Care Res, 1124 Columbia St St 600, Seattle, WA 98104 USA

来源：

HEPATOLOGY | 2019年 / 70卷 / 03期

关键词：

DOSE URSODEOXYCHOLIC ACID; ALKALINE-PHOSPHATASE; BILE-ACIDS; SURVIVAL; FIBROSIS; PREDICTS; PSC;

D O I：

10.1002/hep.30509

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 x upper limit of normal and total bilirubin <= 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7 alpha-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.

引用

页码：788 / 801

页数：14

共 24 条

[1] Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis [J].