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

Publication ,  Journal Article
Trauner, M; Gulamhusein, A; Hameed, B; Caldwell, S; Shiffman, ML; Landis, C; Eksteen, B; Agarwal, K; Muir, A; Rushbrook, S; Lu, X; Xu, J ...
Published in: Hepatology
September 2019

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.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

September 2019

Volume

70

Issue

3

Start / End Page

788 / 801

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Severity of Illness Index
  • Reference Values
  • Receptors, Cytoplasmic and Nuclear
  • Prognosis
  • Middle Aged
  • Male
  • Logistic Models
  • Liver Function Tests
  • Humans
 

Citation

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Trauner, M., Gulamhusein, A., Hameed, B., Caldwell, S., Shiffman, M. L., Landis, C., … Kowdley, K. V. (2019). The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology, 70(3), 788–801. https://doi.org/10.1002/hep.30509
Trauner, Michael, Aliya Gulamhusein, Bilal Hameed, Stephen Caldwell, Mitchell L. Shiffman, Charles Landis, Bertus Eksteen, et al. “The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis.Hepatology 70, no. 3 (September 2019): 788–801. https://doi.org/10.1002/hep.30509.
Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C, et al. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019 Sep;70(3):788–801.
Trauner, Michael, et al. “The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis.Hepatology, vol. 70, no. 3, Sept. 2019, pp. 788–801. Pubmed, doi:10.1002/hep.30509.
Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C, Eksteen B, Agarwal K, Muir A, Rushbrook S, Lu X, Xu J, Chuang J-C, Billin AN, Li G, Chung C, Subramanian GM, Myers RP, Bowlus CL, Kowdley KV. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019 Sep;70(3):788–801.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

September 2019

Volume

70

Issue

3

Start / End Page

788 / 801

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Severity of Illness Index
  • Reference Values
  • Receptors, Cytoplasmic and Nuclear
  • Prognosis
  • Middle Aged
  • Male
  • Logistic Models
  • Liver Function Tests
  • Humans