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

Michael Trauner, Aliya Gulamhusein, Bilal Hameed, Stephen Caldwell, Mitchell L. Shiffman, Charles Landis, Bertus Eksteen, Kosh Agarwal, Andrew Muir, Simon Rushbrook, Xiaomin Lu, Jun Xu, Jen Chieh Chuang, Andrew N. Billin, Georgia Li, Chuhan Chung, G. Mani Subramanian, Robert P. Myers, Christopher Bowlus, Kris V. Kowdley

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)788-801
Number of pages14
JournalHepatology
Volume70
Issue number3
DOIs
StatePublished - Jan 1 2019

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Sclerosing Cholangitis
Cholestasis
Placebos
Liver
Alkaline Phosphatase
Wounds and Injuries
Bile Acids and Salts
Serum
Biochemistry
Transferases
Aspartate Aminotransferases
Alanine Transaminase
Bilirubin
Fibrosis
Safety
Ursodeoxycholic Acid
Tissue Inhibitor of Metalloproteinase-1
Pruritus
Inflammatory Bowel Diseases
C-Reactive Protein

ASJC Scopus subject areas

  • Hepatology

Cite this

The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. / Trauner, Michael; Gulamhusein, Aliya; Hameed, Bilal; Caldwell, Stephen; Shiffman, Mitchell L.; Landis, Charles; Eksteen, Bertus; Agarwal, Kosh; Muir, Andrew; Rushbrook, Simon; Lu, Xiaomin; Xu, Jun; Chuang, Jen Chieh; Billin, Andrew N.; Li, Georgia; Chung, Chuhan; Subramanian, G. Mani; Myers, Robert P.; Bowlus, Christopher; Kowdley, Kris V.

In: Hepatology, Vol. 70, No. 3, 01.01.2019, p. 788-801.

Research output: Contribution to journalArticle

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, JC, Billin, AN, Li, G, Chung, C, Subramanian, GM, Myers, RP, Bowlus, C & Kowdley, KV 2019, '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, pp. 788-801. https://doi.org/10.1002/hep.30509
Trauner, Michael ; Gulamhusein, Aliya ; Hameed, Bilal ; Caldwell, Stephen ; Shiffman, Mitchell L. ; Landis, Charles ; Eksteen, Bertus ; Agarwal, Kosh ; Muir, Andrew ; Rushbrook, Simon ; Lu, Xiaomin ; Xu, Jun ; Chuang, Jen Chieh ; Billin, Andrew N. ; Li, Georgia ; Chung, Chuhan ; Subramanian, G. Mani ; Myers, Robert P. ; Bowlus, Christopher ; Kowdley, Kris V. / The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. In: Hepatology. 2019 ; Vol. 70, No. 3. pp. 788-801.
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title = "The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis",
abstract = "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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T1 - The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis

AU - Trauner, Michael

AU - Gulamhusein, Aliya

AU - Hameed, Bilal

AU - Caldwell, Stephen

AU - Shiffman, Mitchell L.

AU - Landis, Charles

AU - Eksteen, Bertus

AU - Agarwal, Kosh

AU - Muir, Andrew

AU - Rushbrook, Simon

AU - Lu, Xiaomin

AU - Xu, Jun

AU - Chuang, Jen Chieh

AU - Billin, Andrew N.

AU - Li, Georgia

AU - Chung, Chuhan

AU - Subramanian, G. Mani

AU - Myers, Robert P.

AU - Bowlus, Christopher

AU - Kowdley, Kris V.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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