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.

Trial registration: ClinicalTrials.gov NCT02943460.

© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

Figures

Figure 1

Cilofexor improves serum ALP in patients with PSC. (A) Median (IQR) serum ALP between baseline and week 12 of the double‐blind phase of the study. (B) Median absolute change in serum ALP from baseline to week 12 of therapy. P values versus placebo are according to Wilcoxon rank‐sum test. (C) Median (IQR) change in serum ALP relative to the ULN between baseline and week 12 of therapy. (D) Median relative (percentage) change in serum ALP from baseline to week 12 of therapy (overall and according to UDCA treatment). P values versus placebo are according to Wilcoxon rank‐sum test.

Figure 2

Effect of cilofexor on liver biochemistry and markers of fibrosis and bile acid homeostasis. (A) Cilofexor 100 mg leads to improvement in serum GGT, ALT, AST, and TIMP‐1 compared with placebo. P values for cilofexor 100 mg versus placebo are according to Wilcoxon rank‐sum test. (B) Cilofexor leads to reductions in C4, total bile acids, primary bile acids, and secondary bile acids compared with placebo. Total bile acids by enzymatic assay and bile acid species by LC/MS‐MS. UDCA and its conjugates have been removed from secondary bile acids. P values for cilofexor 100 mg versus placebo are according to Wilcoxon rank‐sum test. Abbreviations: BA, bile acid; HA, hyaluronic acid.

Figure 3

Cilofexor 100 mg lowers serum bile acids, but does not alter bile acid composition. (A) Absolute levels of serum bile acid species before and after 12 weeks of treatment with cilofexor 100 mg daily. UDCA and its conjugates have been removed. (B) Relative contribution of serum bile acid species before and after 12 weeks of treatment with cilofexor 100 mg daily. UDCA and its conjugates have been removed. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; GCA, glycocholic acid; GCDCA: glycochenodeoxycholic acid; GDCA, glycolithocholic acid; GLCA, glycolithocholic acid; LCA, lithocholic acid; TCA: taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid.

Figure 4

Relative changes in liver biochemistry, markers of fibrosis, and other biomarkers according to achievement of an ALP response, defined as at least a 25% relative reduction in serum ALP from baseline to week 12, in cilofexor‐treated patients. Responder subgroup includes 7 patients treated with cilofexor 100 mg and 1 patient treated with cilofexor 30 mg. P values are according to Wilcoxon rank‐sum test. Abbreviations: BA, bile acid; HA, hyaluronic acid.