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.

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

“…The non‐steroidal FXR‐agonist, cilofexor has been shown to improve cholestasis and liver injury in a small trial with 52 patients who were randomized to receive a placebo and two groups with different doses of cilofexor. Treatment with the maximum dose of cilofexor over a period of 12 weeks led to a 21% decrease in ALP and to significant improvement in aminotransferase levels . Nor‐UDCA, a side‐chain modified derivate of UDCA, had dose‐dependent beneficial effects on ALP values in a phase II trial .…”

“…Treatment with the maximum dose of cilofexor over a period of 12 weeks led to a 21% decrease in ALP and to significant improvement in aminotransferase levels. 20 Nor-UDCA, a side-chain modified derivate of UDCA, had dose-dependent beneficial effects on ALP values in a phase II trial. 21 A phase III study with NorUDCA for PSC is ongoing.…”

Pediatric Cholestasis: Epidemiology, Genetics, Diagnosis, and Current Management

“…There is a paucity of effective anticholestatic therapeutics, but bile acid binding resins and ursodeoxycholic acid are empirically employed by many clinicians. More recently, attention to interference with the enterohepatic circulation of bile acids or FXR agonism may be direct anticholestatic approaches . Inhibition of ASBT has been recently used to address pruritus .…”

“…27 General management principles of neonatal cholestasis include attention to choice of an medium-chain triglyceride-enriched formula, increased kilocalories, along with fat-soluble vitamin supplementation, because cholestatic infants can have profound deficiencies of vitamins A, D, E, and K. 28 There is a paucity of effective anticholestatic therapeutics, but bile acid binding resins and ursodeoxycholic acid are empirically employed by many clinicians. More recently, attention to interference with the enterohepatic circulation of bile acids or FXR agonism [29][30][31] may be direct anticholestatic approaches. 10,32 Inhibition of ASBT has been recently used to address pruritus.…”

Novel Therapies for Managing Cholestasis

“…Three other FXR agonists are being studied for PBC: cilofexor (GS9674), LJN452, and EDP‐305 (Table , ongoing studies for PBC). Cilofexor was also studied in patients with PSC, with promising results (Table , ongoing studies for PSC).…”