The nonsteroidal FXR agonist cilofexor (GS‐9674) improves markers of cholestasis and liver injury in patients with PSC

Abstract

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a Phase 2 double‐blind, placebo‐controlled study, we tested the safety and efficacy of cilofexor (formerly GS‐9674), a nonsteroidal farnesoid X receptor (FXR) agonist in non‐cirrhotic patients 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) >1.67xULN and total bilirubin ≤2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 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 IBD, 46% on UDCA). Baseline median serum ALP and bilirubin were 348 U/L (IQR 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 vs placebo), GGT (‐30%;p<0.001), ALT (‐49%;p=0.009), and AST (‐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 UDCA‐treated and untreated patients. At week 12, cilofexor‐treated patients with a ≥25% relative reduction in ALP had greater reductions in serum ALT, AST, GGT, TIMP‐1, CRP, and bile acids than non‐responders. 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. Conclusions 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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