Cilofexor Fails to Improve Outcomes in Primary Sclerosing Cholangitis
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on April 17th, 2026
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Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and fibrosis of the bile ducts, which can ultimately progress to cirrhosis and liver failure. Despite its severity, there are currently no approved disease-modifying treatments. Ursodeoxycholic acid is commonly used in practice, but it has not been shown to improve survival or key clinical outcomes. A recent study published in the Lancet evaluated the efficacy of cilofexor, a farnesoid X receptor (FXR) agonist, in patients with PSC.
Funding Source(s): Gilead Sciences
The phase 3 clinical study enrolled 416 patients with a mean age of 43 years who had confirmed PSC. Liver fibrosis was staged using the Ludwig classification: 18% had no fibrosis, 27% had portal fibrosis (F1), 29% had periportal fibrosis (F2), and 25% had septal fibrosis (F3). Baseline laboratory tests showed mean alanine aminotransferase and aspartate aminotransferase levels of 50 U/L and 39 U/L, respectively.
Participants were randomly assigned to receive either placebo or cilofexor at a dose of 100 mg once daily. Disruption of bile acid homeostasis is thought to play a central role in PSC progression. Activation of FXR in the liver and intestine reduces bile acid synthesis, decreases hepatic uptake, and enhances excretion, thereby limiting bile acid accumulation. Cilofexor is a nonsteroidal FXR agonist designed to target these pathways.
After 96 weeks of treatment, cilofexor did not demonstrate a significant benefit over placebo. There was no reduction in the progression of liver fibrosis, nor were there meaningful differences in liver stiffness, bile acid levels, or patient-reported outcomes. Subgroup analyses showed no benefit across different fibrosis stages or baseline alkaline phosphatase levels. Additionally, cilofexor was associated with a higher incidence of pruritus. These findings suggest that FXR activation with cilofexor does not alter disease progression in PSC, underscoring the continued need for effective therapeutic options for this condition.
Funding Source(s): Gilead Sciences
The phase 3 clinical study enrolled 416 patients with a mean age of 43 years who had confirmed PSC. Liver fibrosis was staged using the Ludwig classification: 18% had no fibrosis, 27% had portal fibrosis (F1), 29% had periportal fibrosis (F2), and 25% had septal fibrosis (F3). Baseline laboratory tests showed mean alanine aminotransferase and aspartate aminotransferase levels of 50 U/L and 39 U/L, respectively.
Participants were randomly assigned to receive either placebo or cilofexor at a dose of 100 mg once daily. Disruption of bile acid homeostasis is thought to play a central role in PSC progression. Activation of FXR in the liver and intestine reduces bile acid synthesis, decreases hepatic uptake, and enhances excretion, thereby limiting bile acid accumulation. Cilofexor is a nonsteroidal FXR agonist designed to target these pathways.
After 96 weeks of treatment, cilofexor did not demonstrate a significant benefit over placebo. There was no reduction in the progression of liver fibrosis, nor were there meaningful differences in liver stiffness, bile acid levels, or patient-reported outcomes. Subgroup analyses showed no benefit across different fibrosis stages or baseline alkaline phosphatase levels. Additionally, cilofexor was associated with a higher incidence of pruritus. These findings suggest that FXR activation with cilofexor does not alter disease progression in PSC, underscoring the continued need for effective therapeutic options for this condition.