Drug Overview
Cilofexor (Gilead), a nonsteroidal FXR agonist, is a ligand-activated nuclear hormone receptor that is a key regulator of bile acid synthesis, conjugation, and excretion. It is abundant in the liver, gallbladder, intestines, and kidney. Stimulation of FXR in the intestine by bile acids or an FXR agonist results in the release of fibroblast growth factor 19 (FGF19). FGF19 is a protective hormone and key regulator of post-prandial metabolism which is often reduced in patients with non-alcoholic steatohepatitis (NASH), insulin resistance, and metabolic syndrome. FGF19 moves to the liver through the portal circulation and binds to the fibroblast growth factor receptor 4 (FGFR4)/βKlotho receptor complex. This activates a signaling cascade which downregulates expression of cholesterol 7α-hydroxylase (CYP7A1), thus hindering the rate-limiting step in bile acid synthesis. In addition, activation of FXR in the liver increases expression of specific enzymes involved in canalicular and basolateral bile acid efflux, while inhibiting bile acid synthesis and basolateral bile acid uptake by hepatocytes.
Mixed results from a Phase II trial in NASH patients without cirrhosis cast doubt over the success of cilofexor monotherapy in a Phase III trial. Cilofexor failed to show a significant benefit in liver stiffness measured by magnetic resonance elastography (MRE) or FibroScan compared to placebo. Additionally, while there were improvements in some markers of hepatobiliary damage, only gamma-glutamyl transferase (GGT) and complement component 4 (C4) reached statistical significance. Given these underwhelming data on biomarkers of liver damage, cilofexor may struggle to compete with Ocaliva (obeticholic acid; Intercept Pharmaceuticals), which has already shown definitive reductions in liver fibrosis in the Phase III REGENERATE trial. On a positive note, cilofexor has a favorable safety profile compared to Ocaliva, as pruritis was less common, and while there were increases in cholesterol, they were not statistically significant. As a result, if cilofexor was to show an improvement in fibrosis in a Phase III trial, its cleaner safety profile would likely allow it to capture significant share from Ocaliva.
Cilofexor (Gilead), a nonsteroidal FXR agonist, is a ligand-activated nuclear hormone receptor that is a key regulator of bile acid synthesis, conjugation, and excretion. It is abundant in the liver, gallbladder, intestines, and kidney. Stimulation of FXR in the intestine by bile acids or an FXR agonist results in the release of fibroblast growth factor 19 (FGF19). FGF19 is a protective hormone and key regulator of post-prandial metabolism which is often reduced in patients with non-alcoholic steatohepatitis (NASH), insulin resistance, and metabolic syndrome. FGF19 moves to the liver through the portal circulation and binds to the fibroblast growth factor receptor 4 (FGFR4)/βKlotho receptor complex. This activates a signaling cascade which downregulates expression of cholesterol 7α-hydroxylase (CYP7A1), thus hindering the rate-limiting step in bile acid synthesis. In addition, activation of FXR in the liver increases expression of specific enzymes involved in canalicular and basolateral bile acid efflux, while inhibiting bile acid synthesis and basolateral bile acid uptake by hepatocytes.
Mixed results from a Phase II trial in NASH patients without cirrhosis cast doubt over the success of cilofexor monotherapy in a Phase III trial. Cilofexor failed to show a significant benefit in liver stiffness measured by magnetic resonance elastography (MRE) or FibroScan compared to placebo. Additionally, while there were improvements in some markers of hepatobiliary damage, only gamma-glutamyl transferase (GGT) and complement component 4 (C4) reached statistical significance. Given these underwhelming data on biomarkers of liver damage, cilofexor may struggle to compete with Ocaliva (obeticholic acid; Intercept Pharmaceuticals), which has already shown definitive reductions in liver fibrosis in the Phase III REGENERATE trial. On a positive note, cilofexor has a favorable safety profile compared to Ocaliva, as pruritis was less common, and while there were increases in cholesterol, they were not statistically significant. As a result, if cilofexor was to show an improvement in fibrosis in a Phase III trial, its cleaner safety profile would likely allow it to capture significant share from Ocaliva.
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