Obeticholic acid significantly reduces biochemical features of primary biliary cirrhosis (PBC) in patients with an inadequate response to ursodeoxycholic acid (UDCA) therapy, Gideon M. Hirschfield et al report in the April issue of Gastroenterology.
Hirschfield discusses the details of the study and its findings in a video abstract:
PBC is a progressive, autoimmune cholestatic liver disease characterized by lymphocytic cholangitis and intralobular bile duct destruction, leading to fibrosis, cirrhosis, and liver failure. The only approved treatment is UDCA, a hydrophilic, noncytotoxic bile acid. Not all patients respond to this drug.
Hirschfield et al investigated the effects of obeticholic acid (OCA, INT-747), a semi-synthetic analogue of the primary bile acid chenodeoxycholic acid, which selectively activates the nuclear hormone receptor farnesoid X receptor (FXR). FXR is a nuclear receptor that senses bile acids and regulates their levels in hepatocytes.
Hirschfield et al performed a 3-month trial to determine the effects of adding different doses of OCA (10, 25 and 50 mg) or placebo to UDCA therapy in 165 patients with PBC but an inadequate response to UDCA. The primary endpoint was change in alkaline phosphatase levels between baseline and week 12.
Almost all the patients were women (95%), with baseline levels of alkaline phosphatase 1.5- to 10-fold the upper limit of normal.
Hirschfield et al observed that all 3 doses of OCA produced significant decreases in alkaline phosphatase levels, compared between baseline, at week 12. Levels of alkaline phosphatase decreased an average of 21%–25% from baseline in the OCA groups vs 3% in the placebo group.
“More than two-thirds of patients receiving OCA had a 20% drop in alkaline phosphatase levels, and one-third had a 40% drop in levels,” Hirschfield says in the video.
Among secondary end points, levels of γ-glutamyl transpeptidase decreased an average of 48%–63% in subjects given OCA (vs a 7% decrease in the placebo group). Levels of alanine aminotransferase decreased an average of 21%–35% in subjects given OCA, but did not decrease in the placebo group.
“In the open-label 12-month extension study of OCA, the decrease in levels of alkaline phosphatase levels was maintained, while levels of bile acids and their precursors decreased,” said Hirshfield. He added that there were significant safety concerns. Pruritus was the major side effect, leading to dose reductions in some and treatment discontinuation in 13% of subjects.
In an editorial that accompanies the article, Brent A. Neuschwander-Tetri explains that activation of FXR by OCA reduces levels of bile acids in hepatocytes (see figure).
OCA activates FXR to reduce hepatocyte levels of bile acids and thereby reduce injury of the of biliary epithelium. FXR activation can also decrease lipogenesis, so OCA might be used to treat patients with nonalcoholic steatohepatitis (NASH). In patients with PBC or NASH, decreasing the synthesis of bile acids from cholesterol alters the serum pool of cholesterol, however, which might increase risk of cardiovascular disease.
Hirschfeld concludes that OCA could be a new drug for patients with PBC, who currently lack any additional therapy. “Hopefully this drug has potential for development and might be used to treat other cholestatic and inflammatory liver diseases,” he says in the video.
However, Neuschwander-Tetri adds that more studies are needed to determine whether the changes in alkaline phosphatase levels observed translate into improved liver histology, and whether changes in lipid levels have cardiovascular affects.
Neuschwander-Tetri says that we need to better understand the pathogenesis of PBS and NASH so we can specifically target the immunologic and metabolic abnormalities that cause them.