Obeticholic acid from Intercept Phamaceuticals improved liver scarring in patients with non-alcoholic steatohepatitis.

 Non-alcoholic steatohepatitis (NASH) is estimated to affect 3–12% of U.S. adults. It occurs when fat builds up in the liver and lead to inflammation, which causes liver scarring and eventually cirrhosis. 

Estimates put the prevalence of NASH anywhere from as low as 3% of the U.S. adult population to as high as 12%. Interest in the development of treatments for NASH were initially sparked five years ago, when Intercept Pharmaceuticals achieved positive results for obeticholic acid in a small clinical trial.

Since then, many drug makers have been exploring the possibilities. Most have concluded that, owing to the complexity of NASH, successful treatment will require combination therapies. Despite this general consensus, Intercept is moving forward with its candidate. The company recently reported the results of a large phase III study of obeticholic acid.

It found in the REGENERATE study that treatment of patients with stage 2 or stage 3 liver fibrosis with obeticholic acid led to an improvement of one stage or greater in fibrosis without worsening of NASH at 18 months in 23% of patients given a high dose of the drug –– statistically higher than the 12% who saw a fibrosis improvement on placebo. When all patients, including those with stage 1 liver fibrosis, were included, the response rates were 21% and 11%, respectively. This late-stage study is the first to show an anti-fibrotic effect in NASH patients.

However, treatment with obeticholic acid did not resolve NASH in significantly more patients than placebo (12% vs. 8%). A lower dose of obeticholic acid did not perform as well. In addition, the side effects of obeticholic acid are concerning. Half of the patients on the high dose of the drug experienced dose-related pruritis, or itching, with severe pruritis occurring in 5%. According to the trial plan, any incidence of severe pruritus required treatment discontinuation, and pruritus-related halting of treatment was reported in 9% of patients given the higher dose. Pruritus is a notable side effect because many NASH patients do not see symptoms until later stages of the disease.

Despite the questions raised by the study, Intercepts plans to seek FDA and EMA approval for obeticholic acid later in 2019. If it is successful, it will be the first biopharma company to market a treatment for a disease that is expected in the near future to be the leading cause of liver transplants in the United States. There is competition on the horizon, however. French company Genfit will be reporting phase III results for its candidate selonsertib.