Research in context
Evidence before this study
Non-alcoholic steatohepatitis (NASH) is a chronic progressive liver disease, which can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver-related death. Currently, there are no approved therapeutic options for NASH and treatment is largely limited to lifestyle modifications. We searched PubMed for clinical trials treating NASH published up to Sept 30, 2019, using the terms “nonalcoholic fatty liver disease”, “nonalcoholic steatohepatitis”, “NAFLD”, and “NASH”. Early clinical study results for several compounds with various mechanisms of action have shown evidence of improvement in steatohepatitis or fibrosis, but several such studies lacked placebo controls and none of these results have been confirmed in a pivotal phase 3 study setting. The farnesoid X receptor is a nuclear receptor expressed at high levels in the liver. In animal models of liver disease, activation of farnesoid X receptor has been associated with both anti-inflammatory and antifibrotic effects. The placebo-controlled phase 2b FLINT study showed that obeticholic acid, a potent selective farnesoid X receptor agonist, improved key histological features of NASH, including fibrosis. These promising results led to this randomised, placebo-controlled global phase 3 study of obeticholic acid in patients with fibrosis due to NASH (REGENERATE).
Added value of this study
To our knowledge, REGENERATE is the first positive phase 3 study in patients with NASH. In this interim analysis, a significantly higher proportion of patients treated with obeticholic acid 25 mg had an improvement of fibrosis by at least one stage with no worsening of NASH. Additionally, a post-hoc analysis showed that obeticholic acid treatment resulted in NASH resolution with no worsening of fibrosis based on pathologist diagnostic assessment. Obeticholic acid treatment also improved underlying disease activity, as shown by decreased lobular inflammation and hepatocellular ballooning. In addition to improvement in these key histological features, meaningful reduction in laboratory parameters, including robust normalisation of alanine aminotransferase and aspartate aminotransferase, was observed with obeticholic acid treatment. Consistent with previous obeticholic acid clinical studies, pruritus and increased LDL cholesterol were the most commonly reported adverse events. Pruritus incidence was generally mild to moderate in severity and dose dependent. Greater treatment discontinuation was seen in the obeticholic acid 25 mg group, mainly due to protocol requirements. Early increases in LDL cholesterol were observed with obeticholic acid treatment; however, levels approached baseline by month 18.
Implications of all the available evidence
Halting progression to cirrhosis, and therefore preventing serious liver-related outcomes, is a key treatment goal in patients with NASH with fibrosis. Advanced liver fibrosis is strongly associated with risk of liver-related adverse outcomes and all-cause mortality, so therapies with proven antifibrotic benefit are highly desirable. Because NASH disease progression occurs over a number of years, assessing clinical outcomes requires long-term evaluation. The positive results of the prespecified REGENERATE month-18 interim analysis are based on surrogate endpoints considered to be reasonably likely to predict clinical benefit, and the study is ongoing through clinical outcomes to confirm long-term benefit.