Elsevier

The Lancet

Volume 394, Issue 10215, 14–20 December 2019, Pages 2184-2196
The Lancet

Articles
Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(19)33041-7Get rights and content

Summary

Background

Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.

Methods

In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.

Findings

Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).

Interpretation

Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Funding

Intercept Pharmaceuticals.

Introduction

Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of chronic liver disease, characterised by hepatocellular injury, inflammation, and progressive fibrosis. Models of disease progression project that the overall burden of end-stage liver disease due to NASH is likely to increase two to three times over the next two decades.1 Currently, there are no approved therapies for NASH.

The farnesoid X receptor is a nuclear receptor that plays a central role in the regulation of bile acids and metabolism.2 Recent data indicate that activation of the farnesoid X receptor can also reduce hepatic fibrosis and inflammation.2, 3, 4, 5 Previous placebo-controlled clinical studies have shown that obeticholic acid, a potent and selective farnesoid X receptor agonist, improves glucose disposal after short-term administration6 and key histological features of NASH, including fibrosis.7 Based on a previous phase 3 study, obeticholic acid was approved for the treatment of primary biliary cholangitis, a progressive autoimmune liver disease, in patients with an inadequate response to, or unable to tolerate, ursodeoxycholic acid.8 Collectively, this provided a strong rationale for assessing the efficacy and safety of obeticholic acid in patients with NASH and fibrosis in this pivotal phase 3 study.

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.

Liver-related outcomes in patients with NASH principally occur after the development of cirrhosis; halting progression to cirrhosis is therefore a key treatment goal. Given the length of time to progress to cirrhosis and clinical outcomes, a conditional approval pathway based on demonstration of histological improvement following at least 12 months of treatment is supported by the US Food and Drug Administration (FDA) and the European Medicines Agency.9, 10

The Randomised Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment (REGENERATE) study is a randomised, controlled, phase 3 study of obeticholic acid in patients with NASH and fibrosis.11 Here, we report the results of the prespecified month 18 interim analysis on the safety and efficacy of obeticholic acid in improving fibrosis and underlying disease activity.

Section snippets

Study design and participants

This multicentre, randomised, double-blind, placebo-controlled, phase 3 study is being conducted at 332 centres in 20 countries across the world. Eligible patients were adults (aged ≥18 years) with histological evidence of (per central expert pathologist reading of a liver biopsy obtained ≤6 months from randomisation) definite steatohepatitis; a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of at least 4, including at least one point for each of steatosis, lobular inflammation,

Results

Between Dec 9, 2015, and Oct 26, 2018, 1968 patients were enrolled and randomly assigned to one of the three treatment groups (figure 1). The ITT population included 931 patients randomised to receive placebo (n=311), obeticholic acid 10 mg (n=312), or obeticholic acid 25 mg (n=308). At the time of the interim analysis, 73 (23%) patients in the placebo group, 71 (23%) in the obeticholic acid 10 mg group, and 77 (25%) in the obeticholic acid 25 mg group had discontinued treatment (figure 1); 252

Discussion

To our knowledge, this study is the first positive phase 3 trial in NASH and represents a landmark in the development of new therapies for an increasingly common chronic liver disease.12, 13, 14, 15 Treatment with obeticholic acid 25 mg met the primary endpoint of improvement in fibrosis with no worsening of NASH in patients with stage F2 or F3 fibrosis, at the month-18 interim analysis. The robust antifibrotic effect of obeticholic acid was dose dependent and consistent across different

Data sharing

The authors declare that all data supporting the findings of this interim analysis are available within the Article and its appendix. The study is ongoing at the time of publication and blinded at the individual level; patient-level data therefore will not be available until the end-of-study analysis.

References (28)

  • S Modica et al.

    Deciphering the nuclear bile acid receptor FXR paradigm

    Nucl Recept Signal

    (2010)
  • RM Gadaleta et al.

    Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease

    Gut

    (2011)
  • YD Wang et al.

    Farnesoid X receptor antagonizes NF-κB in hepatic inflammatory response

    Hepatology

    (2008)
  • S Mudaliar et al.

    Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease

    Gastroenterology

    (2013)
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