Projects per year
Abstract
BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years.
METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events.
RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups.
CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.
IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.
Original language | English |
---|---|
Pages (from-to) | 1110-1120 |
Number of pages | 11 |
Journal | Journal of Hepatology |
Volume | 79 |
Issue number | 5 |
Early online date | 28 Jul 2023 |
DOIs | |
Publication status | Published - Nov 2023 |
Bibliographical note
Acknowledgments:Medical writing assistance was provided by MedLogix Communications, LLC and was funded by Intercept Pharmaceuticals, Inc. PNN was supported by the Birmingham NIHR Biomedical Research Centre. This paper presents independent research supported in part by National Institute for Health and Care Research Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS foundation Trust and the University of Birmingham (grant reference number: BRC-1215-20009). The views expressed are those of author(s) and not necessarily those of NIHR or the Department of Health and Social Care.
Copyright:
© 2023 The Authors. Published by Elsevier B.V.
Keywords
- Liver fibrosis
- NASH
- nonalcoholic steatohepatitis
- obeticholic acid
- OCA
Fingerprint
Dive into the research topics of 'Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis'. Together they form a unique fingerprint.Projects
- 1 Finished
-
NIHR Biomedical Research Centre (BRC) - Core Theme
Barrett, T. (Co-Investigator), Adams, D. (Principal Investigator), Newsome, P. (Co-Investigator), Kyte, D. (Co-Investigator), Slade, A. (Co-Investigator) & Calvert, M. (Co-Investigator)
NIHR CENTRAL COMMISSIONING FACILITY
1/04/17 → 30/11/22
Project: Other Government Departments