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
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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.
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Despite improved disease activity (hepatocellular ballooning and lobular inflammation), OCA showed no significant difference in resolution of steatohepatitis.
“Despite improved disease activity (hepatocellular ballooning and lobular in fl ammation) there was no signi fi cant difference in resolution of steatohepatitis.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [382]
In a large phase III registrational trial of individuals with MASH and significant fibrosis (cirrhosis excluded), OCA results were confirmed at interim analysis of 931 individuals and at subsequent analysis on 1,607 individuals by a different consensus pathologists' panel.
“These results were con fi rmed in a large phase III registrational trial of individuals with MASH and signi fi cant fi brosis (cirrhosis excluded) both at the interim analysis of 931 individuals 381 and at a subsequent analysis on 1,607 individuals by a different, consensus, pathologists ' panel.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [382]
At 25 mg daily, OCA achieved both a higher proportion of fibrosis improvement and a lower proportion of worsening than placebo.
“At 25 mg daily, OCA achieved both a higher proportion of fi brosis improvement and a lower proportion of worsening than placebo.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [382]
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- Authors
- Sanyal, A. J., Ratziu, V., Loomba, R., Anstee, Q. M., Kowdley, K. V., Rinella, M. E., Sheikh, M. Y., Trotter, J. F., Knapple, W., Lawitz, E. J., Abdelmalek, M. F., Newsome, P. N., Boursier, J., Mathurin, P., Dufour, J.-F., Berrey, M. M., Shiff, S. J., Sawhney, S., Capozza, T., Leyva, R., Harrison, S. A., & Younossi, Z. M.
- Affiliations
- Virginia Commonwealth University (US)
- Sorbonne Université (FR)
- University of California San Diego (US)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Liver Institute Northwest (US)
- University of Chicago (US)
- The University of Texas at San Antonio Health Science Center (US)
- Mayo Clinic (US)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Université d'Angers (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Intercept Pharmaceuticals (United States) (US)
- Pinnacle Clinical Research (US)
- Inova Health System (US)
- Corresponding author
- Sanyal, Arun J.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-11
- Volume
- 79
- Issue
- 5
- Pages
- 1110-1120
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W4385337271
- Cited by
- 137
- References
- 41
- Citations by year
- 2026: 42 · 2025: 45 · 2024: 46 · 2023: 4
- FWCI
- 27.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute for Health and Care Research (NIHR205082)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- obeticholic acid, nonalcoholic steatohepatitis, liver fibrosis, antifibrotic therapy, farnesoid X receptor agonist, NASH resolution, liver biopsy histology, pruritus, drug safety, long-term tolerability, benefit-risk profile, cirrhosis prevention
- MeSH terms
- Adult, Biopsy, Chenodeoxycholic Acid, Female, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Treatment Outcome, Non-alcoholic Fatty Liver Disease
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