Non-alcoholic steatohepatitis (NASH) is an increasingly common liver disease that lacks a cure with pharmacological therapies.1,2 Recently released findings from the phase 3 REGENERATE trial demonstrated a significant improvement in NASH related liver fibrosis by obeticholic acid, offering a potential treatment option. The results of the trial were presented at the International Liver Congress (ILC) 2019, held in Vienna, Austria.3
NASH is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by the presence of steatosis, hepatocellular ballooning and lobular inflammation.4 The condition is associated with rapid progression of fibrosis, which can eventually lead to the development of cirrhosis and hepatocellular carcinoma.4 Obeticholic acid, the first drug being tested for NASH, is an activator of farnesoid X receptor. Farnesoid X receptors are involved in regulating genes responsible for lipid-glucose metabolism, liver regeneration and inflammation.5 The REGENERATE trial enrolled a total of 931 individuals with biopsy-confirmed NASH and stage 2 or 3 fibrosis. Among them, 308 received obeticholic acid 25mg daily, 312 received 10mg daily, and 311 received placebo.3
The primary end point was the resolution of NASH with no worsening of fibrosis or an improvement in fibrosis of at least one stage. A significant proportion of patients who received 25mg of obeticholic acid achieved an improvement in fibrosis by one stage (95% CI: 0.23-0.12; p=0.0002).3 Even though the end point of NASH resolution was not met, more patients in the 25mg group than in the placebo group improved in hepatocellular ballooning (95% CI: 0.35-0.23; p=0.0011) and in lobular inflammation (95% CI: 0.44-0.36; p=0.0322).3 Additionally, a dose dependent reduction in liver enzymes was observed with both 25mg and 10mg of obeticholic acid.
At the press briefing revealing the results of REGENERATE trial, the lead author of the study Prof. Zobair Younossi, Virginia Commonwealth University, Fairfax, USA, commented “The fibrosis data are very interesting and constitutes the first promising data of obeticholic acid’s efficacy in NASH”.6
Pruritis was the major adverse event reported in REGENERATE and was dose dependent. It was reported in 51% of the patients in the 25mg group, 28% in the 10mg group, and 19% in the placebo group.3 Withdrawal due to pruritus was observed among 9% of patients in the 25mg group.3 Pruritus is not only the adverse effect associated with the drug, as instances of mis-dosing may cause hepatic decompensation and liver failure.7
Currently, the treatments recommended for NASH are lifestyle changes towards healthy diet and habitual physical activity, highlighting the clinical significance of the REGENERATE trial.1 “Up until now, trying to lose weight has been the only way to take action, therefore the trial results are exciting for patients,” commented Prof. Philip Newsome, University Birmingham, United Kingdom.6 He further mentioned that a targeted approach towards NASH could facilitate a sustainable recovery faster than lifestyle modifications only.
With hepatic inflammation, patients may experience fatigue, malaise and anxiety. Prof. Newsome stated that by reducing inflammation with obeticholic acid, these patient-reported outcomes could be relieved.6 Additionally, suppressing inflammation could prevent scarring of the liver and promote healing of liver cirrhosis.
Prof. Younossi concluded the session by saying, “There is an urgent need for effective treatment regimens for NASH, a common liver disease which can lead to cirrhosis, liver failure and need for transplant. These first results from the REGENERATE study give us hope that a new targeted approach to NASH treatment may soon become available and potentially reverse some of the liver damage associated with this important liver disease”.6
1. European Association for the Study of the Liver (EASL). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402.
2. Golabi P, Paik J, Reddy R et al. Prevalence and long-term outcomes of non-alcoholic fatty liver disease among elderly individuals from the United States. BMC Gastroenterol. 2019;19(1):56.
3. Younossi Z, Ratziu V, Loomba R et al. GS-06-Positive Results from REGENERATE: A Phase 3 International, Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for NASH (Abstract). J Hepatol.2019;70(1):e5.
4. Lucas C, Lucas G, Lucas N et al. A systematic review of the present and future of non-alcoholic fatty liver disease. Clin Exp Hepatol. 2018;4(3):165-174.
5. Farnesoid X Receptor – an overview | ScienceDirect Topics. (Accessed May 28, 2019 at, https://www.sciencedirect.com/topics/neuroscience/farnesoid-x-receptor).
6. Obeticholic acid improves liver fibrosis and other histological features of nonalcoholic steatohepatitis (NASH) – The International Liver CongressTM 2019, EASL 2019. (Accessed May 27, 2019 at, https://ilc-congress.eu/press-release/obeticholic-acid-improves-liver-fibrosis-and-other-histological-features-of-nonalcoholic-steatohepatitis-nash/).
7. Misdosing Ocaliva for Liver Disorder Can Be Fatal, FDA Says. (Accessed May 27, 2019 at, https://www.medscape.com/viewarticle/886048).