The development of effective drug therapies for fatty liver diseases was a key topic at the International Liver Congress (ILC), 10-14 April in Vienna. Obeticholic acid (OCA) effectiveness in the treatment of non-alcoholic fatty liver disease NAFLD/NASH has been demonstrated for the first time in an interim analysis of the Phase-III REGENERATE study. (See source 1).
Obeticholic acid (OCA) is already approved for the treatment of primary biliary cholangitis (PBC) and acts as a selective agonist at the nuclear farnesoid X receptor (FXR), reducing the bile acid concentration in liver cells. The ongoing REGENERATE study is investigating OCA in a group of patients with non-alcoholic steatohepatitis (NASH) and liver fibrosis. In view of the presentation of the data at the International Liver Congress (ILC), Prof. Dr. Zobair Younossi from Inova Fairfax Medical Campus in Falls Church, Virginia, pointed to a direct antifibrotic effect of OCA demonstrated in preclinical models and an improvement in fibrosis and other histological parameters in phase II. (See source 2).
In REGENERATE, patients receive OCA 25mg/d, OCA 10mg/d or placebo in a three-arm study design. A success is, in accordance with the criteria of the FDA, defined as achieving one of the two endpoints: Improvement of fibrosis by at least one degree without worsening NASH or healing of NASH without worsening fibrosis. A total of 2400 patients with biopsy-confirmed NASH with fibrosis of grade 2 or 3 and a NAFLD activity score of at least 4 will be included (see source 3).
The current evaluation includes approximately 300 patients per arm - OCA 10mg/d (n=312), OCA 25mg/d (n=308), placebo (n=311) - of which approximately 250 each completed the study. The endpoint of improving fibrosis by at least one degree without worsening NASH was reached. Under OCA 25mg 23.1% of patients achieved the study goal (p=0.0002 vs. placebo), under OCA 10mg 17.6% achieved the study goal (p=0.04 vs. placebo). In the per-protocol population, the efficacy was even more pronounced with 27.5% under OCA 25mg. The second endpoint (NASH healing) was not met. However, Younossi pointed to a number of related secondary endpoints. Thus, OCA 25mg was superior to a "definitive" NASH in terms of healing compared to placebo. The expansion of liver cell volume ("ballooning"), steatosis and lobular inflammation were also favorably influenced by OCA 25mg. In addition, a dose-dependent normalization of the transaminases occurred.
As expected, pruritus was the most common adverse event and occurred in 51% of patients with OCA 25mg/d, 28% with OCA 10mg/d and 19% with placebo. According to Younossi, this 19% could be interpreted as an indication that NASH may not be as asymptomatic as generally assumed. Pruritus was the cause of study termination in 9% of patients in the OCA-25mg group and in less than 1% in each of the remaining two arms. Under OCA there was an initial increase in LDL cholesterol, but the values approached the initial values again in the further course. Cardiovascular events were equally frequent in the three study arms.
Sources:
1. Younossi Z et al.: Positive results from REGENERATE: a phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH. Presented at ILC 2019, GS-06
2. Neuschwander-Tetri BA et al.: Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomized, placebo-controlled trial. Lancet 2015; 385(9972): 956-65
3. Ratzui V et al: REGENERATE: a phase 3, double-blind, randomized, placebo-controlled multicenter study of obeticholic acid therapy for nonalcoholic steatohepatitis. J Hepatol 2016; 64(2): S214-5