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Dietary Carbohydrate Restriction in the Management of NAFLD and Metabolic Syndrome
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Grace Marie Jones, Kathleen Mulligan, Jean-Marc Schwarz, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Obeticholic acid, a synthetic variant of chenodeoxycholic acid, functions to activate the farnesoid X receptor (Cariou, van Harmelen et al. 2006, Porez, Prawitt et al. 2012). Activation of this receptor results in improved insulin sensitivity and decreases in hepatic gluconeogenesis and plasma triglyceride levels (Cariou, van Harmelen et al. 2006, Porez, Prawitt et al. 2012). A randomized controlled study evaluated the efficacy of obeticholic acid in 283 diabetic and nondiabetic volunteers with NASH (farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis study). After 72 weeks, twice the number of subjects treated with obeticholic acid had histological improvements compared to the placebo group (n = 50 [45%] versus n = 23 [21%]) (Neuschwander-Tetri, Loomba et al. 2015). Additionally, the NAFLD activity score and ALT were both reduced and significantly different between the two groups, favoring the treated group. The results of this study show obeticholic acid to be a promising treatment for NASH. However, 23% (n = 33 of 141) of the treatment group suffered from pruritus as compared to 6% (n = 9 of 142) in the placebo-controlled group and an increase in LDL and total cholesterol in the treatment group as compared to the control group. The long-term safety profile and efficacy of the drug requires further study.
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Presently, many FXR agonists are under development, indicated for different hepatic or metabolic diseases, including primary biliary cirrhosis, nonalcoholic steatohepatitis, and type II diabetes (Adorini et al. 2012; Ali et al. 2015; Crawley 2010; Fiorucci et al. 2007, 2010, 2012, 2014; Gioiello et al. 2014; Kemper 2011; Lindor 2011; Modica and Moschetta 2006; Mudaliar et al. 2013; Rader 2007; Silveira and Lindor 2014; Wang et al. 2008a). For example, obeticholic acid (i.e., INT-747), a potent selective FXR agonist, has completed a Phase III trial for the treatment of noncirrhotic, nonalcoholic steatohepatitis (Neuschwander-Tetri et al. 2015). The primary outcome measure is improvement in centrally scored liver histology defined as a decrease in nonalcoholic fatty liver disease activity score by at least two points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supports the decision to continue the trial and shows improved efficacy of obeticholic acid. The 141 patients are randomly assigned to receive obeticholic acid and 142 to placebo. Fifty (45%) of 110 patients in the obeticholic acid group show improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk, 1.9; 95% CI, 1.3 to 2.8; P = 0.0002). Thirty-three (23%) of 141 patients in the obeticholic acid group develop pruritus compared with 9 (6%) of 142 in the placebo group (Neuschwander-Tetri et al. 2015). Obeticholic acid is a 6a-ethyl derivative of the natural human bile acid chenodeoxycholic acid agonist that is ~100-fold more potent than chenodeoxycholic acid. In a Phase II clinical trial, administration of obeticholic acid is well tolerated, has increased insulin sensitivity, and has reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and nonalcoholic fatty liver disease (Mudaliar et al. 2013). In two clinical trials of obeticholic acid in patients with primary biliary cirrhosis, a progressive cholestatic liver disease, obeticholic acid significantly reduces serum alkaline phosphatase levels, an important disease marker that correlates well with clinical outcomes of patients with primary biliary cirrhosis (Hirschfield et al. 2015). FXR may represent a useful therapeutic target for the treatment of nonalcoholic fatty and cholestatic liver diseases, but more clinical studies are warranted to establish its safety and efficacy profiles.
Investigational drugs in early phase development for primary biliary cholangitis
Published in Expert Opinion on Investigational Drugs, 2021
Eric M. Gochanour, Kris V. Kowdley
It is important to note that a subset of patients has been shown to have no changes or worsened outcomes following OCA treatment [31,35,36]. Specifically, hepatotoxicity secondary to the use of OCA leading to deterioration in liver function with potential progression to liver failure has been identified and is postulated to be dose-related in patients with more advanced liver disease [35–37]. In response, the FDA has issued a warning that excessive dosing of obeticholic acid can lead to an increased risk of liver failure and death [36]. A black box warning was added to OCA packaging in 2017 by the FDA after 11 cases of significant liver injury were noted out of 19 reported deaths of patients taking OCA [36,37]. Six of these 11 patients were found to be taken higher than the recommended dose based on the severity of their liver disease [36,37]. Therefore, dosing of OCA should be adjusted based on liver function and patients with decompensated cirrhosis (Child-Pugh B or C) should be started on a dose of 5 mg weekly rather than 5 mg daily with close monitoring of liver enzymes [36,37]. The potential for worsened outcomes with the treatment of OCA further supports the need for alternative agents for the management of PBC.
Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH)
Published in Expert Opinion on Investigational Drugs, 2020
Stefano Fiorucci, Michele Biagioli, Valentina Sepe, Angela Zampella, Eleonora Distrutti
The most advanced FXR agonist is obeticholic acid, a semi-synthetic derivative of CDCA originally developed at the University of Perugia as 6-ethyl-CDCA and INT-747 [39] by investigators that later co-founded Intercept Pharmaceuticals (Roberto Pellicciari and Stefano Fiorucci). The obeticholic acid is the first in a class of FXR ligands that has reached a clinical stage [40–42] and was originally approved in 2016 as a second-line treatment for primary biliary cholangitis (PBC). This agent has recently completed a Phase 3 trial the REGENERATE study (Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment) for the treatment of patients with NASH and biopsy-proven fibrosis [43]. The results of this trial were that 23.1% of patients with NASH and F2 or F3 fibrosis who received 25-mg obeticholic acid and 11.9% of subjects who received placebo (P = 0.0002) demonstrated a ≥ 1 stage improvement in fibrosis without worsening of NASH. Pruritus, a common side effect of obeticholic acid, occurred in 51% of subjects receiving the active ingredient and 18% of subjects receiving placebo. Treatment discontinuation due to pruritus occurred in 9% of patients treated with obeticholic acid and 1% in the placebo group. Other side effects such gallstones and acute cholecystitis were more frequent in the obeticholic acid group than in the placebo (3% and <1%, respectively). Treatment with obeticholic acid associated with an increase in LDL cholesterol. The later results were consistent with the results of the Phase 2 FLINT study [44].
Emerging drugs for the treatment of primary biliary cholangitis
Published in Expert Opinion on Emerging Drugs, 2020
Naw April Phaw, Jessica Katharine Dyson, David Jones
Current treatment guidelines recommend Ursodeoxycholic acid (UDCA) (13–15 mg/kg) in all patients with PBC as first-line therapy [1]. Patients who present at young age (<45 years) or those with premature ductopenic variant or with advanced liver fibrosis (median liver stiffness >9.6 kPa) are considered to be at high risk of progressing to advanced disease requiring liver transplantation [5]. The biochemical response to therapy should be evaluated after 1 year of standard therapy with UDCA using the proposed criteria (Table 1) [5]. Failure to respond to therapy is associated with poorer outcomes and those patients should be considered for second-line treatment with Obeticholic acid, or off license therapy with fibrates (Bezafibrate 400 mg/day or Fenofibrate 200 mg/day) or a clinical trial [5]. Obeticholic acid should be commenced as an adjunct therapy although it can be used as monotherapy in patients who are intolerant to UDCA. The current recommended dose for Obeticholic acid is 5 mg/day but it can be titrated to 10 mg/day if patients fail to achieve the biochemical response after 6 months of treatment [5]. The dose should be reduced in patients with cirrhosis with the maximum dose being no more than 10 mg twice weekly. Patients who are intolerant of or do not respond to these therapies should be assessed for eligibility to participate in clinical trials. The treatment algorithm is as shown below (Figure 1).