EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

Ratziu, Vlad; Rinella, Mary E.; Neuschwander‐Tetri, Brent A.; Lawitz, Eric; Denham, Douglas; Kayali, Zeid; Sheikh, Aasim; Kowdley, Kris V.; Desta, Taddese; Elkhashab, Magdy; DeGrauw, Jeffery; Goodwin, Bryan; Ahmad, Alaa; Adda, Nathalie

doi:10.1016/j.jhep.2021.10.018

Cited by 57 publications

(49 citation statements)

References 37 publications

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“…The prevalence of pruritus in controlled clinical trials with obeticholic acid, cilofexor, and EDP-305 was 19%, 4%, 15%, and 4% at baseline in placebo-treated individuals, respectively [7,[24][25][26]; however, these data are difficult to compare with the Japanese data and our real-life data due to the study-specific selection of patients. As pruritus seems to be a major symptom in individuals with NAFLD, standardized evaluation prior to therapy with FXR agonists should be considered.…”

Section: Discussionmentioning

confidence: 79%

“…Patient-reported outcomes are increasingly important in NAFLD, and pruritus is of special interest for evolving therapies with FXR agonists. Clinical trials with this drug class have started to investigate pruritus in controlled prospective settings and described a prevalence of 4-19% in placebo-treated individuals [ 7 , 24 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Subgroup analyses on the prevalence of pruritus in patients with diabetes mellitus, anxiety, or depression and the potential impact on the tolerability of FXR agonists have not been performed in the clinical NASH trials published so far [ 7 , 24 , 25 , 26 ]. Hence, drug therapy with FXR agonists should be critically evaluated in NAFLD patients who already complain about clinically significant pruritus prior to treatment initiation.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease

et al. 2022

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Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze associations with anxiety and depression. Pruritus was assessed using a visual analogue- (VAS) and 5-D itch-scale (5-D). Anxiety and depression were evaluated by Beck’s-Depression-Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS-A, HADS-D). An optimal logistic regression model was found with a stepwise procedure to investigate variables associated with pruritus. In total, 123 NAFLD patients were recruited. VAS and 5-D were highly correlated (Spearman’s correlation coefficient 0.89). Moderate/severe pruritus was reported in 19% (VAS) and 21% (5-D) of patients. Anxiety and depression were present in 12% and 4% (HADS-A and HADS-D, respectively) and 12% (BDI) of cases. There was a significant association between VAS and BDI (p = 0.019). The final multivariate model for 5-D included diabetes mellitus (OR 4.51; p = 0.01), BDI (OR 5.98; p = 0.024), and HADS-A (OR 7.75; p = 0.011). One-fifth of NAFLD patients reported moderate or severe pruritus. 5-D was significantly associated with diabetes mellitus, depression, and anxiety. These findings should be tested in larger populations and considered in candidates for treatment with FXR agonists.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease

et al. 2022

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“…EDP-305 at a dose of 2.5 mg reduced ALT levels (–27.9 U/L, P =0.049) and liver fat (–7.1%, P =0.0009). However, pruritus occurred in 50.9% of patients in the 2.5 mg group [ 18 ].…”

Section: Targeting Bile Acid Receptors/farnesoid X Receptormentioning

confidence: 99%

State-of-the-Art Overview of the Pharmacological Treatment of Non-Alcoholic Steatohepatitis

Cho

Lee

2022

Endocrinol Metab

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, can progress to cirrhosis, hepatocellular carcinoma, and death. Nevertheless, the current treatment for NAFLD/NASH is limited to lifestyle modifications, and no drugs are currently officially approved as treatments for NASH. Many global pharmaceutical companies are pursuing the development of medications for the treatment of NASH, and results from phase 2 and 3 clinical trials have been published in recent years. Here, we review data from these recent clinical trials and reports on the efficacy of newly developed antidiabetic drugs in NASH treatment.

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“…Finally, a novel non-bile acid class FXR agonist containing steroid and non-steroid components was recently shown to reduce liver fat in non-cirrhotic patients with fibrotic NASH at 2.5 mg/d. Patients receiving 2.5 mg/d EDP-305 ( n = 53) showed decreased HDL-C, increased apoB concentrations and a strong trend towards increased LDL-C compared to placebo ( n = 24), while plasma triglyceride levels were not affected [ 141 ].…”

Section: Bile Acid Synthesis and Plasma Lipidsmentioning

confidence: 99%

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

Zhang

Kuipers

Boer

et al. 2021

JCM

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New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.

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EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

Cited by 57 publications

References 37 publications

Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease

Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease

State-of-the-Art Overview of the Pharmacological Treatment of Non-Alcoholic Steatohepatitis

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

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