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EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. BACKGROUND & AIMS: EDP-305 is an oral farnesoid X receptor (FXR) agonist under development for treating nonalcoholic steatohepatitis (NASH). The efficacy, safety, and tolerability of EDP-305 was evaluated in a Phase 2, randomized, double-blind, placebo-controlled study. METHODS: Non-cirrhotic patients with fibrotic NASH diagnosed by historical biopsy or phenotypically (high body mass index, diagnosis of diabetes (type 2 diabetes/prediabetes), and elevated alanine aminotransferase (ALT) with liver fat content >8% by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), were randomized to EDP-305 1 mg, EDP-305 2.5 mg, or placebo, for 12 weeks. The primary endpoint was mean change from baseline to Week 12 for ALT, and the key secondary endpoint was mean change from baseline to Week 12 in liver fat content. RESULTS: Between January 2018 and July 2019, 134 patients were randomized and 132 were evaluated. At Week 12, least squares (LS) mean reduction from baseline for ALT for patients receiving 2.5 mg EDP-305 and 1 mg EDP-305 was -27.9 U/L (95% CI 0.03 to 24.9; p=0.049) and -21.7 U/L (-5.8 to 18.3: p=0.304), respectively, compared to -15.4 U/L for those receiving placebo. Absolute liver fat reduction was -7.1% (2.0-7.5; p=0.0009) with 2.5 mg EDP-305, -3.3% with EDP-305 1 mg, and -2.4% with placebo. The most common (≥5%) adverse events were pruritus, nausea, vomiting, diarrhea, headache, and dizziness. Pruritus occurred in 50.9%, 9.1%, and 4.2% of patients in the 2.5 mg, 1 mg, and placebo groups, respectively, and 20.8% of patients in the 2.5 mg group and 1.8% in the 1 mg group discontinued. CONCLUSIONS: EDP-305 reduced ALT levels and MRI-PDFF supporting development of EDP-305 in patients with NASH in a longer-term trial assessing liver histology. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic diseases that progresses to non-alcoholic steatohepatitis (NASH), leading to an increased risk of cirrhosis and the need for liver transplant. Results from this Phase 2 study support continued development of EDP-305, an oral farnesoid X receptor (FXR) agonist, for the treatment of patients with NASH. CLINICALTRIALS. GOV NUMBER: NCT03421431.