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Randomized Controlled Trial
, 49 (1), 64-73

Randomised Clinical Trial: Emricasan Versus Placebo Significantly Decreases ALT and Caspase 3/7 Activation in Subjects With Non-Alcoholic Fatty Liver Disease

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Randomized Controlled Trial

Randomised Clinical Trial: Emricasan Versus Placebo Significantly Decreases ALT and Caspase 3/7 Activation in Subjects With Non-Alcoholic Fatty Liver Disease

Mitchell Shiffman et al. Aliment Pharmacol Ther.

Abstract

Background: Lipotoxicity leading to excessive caspase-mediated apoptosis and inflammation is believed to drive liver damage in NAFLD. Emricasan is a pan-caspase inhibitor that decreased serum ALT and apoptotic and inflammatory markers in subjects with chronic hepatitis.

Aims: To assess whether 28 days of emricasan would reduce elevated levels of serum ALT, AST, cleaved cytokeratin-18, full-length cytokeratin-18, and caspase 3/7 in subjects with NAFLD and raised aminotransferases.

Methods: Double-blind, placebo-controlled, office-practice study assessed the efficacy, safety, and tolerability of emricasan in subjects with NAFLD and ALT levels ≥1.5 x ULN during screening. Subjects were randomised to emricasan 25 mg twice daily or matching placebo. Subjects with cirrhosis and other causes for raised aminotransferases were excluded. The primary endpoint was the change in ALT at day 28 in the emricasan group vs placebo.

Results: 38 subjects were randomised, 19 each to emricasan or placebo. Baseline disease factors were well balanced except for lower median ALT values in emricasan subjects. Three subjects randomised to placebo discontinued prior to day 28. ALT values decreased significantly in emricasan-treated subjects vs placebo at days 7 (P < 0.0001) and 28 (P = 0.02). cCK18 (day 7), flCK18 (days 7 and 28), and caspase 3/7 (day 7) were also significantly decreased in emricasan-treated subjects vs placebo. Emricasan treatment was generally safe and well tolerated.

Conclusions: Emricasan decreased ALT and biomarkers in subjects with NAFLD and raised aminotransferases after 28 days. These results support the further development of emricasan in patients with NAFLD.

Trial registration: ClinicalTrials.gov, Identifier: NCT02077374.

Figures

Figure 1
Figure 1
Baseline and on‐treatment (days 7 and 28) values of ALT (mean, panel A) and AST (mean, panel B). On‐treatment values statistically different (P < 0.05) from placebo are indicated and the error bars are the standard deviation (SD) values
Figure 2
Figure 2
Individual subjects treated with emricasan or placebo. A, ALT values, emricasan treatment. B, ALT values, placebo. C, AST values, emricasan treatment. D, AST values, placebo
Figure 3
Figure 3
Baseline and on‐treatment (days 7 and 28) values of cCK18 (mean, panel A), flCK18 (mean, panel B), and caspase‐3/7 (median, panel C). On‐treatment values statistically different (P < 0.05) from placebo are indicated and the error bars are the standard deviation (SD) values

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