TY - JOUR
T1 - Randomised clinical trial
T2 - emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease
AU - Shiffman, Mitchell
AU - Freilich, Bradley
AU - Vuppalanchi, Raj
AU - Watt, Kymberly
AU - Chan, Jean L.
AU - Spada, Al
AU - Hagerty, David T.
AU - Schiff, Eugene
N1 - Funding Information:
Declaration of personal interests: Mitchell Shiffman has served on the advisory boards of Abbvie, Bayer, Bristol Myers‐Squibb, Dova, Gilead, Intercept, Merck, Salix, and Shionogi; has been a speaker for Abbvie, Bayer, Bristol Myers‐Squibb, Daiichi Sankyo, Dova, Enanta, Gilead, Intercept, Merck, Salix, and Shionogi; is a consultant for Optum Rx; and has received grant support from Abbvie, Bristol Myers‐Squibb, CymaBay, Conatus, Enanta, Exalenz, Galectin, Genfit, Gilead, Genky-otex, Intercept, Immuron, Merck, NGMBio and Novartis. Shire Kym-berly Watt has received grant support from Conatus, Gilead and Intercept. Raj Vuppalanchi has received grant support from Bristol Myers‐Squibb, Conatus, Gilead Sciences, Intercept and NGM Bio. Bradley Freilich has been a speaker for Gilead and Intercept and has received grant support from Abbvie, Advanced Accelerator Applications, Array Biopharma, Boston Mbiomedical, Conatus, Effector Pharmaceuticals, EMD Serono, Enanta Pharmaceuticals, Genfit, Gilead, Immuron Ltd, Intercept, NGM Bio, Novartis, Roche, Shire, SillaJen Inc, Synteract and Theravance Biopharma. Eugene Schiff has served on the advisory boards of Bristol‐Myers Squibb, Gilead and Merck; is a consultant for Dova and Arbutus Biopharma; and has received grant support from Beckman, Bristol‐Myers Squibb, Conatus, Discovery Life Sciences, Genfit, Gilead, Intercept, Novo Nordisk, Orasure Technologies, Ortho Diagnostics, Pfizer, Prometheus Lab, Roche Diagnostics, Shire, Siemens, Target Pharma Solutions, Tobira and Wiley. J. Chan, A. Spada, and D. Hagerty are employees of Conatus Pharmaceuticals Inc. A. Spada is a stockholder of Conatus Pharmaceuticals Inc. None of the authors own patents related to emricasan.
Funding Information:
Declaration of funding interests: This study and the preparation of this paper was funded in full by Conatus Pharmaceuticals Inc. The authors who are employees of Conatus Pharmaceuticals Inc. were involved in the data analysis and writing of the manuscript. There was no additional writing support.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
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U2 - 10.1111/apt.15030
DO - 10.1111/apt.15030
M3 - Article
C2 - 30430605
AN - SCOPUS:85056476199
VL - 49
SP - 64
EP - 73
JO - Alimentary Pharmacology and Therapeutics
JF - Alimentary Pharmacology and Therapeutics
SN - 0269-2813
IS - 1
ER -