Gautam Mehta1, Sam Rousell2, Gary Burgess3, Mark Morris2, Gavin Wright4, Stuart McPherson5, Catherine Frenette6, Matthew Cave7, David T Hagerty8, Alfred Spada8, Rajiv Jalan1. 1. Institute for Liver and Digestive Health, Royal Free Campus, UCL, London, UK. 2. Clinical Outcomes Solutions, Folkestone, UK. 3. Vectura Group PLC, Chippenham, UK. 4. Department of Gastroenterology, Basildon and Thurrock University Hospitals NHS Foundation Trust, Basildon, UK. 5. Liver Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 6. Department of Organ Transplantation, Scripps Green Hospital, San Diego, USA. 7. Department of Medicine, University of Louisville School of Medicine, Louisville, USA. 8. Conatus Pharmaceuticals Inc., San Diego, USA.
Abstract
BACKGROUND: Cirrhosis and acute-on-chronic liver failure (ACLF) are associated with systemic inflammation, and caspase-mediated hepatocyte cell death. Emricasan is a novel, pan-caspase inhibitor. Aims of this study were to assess the pharmacokinetics, pharmacodynamics, safety and clinical outcomes of emricasan in acute decompensation (AD) of cirrhosis. METHODS: This was a phase 2, multicentre, double-blind, randomized trial. The primary objective was to evaluate the pharmacokinetics, pharmacodynamics and safety of emricasan in patients with cirrhosis presenting with AD and organ failure. AD was defined as an acute decompensating event ≤6 weeks' duration. Patients were randomized proportionately to emricasan 5 mg bid, emricasan 25 mg bid, emricasan 50 mg bid or placebo. Treatment was continued to 28 days, or voluntary discontinuation. RESULTS: Twenty-three subjects were randomized, of whom 21 were dosed (placebo n = 4; 5 mg n = 5; 25 mg n = 7; 50 mg n = 5). Pharmacokinetic data showed 5 mg dose was associated with low plasma levels (<50 ng/ml), and 25 mg and 50 mg doses showed comparable pharmacokinetic profiles. Therefore, for analysis of secondary endpoints, placebo and 5 mg groups were merged into a 'placebo/low-dose' group, and 25 mg and 50 mg groups were merged into a 'high-dose' group. Five deaths occurred amongst the 21 patients, all due to progression of liver disease (2 in placebo/low-dose, 3 in high-dose). No statistically significant changes from baseline MELD score or CLIF-C ACLF score were noted between placebo/low-dose and high-dose groups at day 7 (MELD -1 vs -1, CLIF-C ACLF 0.7 vs 0.8). An initial reduction in cleaved keratin M30 fragment was noted between placebo/low-dose and high-dose groups (percent relative change: day 2: -11.6 vs -42.6, P = 0.017, day 4: -3.5 vs -38.9 P = 0.017) although this did not persist to day 7 (-3.1 vs -20.8, P = 0.342). CONCLUSION: This study demonstrates that emricasan is safe and well tolerated in advanced liver disease. However, this study fails to provide proof-of-concept support for caspase inhibition as a treatment strategy for ACLF. TRIAL REGISTRATION: EudraCT 2012-004245-33.
BACKGROUND: Cirrhosis and acute-on-chronic liver failure (ACLF) are associated with systemic inflammation, and caspase-mediated hepatocyte cell death. Emricasan is a novel, pan-caspase inhibitor. Aims of this study were to assess the pharmacokinetics, pharmacodynamics, safety and clinical outcomes of emricasan in acute decompensation (AD) of cirrhosis. METHODS: This was a phase 2, multicentre, double-blind, randomized trial. The primary objective was to evaluate the pharmacokinetics, pharmacodynamics and safety of emricasan in patients with cirrhosis presenting with AD and organ failure. AD was defined as an acute decompensating event ≤6 weeks' duration. Patients were randomized proportionately to emricasan 5 mg bid, emricasan 25 mg bid, emricasan 50 mg bid or placebo. Treatment was continued to 28 days, or voluntary discontinuation. RESULTS: Twenty-three subjects were randomized, of whom 21 were dosed (placebo n = 4; 5 mg n = 5; 25 mg n = 7; 50 mg n = 5). Pharmacokinetic data showed 5 mg dose was associated with low plasma levels (<50 ng/ml), and 25 mg and 50 mg doses showed comparable pharmacokinetic profiles. Therefore, for analysis of secondary endpoints, placebo and 5 mg groups were merged into a 'placebo/low-dose' group, and 25 mg and 50 mg groups were merged into a 'high-dose' group. Five deaths occurred amongst the 21 patients, all due to progression of liver disease (2 in placebo/low-dose, 3 in high-dose). No statistically significant changes from baseline MELD score or CLIF-C ACLF score were noted between placebo/low-dose and high-dose groups at day 7 (MELD -1 vs -1, CLIF-C ACLF 0.7 vs 0.8). An initial reduction in cleaved keratin M30 fragment was noted between placebo/low-dose and high-dose groups (percent relative change: day 2: -11.6 vs -42.6, P = 0.017, day 4: -3.5 vs -38.9 P = 0.017) although this did not persist to day 7 (-3.1 vs -20.8, P = 0.342). CONCLUSION: This study demonstrates that emricasan is safe and well tolerated in advanced liver disease. However, this study fails to provide proof-of-concept support for caspase inhibition as a treatment strategy for ACLF. TRIAL REGISTRATION: EudraCT 2012-004245-33.
Entities:
Keywords:
ACLF, acute-on-chronic liver failure; AD, acute decompensation; ALT, alanine aminotransferase; ANCOVA, analysis of covariance; AST, aspartate aminotransferase; Bid, Bis in die (twice a day); DL, decilitre; HCV, hepatitis C virus; INR, international normalised ratio; MELD, model for end-stage liver disease; Mg, milligrams; TNF, tumour necrosis factor; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; apoptosis; cell death; cirrhosis; liver failure
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