Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo

Catherine T. Frenette, Giuseppe Morelli, Mitchell L. Shiffman, R. Todd Frederick, Raymond A. Rubin, Michael B. Fallon, Jason T. Cheng, Matt Cave, Saira A. Khaderi, Omar Massoud, Nikolaos Pyrsopoulos, James S. Park, James M. Robinson, Mason Yamashita, Alfred P. Spada, Jean L. Chan, David T. Hagerty

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Results: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P =.003) and Child-Pugh (P =.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P =.466) or Child-Pugh (P =.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P =.02) and caspase 3/7 (P <.001), but not cleaved CK-18 (P =.092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

Original languageEnglish (US)
Pages (from-to)774-783.e4
JournalClinical Gastroenterology and Hepatology
Volume17
Issue number4
DOIs
StatePublished - Mar 1 2019

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End Stage Liver Disease
Fibrosis
Placebos
Liver
Keratin-18
International Normalized Ratio
Fatty Liver
Bilirubin
3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
Apoptosis
Inflammation
Caspase 7
Caspase Inhibitors
Hepatitis C
Caspases
Serum
Caspase 3
Multicenter Studies
Liver Diseases
Biomarkers

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Keywords

  • Biomarker
  • CASP3
  • CASP7
  • CK-18
  • Cell Death
  • IDN-6556

Cite this

Frenette, C. T., Morelli, G., Shiffman, M. L., Frederick, R. T., Rubin, R. A., Fallon, M. B., ... Hagerty, D. T. (2019). Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo. Clinical Gastroenterology and Hepatology, 17(4), 774-783.e4. https://doi.org/10.1016/j.cgh.2018.06.012
Frenette, Catherine T. ; Morelli, Giuseppe ; Shiffman, Mitchell L. ; Frederick, R. Todd ; Rubin, Raymond A. ; Fallon, Michael B. ; Cheng, Jason T. ; Cave, Matt ; Khaderi, Saira A. ; Massoud, Omar ; Pyrsopoulos, Nikolaos ; Park, James S. ; Robinson, James M. ; Yamashita, Mason ; Spada, Alfred P. ; Chan, Jean L. ; Hagerty, David T. / Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo. In: Clinical Gastroenterology and Hepatology. 2019 ; Vol. 17, No. 4. pp. 774-783.e4.
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abstract = "Background & Aims: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38{\%} with alcohol-associated cirrhosis, 29{\%} with HCV-associated cirrhosis, and 23{\%} with NASH) and model for end-stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Results: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P =.003) and Child-Pugh (P =.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95{\%} CI, –0.2882 to –0.0866) and total bilirubin (95{\%} CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P =.466) or Child-Pugh (P =.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67{\%}) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20{\%}). Serum levels of full-length CK-18 (P =.02) and caspase 3/7 (P <.001), but not cleaved CK-18 (P =.092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.",
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Frenette, CT, Morelli, G, Shiffman, ML, Frederick, RT, Rubin, RA, Fallon, MB, Cheng, JT, Cave, M, Khaderi, SA, Massoud, O, Pyrsopoulos, N, Park, JS, Robinson, JM, Yamashita, M, Spada, AP, Chan, JL & Hagerty, DT 2019, 'Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo', Clinical Gastroenterology and Hepatology, vol. 17, no. 4, pp. 774-783.e4. https://doi.org/10.1016/j.cgh.2018.06.012

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo. / Frenette, Catherine T.; Morelli, Giuseppe; Shiffman, Mitchell L.; Frederick, R. Todd; Rubin, Raymond A.; Fallon, Michael B.; Cheng, Jason T.; Cave, Matt; Khaderi, Saira A.; Massoud, Omar; Pyrsopoulos, Nikolaos; Park, James S.; Robinson, James M.; Yamashita, Mason; Spada, Alfred P.; Chan, Jean L.; Hagerty, David T.

In: Clinical Gastroenterology and Hepatology, Vol. 17, No. 4, 01.03.2019, p. 774-783.e4.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo

AU - Frenette, Catherine T.

AU - Morelli, Giuseppe

AU - Shiffman, Mitchell L.

AU - Frederick, R. Todd

AU - Rubin, Raymond A.

AU - Fallon, Michael B.

AU - Cheng, Jason T.

AU - Cave, Matt

AU - Khaderi, Saira A.

AU - Massoud, Omar

AU - Pyrsopoulos, Nikolaos

AU - Park, James S.

AU - Robinson, James M.

AU - Yamashita, Mason

AU - Spada, Alfred P.

AU - Chan, Jean L.

AU - Hagerty, David T.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background & Aims: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Results: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P =.003) and Child-Pugh (P =.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P =.466) or Child-Pugh (P =.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P =.02) and caspase 3/7 (P <.001), but not cleaved CK-18 (P =.092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

AB - Background & Aims: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. Results: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P =.003) and Child-Pugh (P =.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P =.466) or Child-Pugh (P =.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P =.02) and caspase 3/7 (P <.001), but not cleaved CK-18 (P =.092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.

KW - Biomarker

KW - CASP3

KW - CASP7

KW - CK-18

KW - Cell Death

KW - IDN-6556

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