Guadalupe Garcia-Tsao1, Jaime Bosch2, Zeid Kayali3, Stephen A Harrison4, Manal F Abdelmalek5, Eric Lawitz6, Sanjaya K Satapathy7, Marwan Ghabril8, Mitchell L Shiffman9, Ziad H Younes10, Paul J Thuluvath11, Annalisa Berzigotti12, Agustin Albillos13, James M Robinson14, David T Hagerty14, Jean L Chan14, Arun J Sanyal15. 1. Yale University, New Haven, CT. Electronic address: guadalupe.garcia-tsao@yale.edu. 2. Inselspital, University of Bern, Berne, Switzerland; Hospital Clinic-IDIBAPS-Ciberehd, University of Barcelona, Barcelona, Spain. 3. Inland Empire Liver Foundation, Rialto, CA. 4. Pinnacle Clinical Research, San Antonio, TX. 5. Duke University, Durham, NC. 6. Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX. 7. Methodist University Hospital, University of Tennessee Health Sciences Center, Memphis, TN. 8. Indiana University, Indianapolis, IN. 9. Bon Secours Liver Institute, Richmond, VA. 10. Gastro One, Germantown, TN. 11. Mercy Medical Center and University of Maryland School of Medicine, Baltimore, MD. 12. Inselspital, University of Bern, Berne, Switzerland. 13. Hospital Ramon y Cajal, University of Alcala, IRYCIS, CIBEREHD, Madrid, Spain. 14. Conatus Pharmaceuticals Inc., San Diego, CA. 15. Virginia Commonwealth University, Richmond, VA.
Abstract
BACKGROUND & AIMS:Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. METHODS: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice dailyoral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. RESULTS: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. LAY SUMMARY:Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02960204.
RCT Entities:
BACKGROUND & AIMS:Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. METHODS: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. RESULTS: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. LAY SUMMARY:Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02960204.
Authors: Batuhan Yenilmez; Nicole Wetoska; Mark Kelly; Dimas Echeverria; Kyounghee Min; Lawrence Lifshitz; Julia F Alterman; Matthew R Hassler; Samuel Hildebrand; Chloe DiMarzio; Nicholas McHugh; Lorenc Vangjeli; Jacquelyn Sousa; Meixia Pan; Xianlin Han; Michael A Brehm; Anastasia Khvorova; Michael P Czech Journal: Mol Ther Date: 2021-11-11 Impact factor: 11.454
Authors: Matthew Plassmeyer; Oral Alpan; Michael J Corley; Thomas A Premeaux; Kimberleigh Lillard; Paige Coatney; Tina Vaziri; Suzan Michalsky; Alina P S Pang; Zaheer Bukhari; Stephen T Yeung; Teresa H Evering; Gail Naughton; Martin Latterich; Philip Mudd; Alfred Spada; Nicole Rindone; Denise Loizou; Søren Ulrik Sønder; Lishomwa C Ndhlovu; Raavi Gupta Journal: Allergy Date: 2021-06-02 Impact factor: 14.710