Randomized Placebo-Controlled Trial of Emricasan in Non-alcoholic Steatohepatitis (NASH) Cirrhosis with Severe Portal Hypertension.

Garcia-Tsao, Guadalupe; Bosch, Jaime; Kayali, Zeid; Harrison, Stephen A; Abdelmalek, Manal F; Lawitz, Eric; Satapathy, Sanjaya K; Ghabril, Marwan; Shiffman, Mitchell L; Younes, Ziad H; Thuluvath, Paul J; Berzigotti, Annalisa; Albillos, Agustin; Robinson, James M; Hagerty, David T; Chan, Jean L; Sanyal, Arun J (2020). Randomized Placebo-Controlled Trial of Emricasan in Non-alcoholic Steatohepatitis (NASH) Cirrhosis with Severe Portal Hypertension. Journal of hepatology, 72(5), pp. 885-895. Elsevier 10.1016/j.jhep.2019.12.010

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BACKGROUND AND AIM Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in patients with cirrhosis and portal pressure (assessed by the hepatic venous pressure gradient [HVPG]) ≥12 mmHg. We aimed to confirm these results in a randomized, placebo-controlled, double blind study. METHODS Multicenter study including 263 patients with cirrhosis due to non-alcoholic steatohepatitis (NASH) and baseline HVPG ≥12 mmHg randomized 1:1:1:1 to emricasan 5 (n=65), 25 (n=65), 50 (n=66) mg or placebo (n=67) orally twice daily for up to 48 weeks. 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 by baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated subjects (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 MELD and Child Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS Despite reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH cirrhosis and severe portal hypertension. Compensated subjects with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Bosch, Jaime and Berzigotti, Annalisa

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0168-8278

Publisher:

Elsevier

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

23 Jan 2020 16:21

Last Modified:

20 Apr 2020 01:32

Publisher DOI:

10.1016/j.jhep.2019.12.010

PubMed ID:

31870950

Uncontrolled Keywords:

HVPG Non-alcoholic steatohepatitis caspase inhibition cirrhosis emricasan hepatic venous pressure gradient portal hypertension portal pressure

BORIS DOI:

10.7892/boris.137875

URI:

https://boris.unibe.ch/id/eprint/137875

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