A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis

Harrison, Stephen A.; Goodman, Zachary; Jabbar, Abdul; Vemulapalli, Ravi; Younes, Ziad; Freilich, Bradley; Sheikh, Muhammad Y.; Schattenberg, Jörn M.; Kayali, Zeid; Zivony, Adam; Sheikh, Aasim; García‐Samaniego, J.; Satapathy, Sanjaya K.; Therapondos, George; Mena, Edward; Schuppan, Detlef; Robinson, James M.; Chan, Jean L.; Hagerty, David; Sanyal, Arun J.

doi:10.1016/j.jhep.2019.11.024

Cited by 184 publications

(179 citation statements)

References 37 publications

Supporting

Mentioning

171

Contrasting

Unclassified

Order By: Relevance

“…No effects were seen in patients with acutely decompensated cirrhosis [256]. In contrast, 72 week administration of Emricasan in patients with NASH-associated F1-F3 fibrosis did not improve liver inflammation or fibrosis but rather tended to worse hepatocyte-ballooning, potentially due to activation of other mechanisms of cell death and necrosis [254]. Results from a recently completed clinical trial of Emricasan in the setting of post-transplant HCV-induced fibrosis after SVR are awaited 2020 (NCT02138253).…”

Section: Hepatic Protection Via Inhibition Of Apoptosismentioning

confidence: 99%

“…Accordingly, inhibition of hepatocyte apoptosis decreased HSC activation in animal models of liver fibrosis [251,252]. Following a promising pre-clinical study in a carbon tetrachloride (CCl 4 )-based liver fibrosis rat model [253], just recently two randomized placebo-controlled trials investigated the pan-caspase inhibitor Emricasan in NASH patients with F1-F3 fibrosis [254] or cirrhosis with severe portal hypertension [255]. Garcia-Tsao et al reported small reductive effects on hepatic venous pressure gradient (HVPG) in cirrhotic NASH patients [255].…”

Section: Hepatic Protection Via Inhibition Of Apoptosismentioning

confidence: 99%

“…Consideration of the complex disease pathophysiology, implementation of complementary cell culture, and animal models of liver fibrosis as well as use of validated endpoints will hopefully revolutionize future anti-fibrotic opportunities. Phase 2: Improvement of liver inflammation or fibrosis and tendency towards worsening of hepatocyte ballooning in NASH patients with F1-F3 fibrosis [254]. Small reductive effect on HVPG in cirrhotic NASH patients [255].…”

Section: From Mouse To Men: Challenges In the Clinical Development Ofmentioning

confidence: 99%

See 2 more Smart Citations

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

682

440

View full text Add to dashboard Cite

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

show abstract

Section: Hepatic Protection Via Inhibition Of Apoptosismentioning

confidence: 99%

Section: Hepatic Protection Via Inhibition Of Apoptosismentioning

confidence: 99%

Section: From Mouse To Men: Challenges In the Clinical Development Ofmentioning

confidence: 99%

See 1 more Smart Citation

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

682

440

View full text Add to dashboard Cite

show abstract

“…To this end, different anti-apoptotic agents have been developed and are currently in clinical trials (reviewed in refs. 54,55 ).…”

Section: Lipoapoptosis As An End-point In Lipotoxicity Associated Witmentioning

confidence: 99%

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

et al. 2020

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD stages range from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis and hepatocellular carcinoma. One of the crucial events clearly involved in NAFLD progression is the lipotoxicity resulting from an excessive fatty acid (FFA) influx to hepatocytes. Hepatic lipotoxicity occurs when the capacity of the hepatocyte to manage and export FFAs as triglycerides (TGs) is overwhelmed. This review provides succinct insights into the molecular mechanisms responsible for lipotoxicity in NAFLD, including ER and oxidative stress, autophagy, lipoapotosis and inflammation. In addition, we highlight the role of CD36/FAT fatty acid translocase in NAFLD pathogenesis. Up-to-date, it is well known that CD36 increases FFA uptake and, in the liver, it drives hepatosteatosis onset and might contribute to its progression to NASH. Clinical studies have reinforced the significance of CD36 by showing increased content in the liver of NAFLD patients. Interestingly, circulating levels of a soluble form of CD36 (sCD36) are abnormally elevated in NAFLD patients and positively correlate with the histological grade of hepatic steatosis. In fact, the induction of CD36 translocation to the plasma membrane of the hepatocytes may be a determining factor in the physiopathology of hepatic steatosis in NAFLD patients. Given all these data, targeting the fatty acid translocase CD36 or some of its functional regulators may be a promising therapeutic approach for the prevention and treatment of NAFLD.

show abstract

“…Selonsertib, an ASK-1 inhibitor, failed to achieve reversal of cirrhosis and fibrosis in the STELLAR-4 and STELLAR-3 trials, and thus will not be further explored in monotherapy. Likewise, the caspase inhibitor emricasan did not meet the primary endpoint in both a precirrhotic and a cirrhotic patient population [32]. Interestingly, here, fibrosis tended to even worsen in the active treatment arm.…”

Section: Antifibrotic Drugsmentioning

confidence: 74%

Emerging Pharmacological Treatment in Nonalcoholic Steatohepatitis

Schattenberg

2020

Visc Med

View full text Add to dashboard Cite

Background: The increasing prevalence of nonalcoholic fatty liver disease has led to a strong demand for an optimal therapeutic approach. At present, guidelines recommend lifestyle changes, but it has become apparent that pharmacotherapy will be required in patients with advanced disease to prevent the progression to end-stage liver disease and potentially improve extrahepatic outcomes. Summary: This review discusses current pharmacological approaches focusing on substances studied in pivotal trials and selected phase 2 trials in patients with nonalcoholic steatohepatitis (NASH) and fibrosis. Key Message: Currently, several compounds are subjected to clinical testing to explore predominantly anti-inflammatory, anti-fibrotic, and metabolic treatment for NASH. With current response rates around 20%, the combination of several drugs targeting more than one pathway could lead to increased treatment success in the future.

show abstract

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis

Cited by 184 publications

References 37 publications

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?

Emerging Pharmacological Treatment in Nonalcoholic Steatohepatitis

Contact Info

Product

Resources

About