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

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

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis

Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. NCT03205345

Ascitic microbiota composition is correlated with clinical severity in cirrhosis with portal hypertension

Identification of pathogenic bacteria in ascites correlates with poor clinical outcomes. Ascites samples are commonly reported culture-negative, even where frank infection is indicated. Culture-independent methods have previously reported bacterial DNA in ascites, however, whether this represents viable bacterial populations has not been determined. We report the first application of 16S rRNA gene pyrosequencing and quantitative PCR in conjunction with propidium monoazide sample treatment to characterise the viable bacterial composition of ascites. Twenty five cirrhotic patients undergoing paracentesis provided ascites. Samples were treated with propidium monoazide to exclude non-viable bacterial DNA. Total bacterial load was quantified by 16S rRNA Q-PCR with species identity and relative abundance determined by 16S rRNA gene pyrosequencing. Correlation of molecular microbiology data with clinical measures and diagnostic microbiology was performed. Viable bacterial signal was obtained in 84% of ascites samples, both by Q-PCR and pyrosequencing. Approximately 190,000 ribosomal pyrosequences were obtained, representing 236 species, including both gut and non gut-associated species. Substantial variation in the species detected was observed between patients. Statistically significant relationships were identified between the bacterial community similarity and clinical measures, including ascitic polymorphonuclear leukocyte count and Child-Pugh class. Viable bacteria are present in the ascites of a majority of patients with cirrhosis including those with no clinical signs of infection. Microbiota composition significantly correlates with clinical measures. Entry of bacteria into ascites is unlikely to be limited to translocation from the gut, raising fundamental questions about the processes that underlie the development of spontaneous bacterial peritonitis

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection:a randomised study

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RN