Background The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]).Methods This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009.Findings Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76-0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74-0·95, 0·85; 95% CI 0·83-0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0. InterpretationThe FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease.

No abstract

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double‐blind, placebo‐controlled study in patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open‐label study, we assessed the histological efficacy of NGM282 in patients with biopsy‐confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; −1.9; 95% confidence interval, −2.6 to −1.2; P < 0.001 in the 1 mg group; −2.2, −3.1 to −1.3; P < 0.001 in the 3 mg group) and fibrosis (−0.5; −0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (−58% and −67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; −8% and −9%), alanine aminotransferase (ALT) (−67% and −60%), aspartate aminotransferase (−57% and −52%), and fibrogenesis biomarkers neoepitope‐specific N‐terminal propeptide of type III collagen (Pro‐C3; −22% and −33%) and enhanced liver fibrosis score (ELF; −3% and −6%) at week 12. Greater reductions in Pro‐C3, ELF, and cT1, but not in liver fat content, 7alpha‐hydroxy‐4‐cholesten‐3‐one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open‐label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

No abstract

N ASH affects more 80 million people worldwide and represents one of our most urgent and neglected global health crises, with broad implications on public health. 1,2 It is associated with increased risks of cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and death. The prevalence of NASH and NASH-related end-stage liver disease are predicted to increase significantly over the next decade. 3 There are currently no approved therapies for NASH.NASH is characterized histologically by hepatocellular injury, inflammation, steatosis, and may be accompanied by fibrosis, an important predictor of disease progression and mortality. [4][5][6][7] At present, the US Food and Drug Administration and European Medicines Agency support the use of the histologic end points of fibrosis improvement and NASH resolution for accelerated or conditional approval. 8,9 The pathogenesis of NASH is incompletely understood, although several hypotheses have been proposed. 10 Developing therapeutics for NASH poses a vexing challenge for clinicians and researchers, as none of the agents tested to date has been able to demonstrate concurrent histologic improvement in both fibrosis and NASH resolution. [11][12][13][14][15][16] Aldafermin (also known as NGM282 or M70) is an engineered, non-tumorigenic analog of the human gut hormone, fibroblast growth factor 19 (FGF19). [17][18][19] FGF19 plays a central role in regulating bile acid, carbohydrate, and energy metabolism. 20,21 Physiologically, FGF19 is secreted from the ileum in response to farnesoid X receptor activation, leading to the postulation that the effect of farnesoid X receptor agonists may be largely dependent on the induction of its target gene, FGF19. Aldafermin acts on 2 receptor complexes, FGFR1c-KLB and FGFR4-KLB. Activation of the FGFR1c-KLB receptor leads to reduction in liver steatosis and improvement in insulin sensitivity in patients. 22,23 Activation of the FGFR4-KLB receptor potently suppresses the expression of CYP7A1, which encodes the first and ratelimiting enzyme in the de novo synthesis of bile acids. 17,24 Emerging evidence reveals bile acids as an important risk factor for chronic liver diseases including NASH 25 ; accumulation of bile acids induces hepatic stellate cell activation, mitochondrial dysfunction and endoplasmic reticulum stress, leading to cell death, inflammation and liver injury. 26,27 Given aldafermin's mechanism of action, reducing bile acid burden may contribute to additional antiinflammatory and anti-fibrotic benefits beyond those associated with liver fat reduction.We have previously shown that a 12-week treatment with aldafermin produced reductions in liver fat content (LFC) and liver enzymes, and in an open-label study, improvements in liver histology. 28,29 In the current study, we investigated the efficacy and safety of longer treatment with aldafermin 1 mg compared with placebo in patients with biopsy-proven NASH and stage 2 or stage 3 liver fibrosis.

No abstract

Nonalcoholic steatohepatitis, a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma.Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, doubleblind, placebo-controlled, phase 2b trial randomized 247 non-alcoholic steatohepatitis (NASH) patients (101, 98, 48 in aramchol 400mg, 600mg, placebo, respectively; NCT 02279524). The primary endpoint was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of aramchol. Key secondary endpoints included liver histology and ALT. Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95%CI -6.4 to 0.2, p=0.06), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13/78) of aramchol 600 mg versus 5% (2/40) of the placebo arm (OR=4.74, 95% CI:0.1-22.7) and fibrosis improvement Vlad Ratziu, Study Design, Patient Recruitment and Treatment, Data Analyses and Interpretation, member of study advisory committee, Manuscript Writing

No abstract