studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 291A
olites predictive of fibrosis stage. RESULTS: Age, gender, BMI,
current/past alcohol use/smoking, total HDL/LDL cholesterol
or triglycerides did not differ with fibrosis stage. In univariate
testing, plasma concentrations of alpha-glutamyltyrosine N-acetylcitrulline
palmitoyl-palmitoyl-glycerophosphocholine, glycocholate
glutarate, fucose and fumarate associated with fibrosis
stage (p=0.0007). After controlling for age, gender and DM,
N-acetylcitrulline, alpha glutamytyrosine, palmitoyl-palmitoyl-glycerophosphocholine,
lignoceric acid, glycocholate, and
1-arachidonoyl associated with fibrosis (p=0.0009). Multivariate
analysis using logistic regression yielded an Area Under
the Receiver Operating Characteristic (AUROC) of 0.8804
for I-urobilinogen, malate, glutarate (pentanedioate), taurochenodeoxycholate,
3-hydroxyoctanoate, fucose, isoleucine,
palmitoyl-palmitoyl-glycerophosphocholine, N-acetylcitrulline.
Sparse ordinal regression was used to predict fibrosis stage,
resulting in a correlation coefficient of 0.3757 (p=5x10 -8 )
after leave-one-out cross-validation. The model identified a
69 metabolite signature predictive of fibrosis stage. CONCLU-
SIONS: Analysis of serum from NAFLD patients revealed alterations
in bile acids, steroids hormones, branched-chain amino
acid catabolism, TCA cycle metabolism, and mitochondrial
function in stage 3-4 fibrosis. The role of these metabolites as
potential biomarkers for hepatic fibrosis requires validation.
Pathways involved in bile acid and/or steroid hormone metabolism,
branched-chain amino acids, and/or mitochondrial function
may offer novel targets for anti-fibrotic therapies in NAFLD.
Disclosures:
Lauren N. Bell - Employment: Metabolon, Inc.
Regis Perichon - Employment: Metabolon
Manal F. Abdelmalek - Consulting: Islet Sciences; Grant/Research Support:
Tobira, Gilead Sciences, NIH/NIDDK, Synageva, Genfit Pharmaceuticals,
Immuron, Galmed, TaiwanJ Pharma, Intercept, NGM Pharmaceuticals
The following authors have nothing to disclose: Ricardo Henao, Nigar Hasanaliyeva,
Jacob Wulff, Cynthia A. Moylan, James T. Lu, Cynthia D. Guy, Anna Mae
Diehl
162
Beneficial effects of the dual PPAR α-δ agonist, GFT505,
on hepatic and cardiometabolic markers in adult NASH
patients.
Stephen A. Harrison 3 , Arun J. Sanyal 2 , Sven M. Francque 4 , Pierre
Bedossa 5 , Lawrence Serfaty 6 , Manuel Romero-Gomez 7 , Paul
Cales 8 , Manal F. Abdelmalek 9 , Stephen H. Caldwell 10 , Joost
Drenth 11 , Quentin M. Anstee 12 , Dean W. Hum 13 , Rémy Hanf 13 ,
Alice Roudot 13 , Sophie Megnien 13 , Bart Staels 14 , Vlad Ratziu 1 ;
1 Hepatology, Hopital Pitie Salpetriere, Paris, France; 2 Internal
Medicine/Division of Gastroenterology, Hepatology and Nutrition,
Virginia Commonwealth University, Richmond, VA; 3 Gastroenterology,
Brooke Army Medical Center, Fort Worth, TX; 4 Antwerp
Univesrity Hospital, Gastroenterology Hepatology, Antwerp, Belgium;
5 Pathology, Hopital Beaujon, Clichy, France; 6 Hepatology
Department, Hospital Saint-Antoine, Paris, France; 7 Valme University
Hospital, Digestive Diseases, Sevilla, Spain; 8 Hepatology
Department, Centre Hospitalier Universitaire d’ Angers, Angers,
France; 9 Medicine, Duke University, Durham, NC; 10 Hepatology
Department, University of Virginia, Charlotesville, VA; 11 Hepatology
Department, RUNMC, Nijmegen, Netherlands; 12 Institute
of Cellular Medicine, Newcastle University, Newcastle, United
Kingdom; 13 Genfit, Loos, France; 14 INSERM U1011, European
Genomic Institute for Diabetes (EGID), Université Lille 2, Lille,
France
Introduction: NASH patients (pts) have a high prevalence of cardiometabolic
risk factors, hence cardiovascular disease is the
leading cause of death in this population. Having demonstrated
the efficacy of GFT505 on the histological reversal of NASH,
here we evaluated the biochemical and cardiometabolic effects
of the drug in in this large, international, phase 2 randomized,
controlled trial of adult pts with biopsy-proven NASH. Methods:
Pts from the ITT population of the GOLDEN505 trial randomized
to the GFT505 120 mg (GFT120) and placebo (PBO)
arms were compared for treatment effects on plasma lipid,
glycemic, insulin resistance, inflammatory and liver markers.
Results are expressed as effect size vs. placebo (LS mean±SE).
Analyses were conducted for different stages of disease severity
based on the NAFLD Activity Score (NAS) at baseline (NAS 3:
mild, NAS 4-5: moderate, NAS>5: severe), and fibrosis stage
(F0-F1 vs. F2-F3 according to Kleiner et al). Results: Compared
to PBO, GFT120 significantly improved GGT (-29.31±6.36
U/L, p