F ARNESOID X NUCLEAR RECEPTOR LIGAND OBETICHOLIC ACID FOR NON - CIRRHOTIC, NON - ALCOHOLIC STEATOHEPATITIS (FLINT): A MULTICENTRE, RANDOMISED, PLACEBO - CONTROLLED TRIAL BA Neuschwander-Tetri, R Loomba, AJ Sanyal, for the NASH Clinical Research Network, et al. Lancet (2014) published online Nov (14)

B ACKGROUND : O BETICHOLIC ACID semi-synthetic bile acid analogue ligand for farnesoid X receptor -> FXR activation: suppression of cholesterol 7 alpha- hydroxylase, the rate-limiting enzyme in bile acid synthesis from cholesterol decreased hepatic lipid synthesis increased peripheral clearance of VLDL accelerates reverse cholesterol transport by increasing clearance of HDL FLINT Waltraud Leiss,

M ETHODS 72 weeks 25mg obeticholic acid once-daily vs. Placebo in patients with biopsy evidence of NASH Multicenter: 8 medical centers in the USA Double-blind: patients, investigators, clinical site staff, pathologists Placebo-controlled: identical tablets, identical containers Parallel-group Randomised: computer-generated FLINT Waltraud Leiss,

I NCLUSION C RITERIA ≥ 18 years Histological evidence of definite or borderline non-alcoholic steatosis based on liver biopsy obtained ≤90 days before randomisation NAFLD activity score ≥ 4 FLINT Waltraud Leiss, E XCLUSION C RITERIA Cirrhosis Other causes of liver disease Substantial alcohol consumption assessed for eligibility randomised assigned to obeticholic acid assigned to placebo assessed for eligibility randomised assigned to obeticholic acid assigned to placebo

O UTCOMES Primary: In end-of-treatment biopsies improvement in centrally scored liver histology = decrease in NAFLD activity score by ≥ 2 points without worsening of fibrosis Secondary: - other histologic changes - changes in aminotransferase - γ-GT - HOMA-IR - weight, BMI, waist-to-hip ratio, waist circumference - health-realted quality-of-life scores FLINT Waltraud Leiss,

I NTERIM ANALYSES 1 Serum cholesterol increased more in obeticholic acid-treated patients -> referred to primary care provider for more aggressive approach to lipid management FLINT Waltraud Leiss,

I NTERIM ANALYSES 2 After 140 of 280 planned end-of- treatment biopsies: superiority of obeticholic acid for the primary outcome met in 35 (43%) of 82 in obeticholic acid group vs. 17 (21%) of 82 in placebo group; p= > no biopsy for final 64 patients FLINT Waltraud Leiss,

R ESULTS 1 More patients assigned to obeticholic acid had improvement in fibrosis, hepato cellular ballooning, steatosis, lobular inflammation Mean change in NAFLD activity score greater in patients treated with obeticholic acid (change from baseline= –1.7 vs –0.7; p<0.0001). FLINT Waltraud Leiss,

R ESULTS 2 Significant reductions in: ALAT, ASAT, γ-GT over first 36 weeks of treatment, sustained for the duration of treatment By contrast: alkaline phosphatase increased Changes reversed 24 weeks after treatment discontinuation Obeticholic acid associated with weight loss, greater hepatic insulin resistance, higher cholesterol, higher LDL and decrease in HDL FLINT Waltraud Leiss,

A DVERSE EVENTS 2 patients died, both receiving obeticholic acid (1 sepsis, 1 cardiac ischaemia) Pruritus: 33 (23%) obeticholic acid-treated patients vs. 9 (6%) of 142 placebo-treated patients (p<0·0001) FLINT Waltraud Leiss,

D ISCUSSION 1: F UNDING Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside of Japan and China. «Partial funding for the trial, obeticholic acid, and an identical placebo were provided by Intercept Pharmaceuticals under a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Intercept Pharmaceuticals provided comments on the study protocol but was not involved with the study design, data analyses, and interpretation, or writing and submission of the manuscript.» FLINT Waltraud Leiss,

D ISCUSSION 2: L IMITATIONS decrease in severity of disease but not to the point of resolution of NASH no human data on the efficacy and safety of obeticholic acid as a treatment for NASH lack of detailed tracking of interventions including dose information to treat hyperlipidaemia during trial FLINT Waltraud Leiss,

C ONCLUSION Obeticholic acid improved the histological features of NASH Long-term benefits and safety need further clarification Long-term studies needed to determine the clinical relevance of changes in circulating lipids induced by farnesoid X receptor ligands FLINT Waltraud Leiss,

T HANK YOU FOR YOUR ATTENTION ! FLINT Waltraud Leiss,

A PPENDIX NAFLD Activity Score: NAS <3: NAFL borderline NASH. ≥5 corresponds to NASH FLINT Waltraud Leiss, ItemScoreExtentDefinition and Comment Steatosis0<5%Refers to amount of surface area involved by steatosis as evaluated on low to medium power examination; minimal steatosis (<5%) receives a score of 0 to avoid giving excess weight to biopsies with very little fatty change 15-33% 2>33-66% 3>66% Lobular Inflammation 0No fociAcidophil bodies are not included in this assessment, nor is portal inflammation 1<2 foci/200x 22-4 foci/200x 3>4 foci/200x Hepatocyte Ballooning 0None 1Few balloon cellsThe term "few" means rare but definite ballooned hepatocytes as well as cases that are diagnostically borderline 2Many cells/prominent ballooning Most cases with prominent ballooning also had Mallory's hyalin, but Mallory's hyaline is not scored separately for the NAS

F IGURE 1: T RIAL P ROFILE FLINT Waltraud Leiss,

T ABLE 1: B ASELINE CHARACTERISTICS

T ABLE 2: CHANGES IN HISTOLOGICAL FEATURES OF THE LIVER AFTER 72 WEEKS OF TREATMENT FLINT Waltraud Leiss,

F IGURE 2: C HANGES FROM BASELINE IN LIVER ENZYMES AND BODYWEIGHT ACCORDING TO TREATMENT GROUP FLINT Waltraud Leiss,

T ABLE 3.1: C HANGES IN LIVER ENZYMES, BIOCHEMICAL CONCENTRATIONS, METABOLIC FACTORS, AND QUALITY OF LIFE FROM BASELINE TO 72 WEEKS FLINT Waltraud Leiss,

T ABLE 3.2: C HANGES IN LIVER ENZYMES, BIOCHEMICAL CONCENTRATIONS, METABOLIC FACTORS, AND QUALITY OF LIFE FROM BASELINE TO 72 WEEKS

T ABLE 4: A DVERSE EVENTS FLINT Waltraud Leiss,

P ICTURE CREDITS / FLINT Waltraud Leiss,