FARNESOID X NUCLEAR RECEPTOR LIGAND OBETICHOLIC ACID FOR
FARNESOID X NUCLEAR RECEPTOR LIGAND OBETICHOLIC ACID FOR NONCIRRHOTIC, NON-ALCOHOLIC STEATOHEPATITIS (FLINT): A MULTICENTRE, RANDOMISED, PLACEBOCONTROLLED TRIAL BA Neuschwander-Tetri, R Loomba, AJ Sanyal, for the NASH Clinical Research Network, et al. Lancet (2014) published online Nov 7. http: //dx. doi. org/10. 1016/S 01406736(14)61933 -4
BACKGROUND: OBETICHOLIC ACID semi-synthetic bile acid analogue ligand for farnesoid X receptor FLINT Waltraud Leiss, 02. 2015 -> 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
METHODS 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, 02. 2015 72 weeks 25 mg obeticholic acid once-daily vs. Placebo in patients with biopsy evidence of NASH
INCLUSION CRITERIA ≥ 18 years Histological evidence of definite or borderline nonalcoholic steatosis based on liver biopsy obtained ≤ 90 days before randomisation NAFLD activity score ≥ 4 - 345 assessed Cirrhosis Other causes of liver disease Substantial alcohol consumption FLINT Waltraud Leiss, 02. 2015 EXCLUSION CRITERIA for eligibility - 283 randomised - 141 assigned to obeticholic acid - 142 assigned to placebo
OUTCOMES Primary: 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, 02. 2015 In end-of-treatment biopsies improvement in centrally scored liver histology = decrease in NAFLD activity score by ≥ 2 points without worsening of fibrosis
INTERIM ANALYSES 1 Serum FLINT Waltraud Leiss, 02. 2015 cholesterol increased more in obeticholic acid-treated patients -> referred to primary care provider for more aggressive approach to lipid management
INTERIM ANALYSES 2 After -> no biopsy for final 64 patients FLINT Waltraud Leiss, 02. 2015 140 of 280 planned end-oftreatment 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=0. 0024
RESULTS 1 More FLINT Waltraud Leiss, 02. 2015 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).
RESULTS 2 Significant FLINT Waltraud Leiss, 02. 2015 reductions in: ALAT, ASAT, γGT 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
ADVERSE EVENTS 2 Pruritus: 33 (23%) obeticholic acid-treated patients vs. 9 (6%) of 142 placebo-treated patients (p<0· 0001) FLINT Waltraud Leiss, 02. 2015 patients died, both receiving obeticholic acid (1 sepsis, 1 cardiac ischaemia)
DISCUSSION 1: FUNDING FLINT Waltraud Leiss, 02. 2015 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. »
DISCUSSION 2: LIMITATIONS decrease FLINT Waltraud Leiss, 02. 2015 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
CONCLUSION Obeticholic FLINT Waltraud Leiss, 02. 2015 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
THANK YOU FOR YOUR ATTENTION! FLINT Waltraud Leiss, 02. 2015
APPENDIX NAFLD Activity Score: NAS <3: NAFL. 3 - 4 borderline NASH. ≥ 5 corresponds to NASH Score Steatosis 0 <5% 1 2 3 0 5 -33% >33 -66% >66% No foci 1 <2 foci/200 x 2 2 -4 foci/200 x 3 >4 foci/200 x 0 1 None Few balloon cells 2 Many cells/prominent ballooning Lobular Inflammation Hepatocyte Ballooning Extent Definition and Comment 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 FLINT Waltraud Leiss, 02. 2015 Item Acidophil bodies are not included in this assessment, nor is portal inflammation The term "few" means rare but definite ballooned hepatocytes as well as cases that are diagnostically borderline Most cases with prominent ballooning also had Mallory's hyalin, but Mallory's hyaline is not scored separately for the NAS
FIGURE 1: TRIAL PROFILE FLINT Waltraud Leiss, 02. 2015
TABLE 1: BASELINE CHARACTERISTICS FLINT Waltraud Leiss, 02. 2015
TABLE 2: CHANGES IN HISTOLOGICAL FEATURES OF THE LIVER AFTER 72 WEEKS OF TREATMENT FLINT Waltraud Leiss, 02. 2015
FIGURE 2: CHANGES FROM BASELINE IN LIVER ENZYMES AND BODYWEIGHT ACCORDING TO TREATMENT GROUP FLINT Waltraud Leiss, 02. 2015
TABLE 3. 1: CHANGES IN LIVER ENZYMES, BIOCHEMICAL CONCENTRATIONS, METABOLIC FACTORS, AND QUALITY OF LIFE FROM BASELINE TO 72 WEEKS FLINT Waltraud Leiss, 02. 2015
TABLE 3. 2: CHANGES IN LIVER ENZYMES, BIOCHEMICAL CONCENTRATIONS, METABOLIC FACTORS, AND QUALITY OF LIFE FROM BASELINE TO 72 WEEKS FLINT Waltraud Leiss, 02. 2015
TABLE 4: ADVERSE EVENTS FLINT Waltraud Leiss, 02. 2015
PICTURE CREDITS http: //tpis. upmc. com/changebody. cfm? url=/tpis/schema/NAFLD 2006. jsp 03. 2015 http: //www. milkcapmania. co. uk/Cyclone/64 -The-Flintstones. html 03. 2015 http: //www. animaatjes. de/cliparts/familie-feuerstein/clipart_flintstones_animaatjes-92217412/ 03. 2015 FLINT Waltraud Leiss, 02. 2015
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