Transcript Farnesoid X nuclear receptor ligand obeticholic acid for non

FARNESOID 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 7.
http://dx.doi.org/10.1016/S01406736(14)61933-4
BACKGROUND: OBETICHOLIC ACID
 semi-synthetic
bile acid analogue
 ligand for farnesoid X receptor
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-> FXR activation:
 suppression of cholesterol 7 alphahydroxylase, 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
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72 weeks 25mg obeticholic acid once-daily
vs. Placebo in patients with biopsy
evidence of NASH
INCLUSION CRITERIA
≥ 18 years
 Histological evidence of definite or borderline
non-alcoholic steatosis based on liver biopsy
obtained ≤90 days before randomisation
 NAFLD activity score ≥ 4
- 345 assessed

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for eligibility
EXCLUSION CRITERIA - 283
randomised
 Cirrhosis
- 141 assigned
 Other causes of liver disease
to obeticholic
 Substantial alcohol consumption
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
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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
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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
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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
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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
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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
ADVERSE EVENTS
2
 Pruritus:
33 (23%) obeticholic acid-treated patients
vs.
9 (6%) of 142 placebo-treated patients
(p<0·0001)
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patients died, both receiving obeticholic
acid (1 sepsis, 1 cardiac ischaemia)
DISCUSSION 1: FUNDING
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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
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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
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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!
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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/200x
2
2-4 foci/200x
3
>4 foci/200x
0
1
None
Few balloon cells The term "few" means rare but definite ballooned
hepatocytes as well as cases that are diagnostically
borderline
Many
Most cases with prominent ballooning also had Mallory's
cells/prominent
hyalin, but Mallory's hyaline is not scored separately for the
ballooning
NAS
Lobular
Inflammation
Hepatocyte
Ballooning
2
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
Acidophil bodies are not included in this assessment, nor is
portal inflammation
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Item
FIGURE 1: TRIAL PROFILE
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TABLE 1: BASELINE
CHARACTERISTICS
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TABLE 2: CHANGES IN HISTOLOGICAL FEATURES OF THE LIVER AFTER 72
WEEKS OF TREATMENT
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FIGURE 2: CHANGES FROM BASELINE IN LIVER ENZYMES AND
BODYWEIGHT ACCORDING TO TREATMENT GROUP
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TABLE 3.1: CHANGES IN LIVER ENZYMES, BIOCHEMICAL CONCENTRATIONS,
METABOLIC FACTORS, AND QUALITY OF LIFE FROM BASELINE TO 72 WEEKS
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TABLE 3.2: CHANGES IN LIVER ENZYMES, BIOCHEMICAL
CONCENTRATIONS, METABOLIC FACTORS, AND QUALITY OF LIFE FROM
BASELINE TO 72 WEEKS
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TABLE 4: ADVERSE EVENTS
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PICTURE CREDITS

http://tpis.upmc.com/changebody.cfm?url=/tpis/schema/NAFLD2006.jsp 03.03.2015

http://www.milkcapmania.co.uk/Cyclone/64-The-Flintstones.html 03.03.2015

http://www.animaatjes.de/cliparts/familie-feuerstein/clipart_flintstones_animaatjes92-217412/ 03.03.2015
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