Longitudinal changes in FIB-4
and improvement in fibrosis stage
with obeticholic acid: A
secondary analysis of FLINT trial
Naga P. Chalasani1, Rohit Loomba2, Norah Terrault3, Arthur J. McCullough4,
Manal F. Abdelmalek5, Kris V. Kowdley6, Brent A. Neuschwander-Tetri7,
Saswati Hazra8, Xiaohong Yan8, Reshma Shringarpure8, Leigh MacConell8,
Arun J. Sanyal9
1. Indiana University, Indianapolis, IN; 2. University of California, San Diego, La
Jolla, CA; 3. University of California, San Francisco, San Francisco, CA; 4.
Cleveland Clinic, Cleveland, OH; 5. Duke University, Durham, NC; 6. Swedish
Medical Center, Seattle, WA; 7. Saint Louis University Health Sciences Center, St.
Louis, MO; 8. Intercept Pharmaceuticals, Inc., San Diego, CA; 9. Virginia
Commonwealth University, Richmond, VA, United States
The FLINT trial was conducted by the NASH CRN investigators and was sponsored by NIDDK,
with partial funding support from Intercept Pharmaceuticals, Inc.
This analysis was conducted independently by Intercept Pharmaceuticals, Inc. based on data
provided by the NASH CRN.
Disclosure/Disclaimer

All material is intended for medical information and medical education
purposes only. These materials have been produced in response to an
unsolicited request for information.

Redistribution, reproduction or use of material other than in the discussion
at which it is presented is prohibited.

Obeticholic acid (OCA) is an investigational drug. It is not approved for use
by the FDA, EMA or any other regulatory body. No conclusions can be
drawn concerning the safety or efficacy of OCA at this time.
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Conflicts of interest





Salaried employee: of VCU
Member of Board: McGuire VA Research Institute, unpaid member
Ad hoc consultant:
–
Salix: < $ 5K
–
Ikaria: < $ 5K
–
Abbott: $5-10K
Bristol-Myers: < $ 5K
–
Genfit: $ 5-10 K
–
– Genentech: < $ 5K
– Bristol Myers: < $ 5K
– Echosens: unpaid consultant
– Gilead: unpaid consultant
– Novartis: unpaid consultant
– Takeda: unpaid consultant
Royalties:
–
Elsevier- Boyers Textbook of Hepatology: < $ 5K
Uptodate: < $ 5K
–
Grants (awarded to university):
–
NIH: $ 1.5 million annual direct costs
– Roche, Gilead, Astellas: $ 25-50K total
Salix, Ikaria: $ 50 -100000 each
–
– Gilead: $ 150 K annual direct costs based on recruitment
– Genfit: US PI for GFT505 trial
– Galectin: $ 30000
Background
 Nonalcoholic steatohepatitis (NASH) is a common cause of chronic
liver disease and can progress to cirrhosis
 Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist that
was shown to improve disease activity and fibrosis in patients with
NASH in a phase 2B clinical trial (FLINT)
 Improvement in fibrosis is considered particularly relevant because
fibrosis stage is associated with mortality in patients with NASH
 Thus, there is a need to identify which patients are or are not
experiencing an improvement in fibrosis so they can be managed
accordingly
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Background
 A liver biopsy is the gold standard for
assessment of changes in fibrosis stage
but can not be repeated frequently due to
its invasive nature and attendant risks
 Several non-invasive measures of
fibrosis have been found to relate the
presence of advanced fibrosis in patients
with NASH
 These include the AST: platelet ratio
index (APRI)1, FIB-42 and NAFLD
Fibrosis Score (NFS)3,4
 It is not known whether these indices are
sensitive to change and can identify
those whose fibrosis stage is improving
Figure adapted from Shah A, et al. CGH. 2009; 1. Cales P, et al. J Hepatol. 2009;50:165–73; 2. Shah AG, et al. Clin Gastroenterol Hepatol.
2009;7(10):1104-12; 3. Angulo, et al. Hepatology. 2007;45:846-854; 4. Angulo, et al. Gastroenterology. 2013;145:782-789.
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Objective

Hypothesis: Noninvasive markers of fibrosis improve in
those with improvement in fibrosis stage

Specific Aim: To determine if the APRI, FIB-4 and NFS
improved in those whose fibrosis improved with OCA
treatment in the FLINT clinical trial

The null hypothesis was that none of the parameters would
change with improvement in fibrosis with OCA treatment
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FLINT Trial Design
Vanguard analysis
N=283
Patients w/
Histological Evidence
of NASH1
Screening (Biopsy)
Interim analysis
OCA 25 mg QD
Follow-up
Placebo QD
Follow-up
72-week treatment period
24 week off treatment
Primary endpoint: liver histological improvement defined as decrease
in NAFLD Activity Score (NAS) of ≥2 points with no worsening in fibrosis
1. Neuschwander-Tetri BA, et al. Lancet. 2015;385(9972):956-65.
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Methods

Levels of the three noninvasive markers were computed for baseline, and at
24, 48, 72, and 96 weeks in all patients
– N=283 (n=141 [OCA]; n=142 [Placebo])

Comparison of histology data with noninvasive markers was performed in
patients who had baseline and end-of-treatment biopsies
– N=200 (n=102 [OCA]; n=98 [Placebo])

The specific parameters measured included:
–
FIB-4, APRI and NFS (equations below)

Changes in markers over time in placebo and OCA treatment were
compared in a mixed effects model

A logistic regression model was used to evaluate early changes (24 wks) in
markers as predictors of fibrosis improvement at end of treatment (72 wks)
APRI = {[(AST level) / (AST ULN)] / [platelet count (109/L)]} x 100)
FIB-4 = age (years) × AST [U/L] / (platelets [109/L] × (ALT [U/L])1/2)
NFS = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, no = 0) +
0.99 × AST/ALT ratio – 0.013 × platelets (×109/L) – 0.66 × albumin (g/dL)
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Baseline Characteristics
OCA (25 mg/day)
N=141
Placebo
N=142
P-value†
Age (yrs)
51.9 (0.9)
51.0 (1.0)
0.450
BMI (kg/m2)
35.2 (0.6)*
33.9 (0.5)
0.086
53.2
52.1
0.911‡
AST (U/L)
64.1 (3.2)
58.0 ( 2.8)
0.163
ALT (U/L)
82.8 (4.2)
82.4 (4.3)
0.960
Alk Phos (U/L)
82.2 (2.4)
81.5 (2.1)
0.836
Triglycerides (mg/dL)
216.4 (23.4)
177.7 (12.8)
0.157
Platelets (109/L)
237.5 (5.0)
236.8 (5.5)
0.902
Albumin (g/dL)
4.3 (0.0)
4.3 (0.0)
0.859
APRI
0.7 (0.0)
0.7 (0.0)
0.387
FIB-4
1.7 (0.1)
1.5 (0.1)
0.163
-0.9 (0.1)*
-1.2 (0.1)
0.120
Parameter
Diabetics (%)
NAFLD Fibrosis Score
Data are mean (SE) where applicable. *N=139; †Continuous variable p-values from ANOVA with treatment and stratification strata (center,
diabetes status) as fixed effects; ‡Diabetes status p-value from CMH chi-square stratified by center; All P-values are based on LS Mean.
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FIB-4, APRI and NFS Values Over Time
F IB -4
A P R I
1 .0
1 .9
P la c e b o ( n = 1 4 2 )
1 .8
O C A (n = 1 4 1 )
1 .7
1 .6 6
1 .6
1 .5
1 .5 1
1 .4
1 .3
1 .3
1 .2
1 .1
1 .0
P la c e b o
0 .9
(n = 1 4 2 )
O C A (n = 1 4 1 )
0 .8
0 .7
0 .7 1
0 .6 6
0 .6
0 .5
0 .5
0 .4
0 .3
0 .2
0 .1
0 .0
0
24
-0 .4
M e a n N F S (9 5 % C I) S c o r e
M e a n A P R I (9 5 % C I) S c o r e
M e a n F IB -4 (9 5 % C I) S c o r e
2 .0
48
W eeks
N FS
72
96
0
24
48
72
96
W eeks
P la c e b o ( n = 1 4 2 )
O C A (n = 1 3 9 )
-0 .6
N o n in v a s iv e s c o r e s b e lo w th e c u t-o ff
v a lu e h a v e a lo w p r o b a b ility o f
-0 .8
-0 .9 3
a d v a n c e d fib r o s is
-1 .0
-1 .1 8
-1 .2
-1 .4
-1 .4 5 5
0
24
48
72
96
W eeks
Clincal Practice Guidelines. J Hepatol. 2015;63(1):237-264; Shah A, et al. Clin Gastroenterol Hepatol. 2009;7(10):1104-1112.
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Change from Baseline in FIB-4, APRI and NFS
0 .6
P la c e b o ( n = 1 4 2 )
O C A (n = 1 4 1 )
0 .4
0 .2
0 .0
-0 .2
*
**
***
***
-0 .4
L S M e a n C h a n g e (9 5 % C I)
A P R I
-0 .6
fr o m B a s e lin e in A P R I S c o r e
M e a n C h a n g e (9 5 % C I)
LS
fr o m B a s e lin e in F IB -4 S c o r e
F IB -4
0 .6
P la c e b o ( n = 1 4 2 )
O C A (n = 1 4 1 )
0 .4
0 .2
0 .0
-0 .2
***
***
***
-0 .4
-0 .6
0
24
48
W eeks
72
96
0
L S M e a n C h a n g e (9 5 % C I)
48
W eeks
72
96
N FS
0 .6
fr o m B a s e lin e in N F S S c o r e
24
P la c e b o ( n = 1 4 2 )
O C A (n = 1 3 9 )
0 .4
0 .2
0 .0
*
-0 .2
-0 .4
-0 .6
0
24
48
W eeks
72
96
*p<0.05,**p<0.01,***p<0.0001. P-values were calculated using ANCOVA models, regressing change from baseline at each post-baseline
visit on treatment group and baseline value of the outcome.
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Change from Baseline in FIB-4 by Baseline Fibrosis Stage
O b e t ic h o lic A c id
B a s e lin e in F IB -4 S c o r e
M e a n C h a n g e (9 5 % C I) fr o m
0 .6
P la c e b o
S ta g e 1 a t B L (n = 3 1 )
S ta g e 2 a t B L (n = 2 6 )
0 .4
S ta g e 1 a t B L (n = 2 1 )
0 .6
S ta g e 2 a t B L (n = 3 2 )
S ta g e 3 a t B L (n = 3 4 )
S ta g e 3 a t B L (n = 2 9 )
0 .4
0 .2
0 .2
0 .0
0 .0
-0 .2
-0 .2
-0 .4
-0 .4
-0 .6
0
24
48
72
96
-0 .6
0
W eeks
24
48
72
96
W eeks
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Change from Baseline in APRI by Baseline Fibrosis Stage
O b e tic h o lic
A c id
S ta g e 1 a t B L (n = 3 1 )
0 .6
S ta g e 1 a t B L (n = 2 1 )
S ta g e 2 a t B L (n = 3 2 )
S ta g e 2 a t B L (n = 2 6 )
B a s e lin e in A P R I S c o r e
M e a n C h a n g e (9 5 % C I) fr o m
0 .6
P la c e b o
S ta g e 3 a t B L (n = 3 4 )
0 .4
0 .2
0 .2
0 .0
0 .0
-0 .2
-0 .2
-0 .4
-0 .4
-0 .6
-0 .6
0
24
48
72
S ta g e 3 a t B L (n = 2 9 )
0 .4
96
W eeks
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0
24
48
W eeks
72
96
13
Change from Baseline in NFS by Baseline Fibrosis Stage
O b e t ic h o lic A c id
P la c e b o
S ta g e 1 a t B L (n = 2 1 )
S ta g e 1 a t B L (n = 3 0 )
S ta g e 2 a t B L (n = 3 2 )
S ta g e 2 a t B L (n = 2 6 )
B a s e lin e in N F S S c o r e
M e a n C h a n g e (9 5 % C I) fr o m
0 .6
S ta g e 3 a t B L (n = 3 4 )
S ta g e 3 a t B L (n = 2 9 )
0 .6
0 .4
0 .4
0 .2
0 .2
0 .0
0 .0
-0 .2
-0 .2
-0 .4
-0 .4
-0 .6
-0 .6
0
24
48
72
96
0
24
48
72
96
W eeks
W eeks
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Decrease in FIB-4 Score at 24 Weeks is Associated with
Improvement in Histologic Fibrosis Stage at 72 Weeks
0
F ib r o s is I m p r o v e m e n t a t 7 2 w k s ( n = 5 5 )
F IB -4 M e d ia n %
C h ange
N o F ib r o s is Im p r o v e m e n t a t 7 2 w k s ( n = 1 4 5 )
-5
-1 0
-1 5
0
24
48
72
W eek
A Wilcoxon Rank Sum analysis showed that a 10% reduction in median
FIB-4 values at 24 weeks is associated with a ≥1 stage improvement in
fibrosis stage at 72 weeks (p<0.05)
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Decrease in APRI at 24 Weeks is Associated with Improvement in
Histologic Fibrosis Stage at 72 weeks
0
F ib r o s is I m p r o v e m e n t a t 7 2 w k s ( n = 5 5 )
A P R I M e d ia n %
C hange
N o F ib r o s is Im p r o v e m e n t a t 7 2 w k s ( n = 1 4 5 )
-1 0
-2 0
-3 0
-4 0
-5 0
0
24
48
72
W eek
A Wilcoxon Rank Sum analysis showed that a 34% reduction in median
APRI values at 24 weeks is associated with a ≥1 stage improvement in
fibrosis stage at 72 weeks (p<0.05)
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Worsening of Histologic Fibrosis was Associated with Little
Change in FIB-4 and APRI
P la c e b o ( n = 3 1 )
0 .6
O C A (n = 2 0 )
0 .4
0 .2
0 .0
-0 .2
-0 .4
*
-0 .6
B L
24
48
72
96
M e a n (9 5 % C I) C h a n g e in A P R I S c o r e
M e a n (9 5 % C I) C h a n g e in F IB -4 s c o re
F IB -4
A P R I
P la c e b o ( n = 3 1 )
0 .6
O C A (n = 2 0 )
0 .4
0 .2
0 .0
-0 .2
*
-0 .4
-0 .6
W eeks
B L
24
48
72
96
W eeks
*p<0.05. P-values were calculated using ANCOVA models, regressing change from baseline at each post-baseline visit on treatment group
and baseline value of the outcome.
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ROC Curves for Noninvasive Fibrosis Scores
1 .0
0 .8
F IB -4
A P R I
S e n s it iv it y
0 .6
Parameters
 Fibrosis stage at baseline
 FIB-4/APRI at baseline
 FIB-4/APRI change at 24
weeks
 Treatment
0 .4
0 .2
0 .0
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
1 - S p e c if ic it y
NAME
CUT OFF
AUROC
NPV
PPV
95% CI
FIB-4
0.29
0.6817
80.7%
40.7%
(0.6024, 0.7610)
APRI
0.34
0.7238
80.6%
47.5%
(0.6483, 0.7993)
AUROC: Area under the receiver operator characteristic curve; NPV: negative predictive values; PPV: positive predictive values.
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Summary
 The baseline values of FIB-4, APRI and NFS were similar in patients
receiving OCA or placebo
 APRI and FIB-4 decreased in patients receiving OCA compared to
those who received placebo
 This was related to improvement in fibrosis stage; a 10% and 34%
decrease at 24 weeks in FIB-4 and APRI respectively was
associated with a ≥1 stage improvement in fibrosis at 72 weeks
 These changes in FIB-4 and APRI were seen across all baseline
stages of disease studied
 NFS was not sensitive to changes in fibrosis in this study
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Conclusions
 APRI and FIB-4 scores improved in patients with
improvement in fibrosis stage induced by OCA treatment
 It provides proof of concept that noninvasive markers of
fibrosis can be sensitive to change
 Improvement in FIB4 or APRI on treatment is
encouraging and more studies to refine their diagnostic
utility are needed
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