US-PP-NAS-0299.pptx

Advanced Fibrosis
due to Nonalcoholic
Steatohepatitis (NASH)
Impact, identification and
management
US-PP-NAS-0299 January 2020

Advanced Fibrosis Due to NASH
Impact, Identification and Management
These slides have been created and are provided by Intercept
Pharmaceuticals, Inc. as a professional courtesy. They are intended for
educational purposes only and are for your use only.
2

The Impact of Advanced Fibrosis due to NASH
• Increase in liver-related morbidity and mortality
• Speed of progression to cirrhosis
3
NASH, nonalcoholic steatohepatitis
Identifying Advanced Fibrosis
• Biopsy as Reference Standard
• Role of Non-Invasive Tests (NITs)
• Sequential use of 2 NITs
Managing Patients with Advanced Fibrosis due to NASH
• Management Goals
• Current Options
Advanced Fibrosis due to NASH: Overview
Summary

The impact of
Advanced Fibrosis
due to NASH

Advanced Fibrosis due to NASH represents a
subset of the NASH population
5
*Depiction of “early fibrosis” and “advanced fibrosis” for graphical purposes; based on modelling of the annual estimated number of incident NAFLD cases in 2015
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; US, United States
1. Estes C et al. Hepatology 2018;67(1):123–133; 2. Dulai PS et al. Hepatology 2017;65(5):1557–1565; 3. Hagström H et al. J Hepatol 2017;67:1265 –1273.
Patients with
Advanced Fibrosis are
at greater risk for
serious liver-related
consequences2,3
Distribution of NASH population by fibrosis stage in the US using a Markov population model*1
Without
cirrhosis
With
cirrhosis

Fibrosis is associated with reduced transplant-free survival
6
Fibrosis is associated
with reduced survival,
regardless of the
presence or absence of
NASH; therefore, when
assessing long-term
prognosis of patients, the
focus should be on
fibrosis stage1
Years of follow-up
0 5 10 15
Cumulative
survival
(%)
0.8
0.0
0.2
0.4
0.6
1.0
20
No fibrosis, non-NASH
Fibrosis, non-NASH
No fibrosis, NASH
Fibrosis, NASH
p <0.001
p = 0.018
Adapted from Angulo P et al. Gastroenterology 2015;149:389–397
*From a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand, who underwent laboratory and liver biopsy analysis. NASH includes borderline NASH
plus definitive NASH (n=284)1
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis
1. Angulo P et al. Gastroenterology 2015;149:389–397.
Survival free of liver transplantation in patients diagnosed with NAFLD, grouped
by presence of NASH/ no NASH; and the presence/ absence of fibrosis*

Fibrosis stage substantially increases the risk of
liver-related morbidity and mortality*
7
*Findings based on differing study populations and analyses not intended for comparison purposes
† From a retrospective cohort study of 646 biopsy-proven NAFLD patients, each matched to 10 controls. Severe liver disease was defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma
‡ From a meta-analysis of 5 multinational cohorts (1,495 NAFLD patients with 17,452 PYF). Liver-related mortality was a secondary outcome and was defined by investigators
NAFLD, nonalcoholic fatty liver disease; PYF, patient years of follow-up
1. Hagström H et al. J Hepatol 2017;67:1265 –1273; 2. Dulai PS et al. Hepatology 2017;65(5):1557–1565.
(0.17–11.95) (1.67–54.93) (2.92–95.36) (3.51–510.34)
95% confidence intervals
1.9
14.3
104.5
Liver-related mortality rate ratio‡2
Risk of severe liver disease
compared to controls†1
Risk of liver-related
mortality increases
exponentially with
increasing fibrosis
stage2 and patients
with advanced
fibrosis are at the
greatest risk
5.5
1.7
(0.90–4.10) (0.84–3.24) (3.10–9.70) (7.90–25.8) (57.2–191.1)
95% confidence intervals
0
20
40
60
80
100
120
F0 F1 F2 F3 F4
Hazard
ratio
Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273 Adapted from Dulai PS et al. Hepatology 2017;65(5):1557–1565

In Advanced Fibrosis due to NASH, some patients
may progress quickly
8
*In a study of patients with histologically confirmed NASH, 48 of 217 (22%) patients with stage 3 fibrosis (F3) progressed to cirrhosis at median follow-up of 29 months. Analysis used data from two large, randomized, placebo-controlled, phase 2b
studies of patients with F3 fibrosis and compensated cirrhosis due to NASH in which patients underwent biopsy at screening, Week 48, and Week 96
F3, stage 3 fibrosis; NASH, nonalcoholic steatohepatitis
1. Sanyal AJ et al. Hepatology 2019; doi: 10.1002/hep.30664.
Rapid progression of patients with
F3 to cirrhosis*1
1 in 5
progressed
to cirrhosis
After
approximately
2.5 years
The natural history of Advanced Fibrosis due to NASH may be more rapid
than previously thought1

*Based on estimates from 2015; patients without fibrosis (F0) were not included
†Based on a model with an embedded disease-specific Markov structure that allowed patients to transition from NAFLD to different liver health states (eg, NASH without fibrosis, which could then progress to NASH with fibrosis, cirrhosis, etc);
costs for NASH without fibrosis were not included
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis
1. Estes C et al. Hepatology 2018;67(1):123-133. 2. Younossi ZM et al. Hepatology 2016;64(5):1577-1586.
While only 10% of all NASH patients have cirrhosis,
cirrhosis accounts for >80% of annual direct medical costs1,2
Estimated Distribution of
NASH Population (US)*1
Total Annual Predicted Direct
Medical Costs in NASH†2
(Billions, USD)
90%
$8.3
$1.9
With Cirrhosis
Fibrosis
Without Cirrhosis
10%
9
Patients with cirrhosis account for a disproportionate
amount of NASH-related healthcare costs

Given the increasing risk of Advanced Fibrosis due to NASH,
it is important to identify these patients and take action
*Depiction of “early fibrosis” and “advanced fibrosis” for graphical purposes; based on modelling of the annual estimated number of incident NAFLD cases in 2015
†A retrospective study evaluating patients with histological F3 or F4 fibrosis due to various liver diseases
F3, stage 3 fibrosis; F4, stage 4 fibrosis; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; US, United States
1. Estes C et al. Hepatology 2018;67(1):123–133. 2. Servin-Abad L. Gastroenterol Hepatol 2006;1(1):819-825; 3. Axley P et al. PLOS ONE 2018; 13(8): https://doi.org/10.1371/journal.pone.0197117.
Distribution of NASH population by fibrosis stage in the US using a Markov population model*1
Without
cirrhosis
With
cirrhosis
10
At F4/cirrhosis, disease state may
not be fully reversible2
• F4 may be hard to distinguish from
F3 until the point of hepatic
decompensation†3
• Prognosis is poor and risk of liver-
related outcomes increases
compared to F3†3
URGENT ACTION IS NEEDED TO
PREVENT CIRRHOSIS AND COMPLICATIONS
For patients with F3, mitigating
progression to cirrhosis is therefore
a principle objective

When identifying patients with Advanced Fibrosis, biopsy is the
reference standard for diagnosing and staging
Biopsy has traditionally been used for identification of Advanced
Fibrosis but is associated with numerous limitations:1–5
Patient concerns related to the invasive nature of biopsy, as well as the
potential for pain, discomfort, and complications5,6
Invasive procedure with a risk of rare but life-threatening complications,
not ideal for monitoring patients over time1,5,6
Costly procedure1 which may require additional cost and time of an
interventional radiologist4
Only analyzes 1/50,000 of the liver and interpretation may differ between
pathologists, therefore serial biopsies may provide inconsistent findings1–3,5
SUBJECTIVE
COST
ADVERSE
EVENTS
PATIENT
RELUCTANCE
12
NASH, nonalcoholic steatohepatitis
1. EASL. J Hepatol 2015;63:237–264; 2. Rockey DC et al. Hepatology 2009;49(3):1017–44; 3. Sumida Y et al World J Gastroenterol 2014;20(2):475 – 485; 4. Diehl AM et al. N Engl J Med 2017;23;377(21):2063–2072; 5. Anstee QM et al.
Hepatology 2019; doi: 10.1002/hep.30842; 6. Leoni S et al. World J Gastroenterol 2018; 24(30):3361–3373.

*Based on paired biopsies assessed with Brunt scores 3 and 4. Brunt scores 3 and 4 defined in publication as ‘bridging fibrosis’
†Study to assess the sampling error of liver biopsy and its impact on diagnosis and stage of NASH. Patients with NAFLD (n=51) underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was
assessed by the percentage of discordant results and by the Kappa reliability test
‡The study investigated interobserver agreement for scores of liver fibrosis in 65 biopsy specimens from patients with mixed liver disease etiologies. Concordance between three pathologists was analysed. Bivariate weighted κ for Ishak staging ranged
from 0.57–0.67, and for NASH CRN staging ranged from 0.47–0.59.
AUROC, area under the receiver operating curve; CI, confidence interval; CRN, clinical research network; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis
1. Ratzui V et al. Gastroenterology 2005;128:1898–1906; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 3. Pavlides et al. Am J Clin Pathol 2017;147:364–369.
Liver biopsy is an imperfect reference standard for the
identification of Advanced Fibrosis1,2
13
• AUROC for detection of Advanced Fibrosis in paired
biopsies from 51 patients: 0.87 (95% CI: 0.7–0.95)1
• In a study of patients with Advanced Fibrosis (n=17),
diagnosis would have been missed in 35% of patients if
only one liver biopsy were analyzed*†1
Absence of Advanced Fibrosis*†1
Sensitivity of 85%
15% of patients with Advanced Fibrosis are missed
Presence of Advanced Fibrosis*†1
Specificity of 89%
11% of patients are wrongly diagnosed with
Advanced Fibrosis
Interobserver concordance rates of <67% show that interpretation of
liver biopsy results can vary among trained pathologists‡3

Despite limitations, liver biopsy results are predictive
of patient outcomes*1
14
Fibrosis stage
determined by liver
biopsy predicts
risk of all-cause
mortality in NAFLD
patients1
Kaplan-Meier survival estimates and fibrosis stage1
F0
F2
F4
40
0 10 20 30
Years of follow-up
Proportion
alive
1.00
0.00
0.25
0.50
0.75
Log-rank <0.001
Controls
F1
F3
Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
*From a retrospective cohort study of 646 biopsy-proven NAFLD patients, each matched to 10 controls
NAFLD, nonalcoholic fatty liver disease
1. Hagström H et al. J Hepatol 2017;67:1265 –1273.

Non-invasive tests (NITs) offer alternative ways to
determine the degree of fibrosis
AF, advanced fibrosis; NIT, non-invasive test
1. Tapper EB et al. Am J Gastroenterol 2015; doi: 10.1038/ajg.2015.241; 2. Lucero C et al. Gastroenterol Hepatol (N Y). 2016;12(1):33–40; 3. Srivastava A et al. J Hepatol 2019;71(2):371–378;
4. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842.
Sequential use of NITs may increase the number of patients from
identified with Advanced Fibrosis3
Safe and simple way to support disease monitoring over time1
MONITOR
INCREASED
IDENTIFICATION
OF AF
NITs are reproducible, widely available and relatively low cost1–4
Assess the level – e.g. absence or presence – of fibrosis2
ASSESS
FIBROSIS
May be cost effective as opposed to biopsy1
COST
EFFECTIVE
15

Recent guidelines recognize the value of NITs
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIT, non-invasive test
1. Chalasani N et al. Hepatology 2018;67(1):328–357; 2. EASL-ALEH. J Hepatol 2015;63:237–264.
NITs have prognostic value in predicting both mortality and liver-related
complications in patients with NAFLD/NASH and other chronic liver diseases2
“There is increasing evidence for the
prognostic value of non-invasive tests”2
“There has been significant interest in
developing clinical prediction rules and
noninvasive biomarkers for identifying SH
[steatohepatitis]”1
16

Commonly used NITs
NITs, non-invasive tests
1. EASL. J Hepatol 2015;63:237–264; 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 3. Atay K et al. Biomedical Research 2017;28(2):565–570; 4. Chalasani N et al. Hepatology 2018;67(1):328–357.
• NITs use different approaches to determine liver fibrosis:1
• NITs are an area of active research and learning continues to evolve
17
ELFTM is a trademark of Siemens Healthineers
*ELFTM is not commercially available in the US, but used widely outside of the US
FibroScan® is a registered trademark of EchoSensTM, Paris
FibroTest® is a registered trademark of BioPredictive S.A.S, Paris; FibroSure® is distributed by LabCorp in the US
List of NITs provided above is not exhaustive
• FibroSure®
(FibroTest® outside of the US)2
• ELFTM (Enhanced Liver Fibrosis)2*
• NFS (NAFLD fibrosis score)2
• FIB-4 (Fibrosis-4)2
• APRI (Aspartate aminotransferase/
platelet ratio index)3
• Simple Scores
•use information from standard
liver tests and patient data1
Proprietary Serum Tests
test biomarkers associated with
fibrosis stage1
• Transient elastography
(e.g. FibroScan®)2
• MRE (Magnetic resonance
elastography)4
Imaging techniques
focus on liver stiffness1

What makes a good NIT?
• A good NIT is both sensitive and specific in determining the presence or absence of Advanced Fibrosis1
– Use of two cut-off values can maximize sensitivity and specificity compared to the use of a single cut-off value2
• An acceptable NIT also has an AUROC value closer to 1.0*1
18
*The AUROC (Area Under the Receiver Operating Characteristic curve) gives an average performance of a model (NIT) along all sensitivity thresholds. The higher the AUROC (or the closer to 1.0 or similar) the better the model is at
distinguishing between patients with disease and no disease1
AUROC, area under the receiver operating characteristic curve; NIT, non-invasive test
1. Bewick V et al. Crit Care 2004;8(6):508–512; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842.
Indeterminate Presence of Advanced Fibrosis
Absence of Advanced Fibrosis
Upper cut-off value
Lower cut-off value
Lower threshold maximizes
sensitivity, ensuring that
patients with Advanced Fibrosis
are not wrongly excluded2
Upper threshold maximizes
specificity, ensuring that
patients without Advanced Fibrosis
are not wrongly diagnosed2

Fibrosis 4 (FIB-4) can be easily calculated in office with a
simple blood test and online calculators1
19
FIB-4, fibrosis-4; URL, Uniform Resource Locator
1. Fibrosis-4 calculator. Available at: https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis. (Accessed September 2019); 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668.
• Based on age, platelet count, alanine aminotransferase (ALT) level and aspartate
aminotransferase (AST) level2
• Simple score that uses readily available patient data
FIB-4 =
Calculator available at: https://www.mdcalc.com
Permission to use MDCalc logo and FIB-4 URL has been kindly granted by Dr Graham Walker, Co-Creator of MDCalc

FIB-4 can determine the presence of Advanced Fibrosis1,2
20
• AUROC of 0.78 (95% CI:0.78–0.78)2
• Recognized by AASLD as clinically useful in identifying patients with a higher likelihood of F3 or F43
• LabCorpTM recently incorporated FIB-4, including these cut-off points, into its test report4
Sensitivity of 82%
18% of patients with Advanced
Fibrosis are missed
Specificity of 93%
7% of patients are wrongly
diagnosed with Advanced Fibrosis
FIB-4 cut-off scores and accuracy for measurement of Advanced Fibrosis*2
≥2.67
<1.3
*FIB-4 test results are based on age, hence the accuracy of the test may vary according to age
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; F3, stage 3 fibrosis; F4, stage 4 fibrosis; FIB-4, Fibrosis-4
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 3. Chalasani N et al. Hepatology 2018;67(1):328–357; 4. Available from https://www.labcorp.com/test-
menu/46291/fib-4#. (Accessed September 2019)

FIB-4 score may predict long-term outcomes
21
FIB-4, fibrosis-4
Cumulative probability of death/liver transplantation
is related to FIB-4 score1
1.0
Survival
probability
(%)
Duration (years)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
FIB-4: >2.67
FIB-4: 1.30 to 2.67
FIB-4: <1.30
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789 Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
Liver biopsy
Years of follow-up
P = 0.03
FIB-4 Liver biopsy
Charts are illustrative and not comparative due to differing patient populations described in the studies

NAFLD Fibrosis Score (NFS) can be easily calculated in office
with a simple blood test and online calculators1
22
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score; URL, Uniform Resource Locator
1. NAFLD fibrosis score. Available from https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score (Accessed September 2019); 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668.
• Based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio2
• Simple score that uses readily available information
NFS =
Permission to use MDCalc logo and NAFLD URL has been kindly granted by Dr Graham Walker, Co-Creator of MDCalc

NFS can determine the presence of Advanced Fibrosis
23
*NFS test results are based on age, hence the accuracy of the test may vary according to age
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; F3, stage 3 fibrosis; F4, stage 4 fibrosis; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Chalasani N et al. Hepatology 2018;67(1):328–357.
• AUROC: 0.74 (95% CI:0.74–0.74)1
• Recognized by AASLD as clinically useful in identifying patients with a higher likelihood of F3 or F42
Sensitivity of 89%
Fibrosis are missed
Specificity of 89%
NFS cut-off scores and accuracy for measurement of Advanced Fibrosis*1
≥0.676
<-1.455

NFS may predict long-term outcomes
24
NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score
Cumulative probability of death/liver transplantation is related to NFS1
1.0
Survival
probability
(%)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
NAFLD-FS: -1.455 to 0.676
NAFLD-FS: <-1.455
Duration (years)
NAFLD-FS: >0.676
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789 Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
Liver biopsy
Years of follow-up
P <0.001
NFS Liver biopsy

APRI (aspartate aminotransferase/platelet ratio index) can be easily
calculated in office with a simple blood test and online calculators1
• Based on AST and platelet count1
• Simple score that can be used at the bedside or in an outpatient setting1
APRI, aspartate aminotransferase/platelet ratio index; AST, aspartate aminotransferase; URL, Uniform Resource Locator
1. Kruger FC et al. S Afr Med J 2011;101:477-480.
Permission to use MDCalc logo and APRI URL has been kindly granted by Dr Graham Walker, Co-Creator of MDCalc
U/L
AST
U/L
AST upper limit of normal
X109/L
Platelet count
Norm: 1–40
40
Norm: 150–350
APRI =
25

APRI can exclude Advanced Fibrosis
• AUROC: 0.76 (95% CI:0.74–0.79)1
APRI cut-off scores and accuracy for measurement of Advanced Fibrosis*1
Caution needed with false positives, particularly in patients with acute hepatitis2
May be more useful to exclude, rather than determine, Advanced Fibrosis3
*The study population included patients with histological findings consistent with NAFLD
APRI, aspartate aminotransferase/platelet ratio index; AUROC, area under the receiver operating curve; CI, confidence interval; NAFLD, nonalcoholic fatty liver disease
1. Siddiqui MS et al. Clin Gastroenterol Hepatol 2019; doi: 10.1016/j.cgh.2018.12.031; 2. EASL. J Hepatol 2015;63:237–264; 3. Atay K et al. Biomedical Research 2017;28(2):565–570.
Specificity of 65%
diagnosed with Advanced
Fibrosis
Sensitivity of 90%
10% of patients with
Advanced Fibrosis are missed
Absence of Advanced Fibrosis Presence of Advanced Fibrosis
Indeterminate
>0.84
<0.57
26

Cumulative probability of death/liver transplantation is related to APRI score1
Adapted from Angulo P et al. Gastroenterology 2013;145:782–789
Liver biopsy
Years of follow-up
APRI, aspartate aminotransferase/platelet ratio index
APRI may predict long term outcomes
Liver biopsy
27
1.0
Survival
probability
(%)
Duration (years)
0.0
0.2
0.4
0.6
0.8
25
20
15
10
5
0
APRI: <0.5
APRI: 0.5 to 1.5
APRI: >1.5
APRI

FibroSure® (FibroTest® outside the US)
can determine the presence of Advanced Fibrosis
• Proprietary serum test that combines five biomarkers: haptoglobin, α2-macroglobulin, apolipoprotein A1, total
bilirubin and gamma glutamyl-transferase*1
• AUROC: 0.832 (SE 0.01)
Specificity of 83%
diagnosed with Advanced
Fibrosis
FibroSure® cut-off scores and accuracy for measuring Advanced Fibrosis†2,3
FibroTest® is a registered trademark of BioPredictive S.A.S, Paris; FibroSure® is distributed by LabCorpTM in the US
Sensitivity of 84%
Fibrosis are missed
Early or no Fibrosis Presence of Advanced Fibrosis
Moderate‡
*False positives can arise from haemolysis, Gilbert syndrome, cholestasis and inflammation due to increased levels of α2-macroglobulin and haptoglobin4
†In patients with hepatitis C
‡Moderate, F1–F2 and F2–bridging fibrosis with few septa3
AUROC, area under the receiver operating curve; SE, standard error
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Poynard T et al. Comp Hepatol 2004;3:8; 3. LabCorp NASH FibroSure sample report. Available at: https://files.labcorp.com/testmenu/550140.pdf (Accessed October 2019);
4. Lucero C and Brown RS. Gastroenterol Hepatol 2016;12(1):33–40.
>0.58
≤0.31
28

ELF (enhanced liver fibrosis) score can determine
the presence of Advanced Fibrosis
• Combines three biomarkers of fibrosis: hyaluronic acid, tissue inhibitor of metalloproteinase 1 and amino-terminal peptide of
procollagen III1
• AUROC for identifying Advanced Fibrosis (cut-off ≥9.8): 0.86 (95% CI: 0.83–0.89)2
• ELF is recommended by NICE for the diagnosis of Advanced Fibrosis in adults with NAFLD3
29
Moderate* Presence of Advanced Fibrosis
Sensitivity of 85%
Fibrosis are missed
Specificity of 90%
ELF cut-off scores and accuracy for measurement of Advanced Fibrosis4
Early or no fibrosis
≥9.8
<7.7
*Moderate, categorized as mild–advanced fibrosis, ELF scores of 7.7–9.79
AUROC, area under the receiver operating curve; CI, confidence interval; ELF, enhanced liver fibrosis; NAFLD, nonalcoholic fatty liver disease; NICE, National Institute for Health and Care Excellence
1. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 2. Siemens Healthineers. ELF instructions for use. Available at: https://doclib.healthcare.siemens.com/ (Accessed October 2019); 3. NICE. Non-alcoholic fatty liver disease
(NAFLD): assessment and management. NICE guideline NG49, July 2016. Available at: https://www.nice.org.uk/guidance/ng49 (Accessed October 2019); 4. Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359.

ELF score may predict long-term liver-related outcomes1
30
*Kaplan–Meier survival curves for survival free of liver-related events including complications of portal hypertension, liver cancer, liver transplantation, and death for patients with ELF scores in the ranges <7.70, 7.7–9.79, 9.80–11.29, and ≥11.30
ELF, enhanced liver fibrosis; IFU, instructions for use
1. Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359.
Cumulative probability of liver-related events is related to ELF score*1
Liver biopsy
Years of follow-up
Liver biopsy
Adapted from Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359
Time to event (years)
Cumulative
survival
1.0
0.0
0.2
0.4
0.6
0.8
10
8
6
4
2
0
ELF
≥11.30
9.8–11.29
7.70–9.79
<7.70
ELF IFU cut-offs

Transient Elastography (e.g. FibroScan®) can determine the
presence of Advanced Fibrosis
• Imaging technique that evaluates both fibrosis and steatosis:1
– Liver stiffness expressed as kPa, correlates with fibrosis
– Controlled attenuation parameter, expressed in dB/m, correlates with steatosis
• Recognized by AASLD as clinically useful for the identification of Advanced Fibrosis in patients with NAFLD2
• AUROC: 0.93 (95% CIs:0.89–0.96)3
Presence of Advanced Fibrosis
Sensitivity of 91%
Fibrosis are missed
Specificity of 92%
FibroScan® cut-off scores and accuracy for measurement of Advanced Fibrosis3
Indeterminate
AASLD, American Association for the Study of Liver Diseases; AUROC, area under the receiver operating curve; CI, confidence interval; kPa, kilopascal; NAFLD, nonalcoholic fatty liver disease
1. Mikolasevic I et al. World J Gastroenterol 2016;22(32):7236–7251; 2. Chalasani N et al. Hepatology 2018 Jan;67(1):328–357; 3. Wong VWS et al. Hepatology 2010;51(2):454–462.
≥9.6 kPa
<7.9 kPa
31

Transient Elastography (e.g. FibroScan®) measures
liver stiffness, which correlates with fibrosis1
32
BMI, body mass index
1. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585; 2. Kemp W and Roberts S. Aust Fam Physician 2013;42(7):468–471.
Measures liver
stiffness over an
area estimated to
be 100x greater
than that of liver
biopsy1
Failure to obtain
readings is more
likely in patients
with a high BMI
(>30 kg/m2),
however, use of XL
probe may help
overcome this
limitation1
Over-estimation of
fibrosis can occur in
cases of hepatitis,
cholestasis, liver
congestion and if
mass lesions are
present in the liver2
• Liver stiffness is measured via a mechanically induced, controlled
50 Hz frequency shear wave1
• The propagation speed of the shear wave is measured with pulse
echo ultrasound, with the results presented as kilopascals (kPa)1

Fibrosis stage measured by
Transient Elastography is predictive of mortality
33
LSM, liver stiffness measurement; TE, transient elastography
1. Boursier J et al. J Hepatol 2016;65(3):570–578.
Cumulative probability of death is related to Transient Elastography score1
Adapted from Boursier J et al. J Hepatol 2016;65(3):570–578 Adapted from Hagström H et al. J Hepatol 2017;67:1265 –1273
1.0
Overall
survival
Follow-up (years)
0.0
0.2
0.4
0.6
0.8
10
8
6
4
2
0
LSM fibrosis classification:
LSM1 (F0/1)
LSM3 (F1/2)
LSM4 (F2/3)
LSM6 (F3/4)
LSM7 (F4)
P <0.001
Liver biopsy
TE
Years of follow-up
TE Liver biopsy

Magnetic resonance elastography (MRE) can determine the
presence of Advanced Fibrosis
*Moderate is classified as patients with fibrosis staging of F2
AUROC, area under the receiver operating curve; CI, confidence interval; F0–F2, stage 0–2 fibrosis; F2, stage 2 fibrosis; F3, stage 3 fibrosis; MRE, magnetic resonance elastography
1. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585; 2. Hsu C et al. Clin Gastroenterol Hepatol 2019;17(4):630–637.e8.
• Imaging technique that assesses the propagation of mechanical waves through liver tissue to estimate the
degree of fibrosis1
• AUROC for identifying Advanced Fibrosis (≥F3) vs F0–2: 0.93 (95% CIs: 0.90–0.96)2
Moderate* Presence of Advanced Fibrosis
Sensitivity of 85%
Fibrosis are missed
Specificity of 83%
MRE cut-off scores and accuracy for measurement of advanced fibrosis2
Early or No Fibrosis
>3.62
<2.97
34

MRE in clinical practice
MRE has been
shown to be both
sensitive and
specific when
identifying different
stages of liver
fibrosis2
Unlike other NITs
and liver biopsy,
MRE estimates the
average degree of
fibrosis throughout
the entire liver2
Limitations include
the high cost of the
equipment and the
level of expertise
required to interpret
results2
MRE is recognized by AASLD as “clinically useful” for the identification of Advanced Fibrosis*1
Inflammation/
fibrosis
Healthy
liver
†
*Identification of Advanced Fibrosis in patients NAFLD1
†MRE image indicates Advanced Fibrosis (F3) – liver stiffness 6.1 kPa. Adapted from Venkatesh SK et al. J Magn Reson Imaging 2013;37:544–555
AASLD, American Association for the Study of Liver Diseases; kPa, kilopascal; MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; NIT, non-invasive test
1. Chalasani N et al. Hepatology 2018 Jan;67(1):328–357; 2. Grandison GA and Angulo P. Clin Liver Dis 2012;16(3):567–585. 35

Summary of common tests for determining fibrosis stage*
Test AUROC Lower cut-off to rule out
Advanced Fibrosis
Sensitivity for lower
cut-off (%)
Upper cut-off to rule in
Advanced Fibrosis
Specificity for upper
cut-off (%)
Simple scores
FIB-41 0.78 <1.3 82 ≥2.67 93
NFS1 0.74 <-1.455 89 ≥0.676 89
APRI2 0.76 <0.57 90 >0.84 65
Proprietary serum tests
FibroSure®3 0.83 ≤0.31 84 >0.58 83
ELF4,5 0.86† <7.7 85 ≥9.8 90
Imaging techniques
FibroScan®6 0.93 <7.9 kPa 91 ≥9.6 kPa 92
MRE7 0.93‡ <2.97 kPa 85 >3.62 kPa 83
Histological tests
Liver biopsy8 0.87 ≤F2 85 ≥F3 89
*For informational purposes only – not intended for comparison
†AUROC is for upper cut-off of ≥9.6 to detect patients with Advanced Fibrosis
‡AUROC is for upper cut-off of >3.62 kPa to detect patients with ≥F3 fibrosis
APRI, aspartate aminotransferase/platelet ratio; AUROC, area under the receiver operating curve; ELF, enhanced liver fibrosis; FIB-4, fibrosis 4; kPa, kilopascal; MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty
liver disease; NFS, NAFLD fibrosis score
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Siddiqui MS et al. Clin Gastroenterol Hepatol 2019; doi: 10.1016/j.cgh.2018.12.031; 3. Poynard T et al. Comp Hepatol 2004;3:8; 4. Siemens Healthineers. ELF
instructions for use. Available at: https://doclib.healthcare.siemens.com/ (Accessed October 2019); 5. Day J et al. JALM 2019;DOI:10.1373/jalm.2018.027359; 6. Wong VWS et al. Hepatology 2010;51(2):454–462; 7. Hsu C et al.
Clin Gastroenterol Hepatol 2019;17(4):630–637.e8; 8. Ratzui V et al. Gastroenterology 2005;128:1898–1906. 36

Both histological and non-invasive tests are
viable options for identifying advanced fibrosis
NAFLD, nonalcoholic fatty liver disease
1. EASL. J Hepatol 2015;63:237–264; 2. Alkhouri N et al. Gastroenterol Hepatol (NY) 2012;8(10): 661–668; 3. Atay K et al. Biomedical Research 2017;28(2):565–570; 4. Chalasani N et al. Hepatology 2018;67(1):328–357; 5. Rockey DC et al.
Hepatology 2009;49(3):1017–1043 .
• Different approaches to determine liver fibrosis:1
37
• FibroSure® (FibroTest®
outside of the US)2
• ELFTM
(Enhanced Liver Fibrosis)2*
• NFS (NAFLD fibrosis
score)2
• FIB4 (Fibrosis-4)2
• APRI (Aspartate
aminotransferase/ platelet
ratio index)3
• Transient elastography
(e.g. FibroScan®)2
• MRE (Magnetic resonance
elastography)4
Histological assessment
• Liver biopsy5
ELFTM is a trademark of Siemens Healthineers
*ELFTM is not commercially available in the US, but used widely outside of the US
FibroTest® is a registered trademark of BioPredictive S.A.S, Paris; FibroSure® is distributed by LabCorp in the US
List of NITs provided above is not exhaustive
•Simple Scores
•use information from
standard liver tests and
patient data1
Proprietary Serum Tests
test biomarkers associated
with fibrosis stage1
Imaging techniques
focus on liver stiffness1

The sequential use of NITs maintains sensitivity and specificity while decreasing the
number of patients in the indeterminate zone1–3
The use of a second NIT for patients in the indeterminate zone could
increase the number of patients identified with advanced fibrosis1–3
38
Adapted from Younossi ZM et al. Presented at: AASLD; November 9–13, 2018; San Francisco, United States; Abstract LB-10.
NIT #1
NIT #2
Indeterminate
Absence of advanced fibrosis Presence of advanced fibrosis
Indeterminate
Absence of advanced fibrosis Presence of advanced fibrosis
AASLD, American Association for the Study of Liver Diseases; NIT, non-invasive test
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Younossi ZM et al. Presented at: AASLD; November 9–13, 2018; San Francisco, United States; Abstract LB-10; 3. Srivastava A et al. BMC Gastroenterol 2019;19(1):122. doi:
10.1186/s12876-019-1039-4.

Utilization of a second NIT for patients in the
indeterminate zone following a single NIT
NIT, non-invasive test
1. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 2. Srivastava A et al. J Hepatol 2019;71(2):371–378; 3. Chan et al. Clin Gastroenterol Hepatol 2019; oi: 10.1016/j.cgh.2019.03.006;
4. Srivastava A et al. BMC Gastroenterol 2019;19(1):122.
The sequential use of NITs can lead to identification of a greater number of
patients with Advanced Fibrosis and improve patient care1,2,4
… maintain
sensitivity and
specificity1
… detect up
to 5 times
more cases of
Advanced
Fibrosis and
cirrhosis2
… reduce the
rate of
indeterminate
results to as low
as 20%1,3
However, when
two NITs are
utilized
sequentially,
misclassification
rate also
increases1
• Utilization of NITs sequentially may…
39

Algorithmic approach for the screening of Advanced Fibrosis
using two NITs*1–5
40
*This graphic is for illustrative purposes and is not intended to be prescriptive. Clinical algorithms1–3,5 have been published to guide screening of Advanced Fibrosis; this is an adaptation, summary and overview of the recommended algorithms
NIT, non-invasive test
1. Patel PJ et al. Hepatol Commun 2018;2(8):893–905; 2. Festi D et al. Aliment Pharmacol Ther 2013;37:392–400; 3. Castera L et al. Gastroenterology 2019;156(5):1264–1281; 4. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842;
5. Alkhouri N et al. Hepatol Commun 2019;3(5):605–613.
Manage as clinically
significant Fibrosis1
CARRY OUT NIT #2
Indeterminate
Absence of Advanced
Fibrosis
Presence of Advanced
Fibrosis
Recommend lifestyle
modifications and monitor
Use Clinical Judgment
for Next Steps
CARRY OUT NIT #1
Use 2nd NIT
Indeterminate
Absence of Advanced
Fibrosis
Presence of Advanced
Fibrosis

Identifying Advanced Fibrosis
The sequential use of
more than one NIT,
following an
indeterminate result
from a single NIT, can
reduce the number of
unclassified Advanced
Fibrosis patients2,3
NITs offer a cost-
effective alternative
for determination of
Advanced Fibrosis,
and their value is
recognized in recent
guidelines3–5
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIT, non-invasive test
1. Dyson JK et al. Frontline Gastroenterol 2014;5:211–218; 2. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 3.EASL-EASD-EASO. J Hepatol 2016;64:1388–1402; 4. Tapper EB et al. Am J Gastroenterol 2015; doi:
10.1038/ajg.2015.241; 5. EASL. J Hepatol 2015;63:237–264. 41
The majority of
patients with
Advanced Fibrosis
can be effectively
identified with NITs,
reducing the need for
liver biopsy1,2

Managing Patients with
Advanced Fibrosis
due to NASH

For patients with Advanced Fibrosis without cirrhosis,
halting progression is an important goal1,2
1. Filozof C et al. Hepatol Commun 2017; 1(7): 577–585; 2. FDA Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry. December 2018;
HALT or REVERSE
FIBROSIS
• Preventing progression to
cirrhosis is a principle
objective of management1
PREVENT
Progression to CIRRHOSIS
• Fibrosis stage is associated
with overall survival and
liver-related complications3
• Presence and severity of
fibrosis may predict long-
term outcomes3
43

With no indicated pharmacological treatments,
management options are currently limited1,2
EASD, European Association for the Study of Diabetes; EASL, European Association for the Study of the Liver; EASO, European Association for the Study of Obesity; FDA, Food and Drug Administration; NASH, nonalcoholic steatohepatitis;
US, United States
1. Chalasani N et al. Hepatology 2018;67(1):328–357; 2. EASL-EASD-EASO. J Hepatol 2016;64:1388–1402. 3. Oseini AM et al. Liver Int 2017;37 Suppl 1:97–103; 4. FDA Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis:
Developing Drugs for Treatment Guidance for Industry, December 2018.
Lifestyle Modification
• Lifestyle modification, including changes
such as diet, weight loss, and exercise, is
recommended as a first-line treatment3
• Lack of patient compliance may be a key
limitation of this approach1
• Non-indicated treatments, such as
vitamin E or pioglitazone, may be
considered in select patients1,2
• Data are limited and risks and benefits
should be discussed with each patient
before starting therapy1
Non-indicated pharmacological treatments
Commonly Used Treatment Options for NASH and Advanced Fibrosis due to NASH
“Currently, there are no approved drugs for the treatment of NASH.” – FDA-US, 20184
“No specific therapy can be firmly recommended [for NASH]” – EASL-EASD-EASO, 20162
There is an urgent need for options for patients
with Advanced Fibrosis due to NASH3
44

Focus on Advanced Fibrosis due to NASH
• Biopsy is the current reference
standard but has limitations4–7
• NITs offer alternative ways to
determine the presence of fibrosis,
and are predictive of long-term
outcomes4,7–10
• When used sequentially, and
following an indeterminate result
from a single NIT, two NITs may
reduce the number of patients in the
‘indeterminate’ zone7,11
• Liver-related morbidity and
mortality increase substantially
with fibrosis stage1
• Some patients may progress to
cirrhosis in as few as 2.5 years2
• Fibrosis stage is associated with
overall survival and
liver-related complications3
•Patients with Advanced Fibrosis
due to NASH are at a greater risk
of serious liver-related
consequences
There are alternatives to biopsy
for determining Advanced Fibrosis
due to NASH4–11
• Management options for patients
with Advanced Fibrosis due to
NASH are currently limited14,15
• There is an urgent need for options
for these patients16,17
It is important to halt fibrosis
progression and address
inflammation, an underlying
driver of fibrosis12,13
45
NASH, nonalcoholic steatohepatitis; NIT, non-invasive test
1. Dulai PS et al. Hepatology. 2017;65(5):1557–1565; 2. Sanyal AJ et al. Hepatology 2019; doi: 10.1002/hep.30664; 3. Angulo P et al. Gastroenterology 2015;149:389–397; 4. Leoni S et al. World J Gastroenterol 2018; 24(30):3361–3373; 5. EASL-
ALEH. J Hepatol 2015;63:237–264; 6. Rockey DC et al. Hepatology 2009;49(3):1017–44; 7. Anstee QM et al. Hepatology 2019; doi: 10.1002/hep.30842; 8. Tapper EB et al. Am J Gastroenterol 2015; doi: 10.1038/ajg.2015.241; 9. Angulo P et al.
Gastroenterology 2013;145:782–789; 10. Boursier J et al. J Hepatol 2016;65(3):570–578; 11. Younossi ZM et al. Presented at: AASLD; November 9–13, 2018; San Francisco, United States; Abstract LB-10; 12. Diehl AM et al N Engl J
Med 2017;23;377(21):2063–2072; 13. Czaja AJ. World J Gastroenterol 2014; 20(10):2515–2532; 14. Chalasani N et al. Hepatology. 2018;67(1):328–357; 15. EASL-EASD-EASO. J Hepatol 2016;64:1388–1402; 16. FDA Noncirrhotic Nonalcoholic
Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry. December 2018; 17. Oseini AM et al. Liver Int 2017;37 Suppl 1:97–103.

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