Clinical Impact of New NAFLD/NASH Data From EASL 2018

1. Clinical Impact of New NAFLD/NASH Data From
EASL 2018
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This program is supported by educational grants from AbbVie and Gilead Sciences
CCO Independent Conference Coverage*
of the 2018 International Liver Congress, April 11-15, 2018

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Slide credit: clinicaloptions.com

3. Faculty
Vlad Ratziu, MD, PhD
Professor of Hepatology
University Pierre et Marie Curie Hospital La Pitié-Salpêtrière
Paris, France
Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD
Chairman, Department of Medicine
Professor of Medicine
Inova Fairfax Hospital
Inova Health System
Falls Church, Virginia

4. Disclosures
Vlad Ratziu, MD, PhD, has disclosed that he has received
consulting fees from Allergan, Boehringer Ingelheim, Genfit,
Intercept, Novartis, and Novo-Nordisk and funds for research
support from Gilead Sciences and Intercept Pharmaceuticals.
Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD,
has disclosed that he has received consulting fees or funds for
research support from Allergan, Bristol-Myers Squibb, Gilead
Sciences, Intercept, Novartis, NovoNordisk, and Shinogi.

5. Outline
 Noninvasive Screening for NAFLD/NASH
 Clinical Outcomes in Patients With NAFLD/NASH
 Treatment of NAFLD/NASH
Slide credit: clinicaloptions.com

6. Noninvasive Screening
for NAFLD/NASH

7. Detection of NASH in Patients With T2DM
 Prospective, multicenter UK study
of patients undergoing liver biopsy
for possible NAFLD (N = 408)
– Noninvasive algorithm developed
in subset of evaluable patients with
NAFLD and T2DM
 Algorithm based on ALT, CAP, and
elastometry values measured by
FibroScan
 Goals for algorithm
– To identify NASH with activity > 2
– Activity (SAF score) based on sum
of ballooning (graded 0-2) and
lobular inflammation (graded 0-2)
– To improve SFR by > 30%
– To keep missed cases < 15%
Eddowes P, et al. EASL 2018. Abstract FRI-424. Slide credit: clinicaloptions.com
Patient Characteristic T2DM (n = 176)
Median age, yrs (IQR) 58 (14)
Female, n (%) 86 (49)
Median BMI (IQR) 34.4 (8.7)
NASH, n (%) 135 (77)
NASH with activity > 2, n (%) 90 (51)

8. Algorithm Improves Noninvasive Detection of
NASH With Activity > 2 in Patients With T2DM
 SFR improved by 35%, missed cases < 15%, 36% of patients
could have avoided liver biopsy with this algorithm
Eddowes P, et al. EASL 2018. Abstract FRI-424. Slide credit: clinicaloptions.com
All T2DM
Patients
N = 176
NA > 2 = 90
SFR = 49%
MCR = 0%
SIR = 0%
Step 1
ALT/ULN ≥ 0.71
N = 135
NA > 2 = 85
SFR = 37%
MCR = 6%
SIR = -23%
Step 2
CAP ≥ 270 dB/m
N = 123
NA > 2 = 81
SFR = 34%
MCR = 10%
SIR = -30%
Step 3
E ≥ 6.1 kPa
N = 113
NA > 2 = 77
SFR = 32%
MCR = 14%
SIR = -36%

9. Multiparametric MRI Identifies, Stratifies
NAFLD/NASH
 Utility of multiparametric MRI to
identify and stratify NAFLD/NASH
assessed in 2 large cohorts
– In all patients, LiverMultiScan™
protocol estimated PDFF and cT1
– UK Biobank cohort: ongoing national
study to collect imaging data from
100,000 individuals (n = 2895)
– US San Antonio cohort: patients with
no prior liver disease or alcohol abuse
undergoing routine colon cancer
screen (n = 477)
– Offered biopsy if FibroScan ≥ 7 kPa,
MRE ≥ 3 kPa, PDFF ≥ 5%, or LIF ≥ 2
 Of 139 biopsied US patients with
PDFF ≥ 5% and cT1 ≥ 800 ms:
– 98% had NAFLD, 67% had NASH,
and 29% had NASH with F2/3 fibrosis
– Addition of cT1 to PDFF enriched
NASH stratification 116% to 253%
 Based on US biopsy analysis,12%
projected NASH prevalence in UK
cohort
– In UK subset with PDFF ≥ 5%, NASH
predicted at 49%; NASH with F2/3
fibrosis at 15%
Harrison S, et al. EASL 2018. Abstract FRI-421. Slide credit: clinicaloptions.com

10. Hepamet Score Improves Noninvasive
Classification of Fibrosis in Patients With NAFLD
 Noninvasive panel to predict fibrosis
stage developed in patients with
biopsy-proven NAFLD
– Spain, n = 758; France, n = 444; Cuba,
n = 344; Italy, n = 288
– 36% significant fibrosis, 20% advanced
fibrosis, 6% cirrhosis
– Estimation in Spanish cohort,
validation in remaining patients
 Variables associated with advanced
fibrosis: older age, female sex, T2DM,
HOMA ≥ 4, AST ≥ 35 IU/mL, albumin
< 4 g/dL, and PLT ≤ 220 x 109
 Compared with FIB-4 and NFS,
Hepamet Fibrosis Score:
– Improved classification of fibrosis in
patients with NAFLD
– Reduced proportion of patients falling
in the grey zone
– Avoided age-adjusted cutoffs
Ampuero J, et al. EASL 2018. Abstract PS-179. Slide credit: clinicaloptions.com
AUROC
(N = 1834)
Hepamet NFS FIB-4
P
Value
F2-F4 0.758 0.679 0.731 .0001
F3-F4 0.847 0.767 0.797 .0001
F4 0.902 0.863 0.875 .0397

11. Pooled Analysis of MRE vs TE to Detect Fibrosis
in Patients With NAFLD
 Systematic review and meta-analysis of pooled patient data from
studies comparing MRE vs TE for fibrosis staging in NAFLD[1]
 Study eligibility:
– MRE and TE used to assess liver stiffness
– Liver biopsy used as reference
– Fibrosis staging system comparable to biopsy staging
– Included adult patients with NAFLD
 3 studies met criteria for inclusion[2-4]
1. Hsu C, et al. EASL 2018. Abstract FRI-439. 2. Chen J, et al. Radiology. 2017;283:418-428.
3. Imajo K, et al. Gastroenterology. 2016;150:626-637.e7. 4. Park CC, et al. Gastroenterology.
2017;152:598-607.e2. Slide credit: clinicaloptions.com

12. Overall
(n = 230)
AUROC
Optimal
Threshold,
kPa
Sensitivity,
%
Specificity,
%
PPV, % NPV, %
P
Value
Stage 1-4 (n = 157) vs 0 (n = 73)
 MRE
 TE
0.8685
0.8184
2.61
6.2
71.3
65.6
72.6
67.1
84.9
81.1
54.1
47.6
.0394
Stage 2-4 (n = 93) vs 0-1 (n = 137)
 MRE
 TE
0.9193
0.8664
2.97
7.6
84.9
76.3
85.4
79.6
79.8
71.7
89.3
83.2
.0265
Stage 3-4 (n = 57) vs 0-2 (n = 173)
 MRE
 TE
0.9295
0.8411
3.62
8.8
82.5
77.2
83.2
78.0
61.8
53.7
93.5
91.2
.0004
Stage 4 (n = 25) vs 0-3 (n = 205)
 MRE
 TE
0.9423
0.8357
4.7
11.8
80.0
80.0
85.9
81.0
40.8
33.9
97.2
97.1
.0046
Significantly Higher Diagnostic Accuracy With
MRE vs TE for Fibrosis Staging in NAFLD
Hsu C, et al. EASL 2018. Abstract FRI-439. Slide credit: clinicaloptions.com

13.  Serum biomarkers (eg, THBS2,
COLEC11) validated by ELISA
Comparison
L1OXV
Accuracy, %
NASH vs simple steatosis
 5-protein NASH
predictor panel
91.7
NASH F0-2 vs F3-4
 43-protein principal
component analysis
 6-protein fibrosis
predictor panel
95
97.5
SOMAscan: Serum Biomarker Analysis to
Distinguish Simple Steatosis From NASH
 Multiplexed proteomics tool used to
examine serum biomarkers
– Simple steatosis, n = 20
– NASH with F0-2 fibrosis, n = 20
– NASH with F3-4 fibrosis, n = 20
 Objectives:
– Develop simple noninvasive
screening test to differentiate
between NASH and simple
steatosis, and fibrosis stages
– Identify new therapeutic targets
Lai M, et al. EASL 2018. Abstract PS-181. Slide credit: clinicaloptions.com

14.  Hierarchical clustering of 45
statistically significant proteins
discriminates NASH vs simple
steatosis
SOMAscan: Clear Biomarker Profiles Identify
NASH vs Simple Steatosis
 Hierarchical clustering of 20
statistically significant proteins
discriminates NASH F0-2 vs
simple steatosis
Lai M, et al. EASL 2018. Abstract PS-181. Reproduced with permission. Slide credit: clinicaloptions.com
Upregulated
Downregulated
NASH
Simple
Steatosis
NASH F0-2
Simple
Steatosis

15. Clinical Outcomes
in Patients With NAFLD/NASH

16. Economic and Disease Burden of NAFLD/NASH
in German Claims Database
 Retrospective cohort study of anonymized healthcare claims from
German InGef research database (N = 4,580,434)
– Mortality, comorbidities, resource utilization, and healthcare costs
examined in subset of 800 adults diagnosed with NAFLD/NASH
and compensated cirrhosis
Canbay A, et al. EASL 2018. Abstract PS-057. Slide credit: clinicaloptions.com
Characteristic
NAFLD/NASH + CC
(n = 800)
Progressors*
(n = 245)
Nonprogressors†
(n = 555)
Mean age, yrs (SD) 67.8 (12.4) 72.0 (11.1) 66.1 (12.5)
Male, % 58 60 57
*Did or †did not progress to ESLD (ie, decompensated cirrhosis, HCC, or liver transplant) within 1 yr of CC diagnosis.

17. High Mortality and Comorbidity Burden in
German NAFLD/NASH Patients With Cirrhosis
 19.4% of patients died in first yr after cirrhosis diagnosis
– Rate significantly higher in progressors vs nonprogressors
(46.1% vs 7.6%, respectively; P < .0001)
Canbay A, et al. EASL 2018. Abstract PS-057. Canbay A, et al. EASL 2018. Abstract SAT-252. Slide credit: clinicaloptions.com
Comorbidity in Yr
Preceding CC, %
NAFLD/NASH + CC
(n = 800)
Progressors
(n = 245)
Nonprogressors
(n = 555)
CVD 49 57 45
Renal impairment 32 39 29
Obesity 37 40 36
Hypertension 79 84 77
Hyperlipidemia 48 47 48

18. Healthcare Costs Spike Following Cirrhosis
Diagnosis in Patients With NAFLD/NASH
 Mean annual all-cause healthcare costs increased 93% by 1 yr post CC
– Primarily driven by a 214% increase in inpatient costs; elevations significantly
more pronounced in progressors vs nonprogressors
 Mean cumulative all-cause total healthcare costs also significantly increased
– At 5 yrs post CC, 169% for progressors vs 132% for nonprogressors
Canbay A, et al. EASL 2018. Abstract PS-057. Canbay A, et al. EASL 2018. Abstract SAT-252. Slide credit: clinicaloptions.com
Annual Healthcare
Resource Utilization
NAFLD/NASH + CC
(n = 800)
Progressors
(n = 245)
Nonprogressors
(n = 555)
Pre CC Post CC Pre CC Post CC Pre CC Post CC
Mean hospitalizations, n 0.8 1.5 1.0 2.4 0.7 1.1
Mean length of stay, days 8.8 14.8 12.2 25.8 7.4 10.0
Mean ED visits, n 3.5 7.3 5.7 13.3 2.6 4.7

19. Economic and Disease Burden of NAFLD/NASH
in US Medicare Claims Database
 Retrospective, observational cohort study of 20% sample of US
Medicare patients from 2007-2015 (N = 10,826,456)
– Comorbidities and healthcare costs examined in subset of
3775 adults with NAFLD/NASH and compensated cirrhosis
– Follow-up: CC index to death, end of Medicare coverage, end of
2015, or 5 yrs post index
Loomba R, et al. EASL 2018. Abstract SAT-251. Slide credit: clinicaloptions.com
Characteristic
NAFLD/NASH + CC
(n = 3775)
Progressors*
(n = 1048)
Nonprogressors†
(n = 2727)
Mean age, yrs (SD) 66.95 (10.90) 68.01 (10.70) 66.55 (10.90)
Male, % 37 35 37
*Did or †did not progress to ESLD (ie, decompensated cirrhosis, HCC, or liver transplant) during study period.

20. Comorbidity, %
NAFLD/NASH + CC
(n = 3775)
Progressors
(n = 1048)
Nonprogressors
(n = 2727)
7-Yr Cost Increase*
Diabetes 75 79 73 47
Hyperlipidemia 92 93 91 37
Hypertension 94 96 93 104
CVD 84 93 81 128
High Metabolic Comorbidity, Cost Burden in US
NAFLD/NASH Patients With Cirrhosis
 High burden of metabolic comorbidity in
US NAFLD/NASH patients with CC
– Numerically higher but similar levels in
progressors vs nonprogressors
 Mean annual healthcare costs significantly
greater in progressors vs nonprogressors,
P < .0001
 7-yr cumulative healthcare costs highest
in comorbid patients, progressors to
ESLD
– Overall: 891%
– Progressors: 1120%
– Nonprogressors: 698%
Loomba R, et al. EASL 2018. Abstract SAT-251. Slide credit: clinicaloptions.com
*Cumulative healthcare costs in those with vs without comorbidity (ie, 2 yrs prior to CC index to 5 yrs postindex).

21. Incidence of Serious Liver Disease in European
Patients With NAFLD/NASH
 Analysis of cirrhosis, HCC
incidence in patients with
NAFLD/NASH from 4 European
primary care databases (UK,
Netherlands, Italy, Spain; N =
145,590)
– Registration from 2004 to 2015;
median follow-up: 3.3 yrs
– Exclusion criteria: follow-up
< 1 yr, age/sex missing,
previous cirrhosis, HCC, or
alcohol abuse
Alexander M, et al. EASL 2018. Abstract PS-106. Slide credit: clinicaloptions.com
Parameter
NAFLD/
NASH
Matched
Controls*
Mean age, yrs 55.8 54.6
Male, % 52.7 50.1
Current smoker, % 16.5 14.4
Mean BMI 31.3 28.5
Obesity, % 36.0 15.4
T2DM, % 19.8 9.6
Hypertension, % 42.2 29.6
Mean AST, U/mL 28 21
Mean ALT, U/mL 35 21
*For each NAFLD/NASH patient, up to 100 non-NAFLD/NASH
patients matched by site, sex, age at index date ± 5 yrs, visit
date at index date ± 6 mos.

22. Associations Between NAFLD/NASH and
Cirrhosis or HCC
 Like NAFLD/NASH, diabetes also independently predicted
cirrhosis or HCC outcome (HR: 2.66; 95% CI: 2.52-2.81)
Alexander M, et al. EASL 2018. Abstract PS-106. Reproduced with permission. Slide credit: clinicaloptions.com
Cirrhosis
*UK/Spain only.
†Adjusted for age, smoking, BMI.
NAFLD/NASH
NAFLD*
NASH*
4.73 (2.43-9.19)
5.83 (1.87-18.13)
22.67 (5.96-86.23)
HR (95% CI)†
HCC
NAFLD/NASH
NAFLD*
NASH*
3.51 (1.72-7.16)
3.15 (1.16-8.56)
8.02 (4.08-15.77)
HR (95% CI)†
0.6 1 2 4 6 16 32 64128252 0.1 0.6 1 2 4 8 16 32 641280.3 252

23. Progression to NASH, Cirrhosis Variable by
Geographic Region
 Likelihood of progression from NAFLD to NASH significantly
higher in UK vs Spain
– Regional variations suggest underdiagnosis in UK settings
Alexander M, et al. EASL 2018. Abstract PS-106. Slide credit: clinicaloptions.com
Progression to
Cirrhosis
Incidence/
1000 PY
Median
Time, Yrs
From NAFLD
 Spain
 UK
0.66
2.17
3.0
2.0
From NASH
 Spain
 UK
2.8
5.8
3.0
0.5
Progression to NASH HR (95% CI)
Unadjusted
 Spain
 UK
0.03 (0.01-0.05)
1.29 (1.06-1.57)
Adjusted for age, smoking
 Spain
 UK
3.14 (1.47-6.72)
25.13 (20.12-31.38)

24. HCHS/SOL: Alcohol Use and NAFLD in
Hispanics/Latinos Living in the US
 Longitudinal, population-based
cohort of Hispanic/Latino adults
living in the US (N = 16,415)
– BL data collected 2008-2011
 Relationship between alcohol use
and NAFLD assessed
– Analyzed in subset of individuals
with no HBV or HCV infection, iron
overload, or heavy alcohol use
(> 14 drinks/wk for women,
> 21 drinks/wk for men)
Unalp-Arida A, et al. EASL 2018. Abstract SAT-514. Slide credit: clinicaloptions.com
Weighted Prevalence, %
Analyzed
(n = 14,786)
Alcohol use
 Never
 Former
 Occasional*
 Low to moderate†
19.6
30.7
16.6
33.2
NAFLD and liver fibrosis
 No NAFLD
 NAFLD without fibrosis
 NAFLD with fibrosis
 Undetermined fibrosis status
82.8
15.3
1.6
0.3
Drinks/wk: *< 1, †1-14 for women, 1-21 for men.

25. Association Between Alcohol Use and NAFLD
in US Hispanics/Latinos
 In age-adjusted model
– NAFLD prevalence lower in occasional, low to moderate vs never, former
alcohol users (P < .05)
 In multivariable-adjusted model
– NAFLD odds reduced ~ 30% in occasional and low to moderate, 20% in
former vs never alcohol users
– Stronger association between low to moderate, former drinking and
NAFLD in those with vs without fibrosis
– No association between alcohol use category and NAFLD after further
adjustment for insulin resistance
Unalp-Arida A, et al. EASL 2018. Abstract SAT-514. Slide credit: clinicaloptions.com

26. Treatment of NAFLD/NASH

27. Agents in Phase III Clinical Trials for Treatment of
NASH
Slide credit: clinicaloptions.comReferences in slidenotes.
Agent MoA Trial N Study Population
Cenicriviroc CCR2/5 antagonist AURORA[1] 2000 NASH with fibrosis
Elafibranor PPARα/σ agonist RESOLVE-IT[2] 2000 NASH with fibrosis
Obeticholic acid FXR agonist
REGENERATE[3] 2370 NASH with fibrosis
REVERSE[4] 540 NASH with compensated cirrhosis
Selonsertib ASK1 inhibitor
STELLAR 3[5] 800 NASH with fibrosis
STELLAR 4[6] 883 NASH with compensated cirrhosis

28. Phase II Data on Investigational NASH Therapies
Presented at EASL 2018
Slide credit: clinicaloptions.com
Agent Mechanism of Action
Cenicriviroc[1,2] CCR2/5 antagonist
GR-MD-02[3,4] Galectin-3 inhibitor
GS-0976*[5-7] ACC inhibitor
(GS-0976 or GS-9674) ± selonsertib[8,9] (ACC inhibitor or FXR agonist) ± ASK1 inhibitor
JKB-121[10,11] TLR-4 antagonist
MGL-3196[12,13] THR-β agonist
NGM282*[14] FGF19 analogue
Semaglutide†[15,16] GLP-1 receptor agonist
References in slidenotes.
*Includes single-arm exploratory or proof-of-concept studies; all others phase II.
†FDA approved as adjunct to diet and exercise to improve glycemic control in adults with T2DM.

29. CENTAUR: Final Analysis of Cenicriviroc vs
Placebo in Patients With NASH
 International, randomized, double-blind, placebo-controlled phase IIb study[1]
– Cenicriviroc: CCR2/5 antagonist
 Primary analysis at Yr 1 observed significant improvement in fibrosis stage with no
worsening of NASH with use of cenicriviroc vs placebo[2]
1. Ratziu V, et al. EASL 2018. Abstract GS-002. 2. Friedman SL, et al. Hepatology. 2018;67:1754-1767. Slide credit: clinicaloptions.com
Cenicriviroc 150 mg PO QD
(n = 145)
Placebo PO QD
(n = 72)
Stratified by NAS (4 vs ≥ 5),
fibrosis stage (≤ vs > 2)
Yr 1
Primary Endpoint
Yr 2
Final Analysis
Placebo PO QD
(n = 72)
Cenicriviroc 150 mg PO QD
(n = 61)
Placebo PO QD
(n = 60)
Patients underwent 3 serial liver biopsies during 2-yr study: BL, Yr 1, Yr 2.
Arm A
Cenicriviroc 150 mg PO QD
(n = 121)
Patients with NASH,
NAS ≥ 4, and
F1-3 fibrosis
(N = 289)
Arm B
Arm C

30. CENTAUR: Continued Antifibrotic Activity in Yr 1
Responders Twice as Frequent With Cenicriviroc
Ratziu V, et al. EASL 2018. Abstract GS-002. Reproduced with permission. Slide credit: clinicaloptions.com
11%
 Pooled analysis of all
patients receiving 1 yr
of CVC supports
primary findings
 Use of CVC
associated with
reduction in hs-CRP
and fibrinogen at Yr 2
vs apparent increase
with PBOWorsened from BL
Maintained ≥ 1-stage improvement in fibrosis
No change from BL
Antifibrotic Activity in
Previous Responders*
Yr 1 to Yr 2
100
80
60
40
20
0
Patients(%)
Arm A: CVC
(n = 30)
Arm C: PBO
(n = 10)
*Subset achieving ≥ 1-stage improvement in fibrosis at Yr 1.
60%
30%
Improvement in Fibrosis by ≥ 2
Stages and no Worsening of NASH
BL to Yr 2
Patients(%)
Arm A: CVC
(n = 65)
Arm C: PBO
(n = 34)
14
8
6
4
2
0
10
12
P = .13
3%

31. Safety Outcome, n (%)
Arm A: CVC
(n = 121)
Arm B: PBO/CVC
(n = 61)
Arm C: PBO
(n = 60)
TEAEs
 By maximum severity
• Grade 1
• Grade 2
• Grade 3
• Grade 4
 Leading to discontinuation
 Study drug-related
105 (86.8)
40 (33.1)
47 (38.8)
17 (14.0)
1 (0.8)
19 (15.7)
5 (4.1)
46 (75.4)
25 (41.0)
17 (27.9)
4 (6.6)
0
6 (9.8)
0
50 (83.3)
22 (36.7)
19 (31.7)
8 (13.3)
1 (1.7)
9 (15.0)
0
Grade ≥ 2 study drug-related
TEAEs occurring in ≥ 2% patients
 ALT elevation
10 (8.3)
3 (2.5)
0
0
3 (5.0)
2 (3.3)
Treatment-emergent SAEs
 Leading to discontinuation
13 (10.7)
1 (0.8)
3 (4.9)
0
9 (15.0)
0
CENTAUR: Cenicriviroc Well Tolerated in Yr 2
 No deaths or study drug-related, treatment-emergent SAEs
Ratziu V, et al. EASL 2018. Abstract GS-002. Slide credit: clinicaloptions.com

32. NASH-CX: GR-MD-02 vs Placebo in Patients With
NASH Cirrhosis and Portal Hypertension
 Multicenter, randomized, double-blind, placebo-controlled phase II trial
– GR-MD-02: galectin-3 inhibitor
 Primary endpoint: change in HVPG at Wk 54
Chalasani N, et al. EASL 2018. Abstract LBO-001. ClinicalTrials.gov. NCT02462967. Slide credit: clinicaloptions.com
Patients with NASH cirrhosis
on biopsy, HVPG ≥ 6 mm Hg,
no decompensating event, and
no or small varices
(N = 161)
GR-MD-02 8 mg/kg
(n = 54)
GR-MD-02 2 mg/kg
(n = 53)
Wk 54
Placebo
(n = 54)
Treatment administered every other week by IV infusion x 26.

33. NASH-CX: GR-MD-02 Significantly Reduced
HVPG at Wk 54 in Subset With Mild Portal HTN
 GR-MD-02 use improved hepatocyte ballooning
 In patients with no varices at BL, GR-MD-02 2 mg/kg associated with significant difference in change
in HVPG, percentage of responders, development of new varices
Chalasani N, et al. EASL 2018. Abstract LBO-001. Reproduced with permission. Slide credit: clinicaloptions.com
Total Patient Population Patients With Mild Portal Hypertension*
MeanChangeinHVPGFrom
BLtoWk54±SEM(%)
MeanChangeinHVPGFrom
BLtoWk54±SEM(%)
15
10
5
0
-5
GR-MD-02
8 mg/kg
GR-MD-02
2 mg/kg
Placebo
n = 53n = 54
-2%-2%
P = .10
n = 54
8%
P = .10
40
30
20
0
-10
GR-MD-02
8 mg/kg
GR-MD-02
2 mg/kg
Placebo
n = 16n = 16
-3%
-2%
P = .027
n = 21
26%
P = .021
10
-20
*Prespecified analysis in subset with ≥ 6 and < 10 mm Hg.

34. NASH-CX: GR-MD-02 Well Tolerated at Wk 54
Chalasani N, et al. EASL 2018. Abstract LBO-001. Slide credit: clinicaloptions.com
Safety Outcome
All Patients
(N = 161)
GR-MD-02
8 mg/kg
(n = 54)
GR-MD-02
2 mg/kg
(n = 53)
Placebo
(n = 54)
TEAEs, n 1323 383 509 431
Grade ≥ 3 AE, n (%) 33 (20.5) 11 (20.4) 11 (20.8) 11 (20.4)
≥ 1 treatment-
emergent SAE, n
(total)
25 (34) 12 (14) 5 (10) 8 (10)
D/c for AE, n 3 3 0 0
Death, n 1 0 1 0

35. GS-0976 Reduces Liver Fat, ALT in Preliminary
Study of Patients With NASH Cirrhosis
 Proof-of-concept study to examine
pharmacodynamics, efficacy, and
safety of 12-wk GS-0976 20 mg
PO QD in patients with Child-Pugh
A cirrhosis due to NASH (N = 10)
 ≥ 30% MRI-PDFF reduction at Wk
12 in 70% of patients
 MRE stiffness unchanged from BL
to Wk 12
 Significant increase in median
fasting triglycerides: 147 mg/dL at
BL, 156 mg/dL at Wk 12; P = .004
Harrison S, et al. EASL 2018. Abstract FRI-487. Slide credit: clinicaloptions.com
Change From BL to
Wk 12, %
GS-0976
(N = 10)
P
Value
De novo lipogenesis -32 .01
Liver fat by MRI-PDFF -39 .004
ALT -29 .004
Safety Outcome, n
GS-0976
(N = 10)
TEAEs
 Grade 3
8
1
Treatment-related AEs
 Grade ≥ 2
4
2
TE grade 3 lab abnormalities 4

36. Wk 1
No Lasting Lipid Disturbance in Noncirrhotic
Patients With NASH Receiving GS-0976
 Subanalysis of randomized, double-blind,
placebo-controlled phase II trial[1,2]
– GS-0976: ACC inhibitor
– 16% of GS-0976 recipients had grade 3/4 ↑ TG
at Wk 12 during primary analysis[3]
 Current aim: to further characterize 12-wk lipid
changes with GS-0976 20 mg
 TG and VLDL-TG significantly increased vs
placebo at Wk 1, with no differences by Wk 12
 No significant changes in TC, LDL-C, LDL-P,
HDL-C, HDL-P, or VLDL-P following 12-wk
GS-0976 20 mg treatment
References in slidenotes Slide credit: clinicaloptions.com
Noncirrhotic
adults with
NASH
(N = 126)
GS-0976 20 mg PO QD
(n = 49)
GS-0976 5 mg PO QD
(n = 51)
Placebo PO QD
(n = 26)
Wk 12
*P < .05 vs BL. †P < .05 for change from BL vs placebo.
MedianΔ,mg/dL(IQR)
Changes in TG With GS-0976 20 mg Treatment
400
300
200
100
0
BL Wk 4 Wk 8 Wk 12
GS-0976 20 mg
Placebo
*
***
†

37. Selonsertib, GS-0976, and GS-9674—Alone or in
Combination—for Patients With NASH
 Open-label, proof-of-concept phase II study
– Selonsertib: ASK1 inhibitor, GS-0976: ACC inhibitor, GS-9674: FXR agonist
 Endpoints: change in liver fat by MRI-PDFF, liver stiffness by MRE; safety
Lawitz E, et al. EASL 2018. Abstract PS-105. ClinicalTrials.gov. NCT02781584. Slide credit: clinicaloptions.com
Patients with a clinical
diagnosis of NAFLD;
MRI-PDFF ≥ 10% and
MRE ≥ 2.88 kPa or biopsy
consistent with NASH and
F2/3 fibrosis; no cirrhosis
(N = 70)
Selonsertib 18 mg PO QD
(n = 10)
GS-0976 20 mg PO QD
(n = 10)
GS-9674 30 mg PO QD
(n = 10)
Selonsertib 18 mg + GS-0976 20 mg PO QD
(n = 20)
Selonsertib 18 mg + GS-9674 30 mg PO QD
(n = 20)
Wk 12

38. Combination Regimens Improved Liver Fat,
Biochemistry at Wk 12
 Robust reductions in liver fat and ALT with
GS-0976 ± selonsertib
 Reduction in ALT with GS-9674
monotherapy, in GGT with GS-9674 ±
selonsertib
Lawitz E, et al. EASL 2018. Abstract PS-105. Reproduced with permission. Slide credit: clinicaloptions.com
Median Relative
Change at Wk 12, %
SEL
(n = 10)
GS-0976
(n = 10)
GS-9674
(n = 10)
SEL + GS-0976
(n = 20)
SEL + GS-9674
(n = 20)
MRE-stiffness -8.6 (-15.6 to 13.6) -8.9 (-15.1 to -6.3) -8.3 (-14.7 to 6.7) -4.5 (-17.7 to 9.3) -5.2 (-15.3 to 13.8)
*P < .05 for Wk 12 vs BL.
MedianRelative
ChangeatWk12(%)
20
0
-20
-40
-60
MRI-PDFF ALT GGT
GS-9674
7.1 10.1
-42.7*
-15.6*
-32.0*
-9.4
-1.2
-33.5
-29.7 -27.2*
-3.0 -4.4
-1.6
-19.3*
-14.7*
SEL + GS-9674SEL + GS-0976GS-0976SEL

39. Combination Regimens Well Tolerated at Wk 12
 All patients completed study treatment; no deaths observed
 AEs occurring in > 1 patient included headache, diarrhea, acute sinusitis,
fatigue, constipation, cough, mood swings, and noncardiac chest pain
Lawitz E, et al. EASL 2018. Abstract PS-105. Slide credit: clinicaloptions.com
Safety Outcome, n (%)
SEL
(n = 10)
GS-0976
(n = 10)
GS-9674
(n = 10)
SEL +
GS-0976
(n = 20)
SEL +
GS-9674
(n = 20)
Any AE
 Treatment-related
 Grade 3/4
5 (50)
3 (30)
0
6 (60)
1 (10)
0
5 (50)
0
0
8 (40)
5 (25)
0
5 (25)
2 (10)
1 (5)
Serious AE 0 0 0 1 (5) 1 (5)
Grade 3/4 lab abnormality
 TG > 500 mg/dL
2 (20)
0
2 (20)
1 (10)
4 (40)
0
4 (20)
2 (10)
2(10)
0

40. Followed
through
Wk 28
No Difference in Liver Fat Change by MRI-PDFF
for JKB-121 vs Placebo in Patients With NASH
 Randomized, double-blind, placebo-
controlled phase IIa trial
– JKB-121: TLR-4 antagonist
 Primary endpoints: safety, change in
liver fat by MRI-PDFF
 At Wk 24, no difference for JKB-121
vs placebo in change of MRI-PDFF,
serum ALT, or body weight
– Significant improvement from BL in
MRI-PDFF and FIB4 with placebo
Diehl AM, et al. EASL 2018. Abstract LBO-006. Reproduced with permission. Slide credit: clinicaloptions.com
Adults with NASH;
F1-3 fibrosis in
last 12 mos; MRI-
PDFF ≥ 6%; ALT
increased at
screening and ≥
1x in last 12 mos;
A1C ≤ 9.0%; no
other chronic liver
disease
(N = 65)
JKB-121 10 mg PO BID
(n = 22)
JKB-121 5 mg PO BID
(n = 21)
Placebo PO BID
(n = 22)
Wk 24
ChangeinMRI-PDFF
atWk24(%)
5
10
-5
-10
-15
JKB-121 10 mg
(n = 11)
P = .28 vs BL
JKB-121 5 mg
(n = 17)
P = .04 vs BL
Placebo
(n = 19)
P < .01 vs BL
0

41. MGL-3196 vs Placebo in Patients With NASH
 Multicenter, randomized, double-blind, placebo-controlled phase II trial
– MGL-3196: THR-β agonist
 Primary endpoint: relative liver fat reduction by MRI-PDFF at Wk 12
 Secondary endpoints: ≥ 30% relative reduction and absolute reduction in liver fat,
lipids, fibrosis and inflammatory biomarkers at Wk 12
Harrison S, et al. EASL 2018. Abstract GS-009. ClinicalTrials.gov. NCT02912260. Slide credit: clinicaloptions.com
Extension
study to Wk 48
*20-mg dose adjustment up or down allowed at Wk 4.
Patients with biopsy-confirmed
NASH, NAS ≥ 4, F1-3 fibrosis, ≥
10% liver fat on MRI-PDFF
(N = 125)
MGL-3196 80 mg PO QD*
(n = 84)
Placebo PO QD
(n = 41)
Wk 36
Primary Endpoint
Wk 12

42. MGL-3196 Significantly Reduced Liver Fat and
Markers of Inflammation at Wk 12
 Compared with placebo at Wk 12,
MGL-3196 significantly reduced:
– Blood pressure (P = .002 for diastolic;
P = .005 for systolic)
– Atherogenic lipids (P < .0001 for LDL-C,
Lp(a), Apo B, and TG)
– Liver enzymes in patients with high MGL-
3196 exposure (P = .04 for ALT; P = .02
for AST)
– Fibrosis biomarkers in patients with BL
elevations (P = .002 for pro-C3; P = .009
for ELF)
 2/9 (22%) discontinuations for AEs
 At Wk 12, significant relative ↓ in MRI-
PDFF, ↑ in proportion with ≥ 30% fat
reduction with MGL-3196 vs placebo was
independent of NAS, fibrosis stage
Harrison S, et al. EASL 2018. Abstract GS-009. Slide credit: clinicaloptions.com
Efficacy Endpoint*
MGL-3196
(n = 78)
Placebo
(n = 38)
Relative Δ in MRI-PDFF, % -36.3 -9.6
Absolute Δ in MRI-PDFF -7.6 -2.4
≥ 30% fat reduction, % 60.3 18.4
*P < .0001 for each. †Study is blinded; 3 SAEs, none tx-related.
Safety Endpoint,† n (%)
MGL-3196
(n = 84)
Placebo
(n = 41)
Mild 55 (65.5) 19 (46.3)
Moderate 18 (21.4) 7 (17.1)

43. NGM282 in Patients With NASH
 Exploratory single-center, single-arm study
– NGM282: FGF19 analogue
 Primary endpoint: decrease in absolute liver fat ≥ 5% at Wk 12
 Exploratory endpoint: change in liver histology at Wk 12
Harrison S, et al. EASL 2018. Abstract GS-014. Slide credit: clinicaloptions.com
Patients with biopsy-
confirmed NASH, NAS ≥ 4,*
stage 1-3 fibrosis, liver fat ≥
8% by MRI-PDFF
(N = 22)
NGM282 3 mg SC QD†
*≥ 1 point in each component. †Option for rosuvastatin 20 mg at Wk 2 if 10 mg/dL LDL-C increase observed; titrated up
to 40 mg in Wks 4-8 if LDL-C remained above BL.
Wk 12
Followed
through Wk 18

44. NGM282 Reduced Liver Fat, Improved Histology
at Wk 12
 Significant reductions in ALT, AST, pro-
C3, ELF, LIF, and cT1 at Wk 12
 8/19 (42%) patients with BL F2/3 had ≥ 1
stage improvement in fibrosis at Wk 12
– Regression of fibrosis or no change in
89% of patients
 Mild GI symptoms most common TEAE,
resolved during treatment
 All patients exhibited ≥ 5% absolute and ≥
30% relative reduction in liver fat at Wk 12
– 12/19 (63%) patients with liver fat ≤ 5%
Harrison S, et al. EASL 2018. Abstract GS-014. Slide credit: clinicaloptions.com
*P < .0001
Mean Change in Liver
Fat at Wk 12, % (SD)
Evaluable Patients
(n = 19)
Absolute -11.2 (4.2)*
Relative -67 (17)
Histologic Response at Wk 12, % NAS Steatosis Inflammation Ballooning Fibrosis
Improvement 84 74 42 53 42
No change 11 26 53 42 47
Worsened 5 0 5 5 11
Mean change (SD) -2.3 (1.8) -1.1 (0.9) -0.5 (0.8) -0.7 (0.9) -0.5

45. Semaglutide vs Placebo in Obese, Nondiabetic
Patients
 Post hoc analysis of randomized, double-blind phase II trial[1,2]
– Semaglutide: GLP-1 receptor agonist
– Superior, dose-related mean reductions in body weight at Wk 52 with semaglutide vs
placebo in primary analysis (6.0% to 13.8% vs 2.3%, respectively; P < .0001)[3]
 ALT changes evaluated in subgroups with vs without elevated ALT at BL; 18%
(174/954) predicted to be at risk for or have NAFLD/NASH with advanced fibrosis
References in slidenotes Slide credit: clinicaloptions.com
Nondiabetic adults with BMI ≥ 30,
≥ 1 failed weight loss attempt,
A1C < 6.5%
(n = 649)*
Follow-up
to Wk 59
All patients received lifestyle intervention of -500 kcal/day diet and physical activity. *Examined population within larger trial of 957
participants from 8 countries. †Dose groups: 0.05 mg, n = 103; 0.1 mg, n = 102; 0.2 mg, n = 103; 0.3 mg, n = 103; 0.4 mg, n = 102.
Semaglutide 0.05-0.4 mg SC QD†
(n = 513)
Placebo SC QD
(n = 136)
Wk 52

46. Elevated ALT Declined, Often Normalized With
Semaglutide Treatment by Wk 52
 ALT decline most marked around
Wk 28 but generally continued
through EOT with semaglutide in
patients with BL ALT elevation
 By Wk 52, ALT normalized in
25% to 46% of patients receiving
semaglutide vs 18% receiving
placebo
Newsome P, et al. EASL 2018. Abstract FRI-483. Reproduced with permission. Slide credit: clinicaloptions.comEstimatedMeanALT
RatiotoBL(+SE)
1.2
1.1
1.0
0.9
0.8
0.7
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Treatment Wk
0.05 mg
0.3 mg
0.1 mg
0.4 mg
0.2 mg
Placebo
Outcome at
Wk 52, % (n/n)
Semaglutide
Placebo
0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 mg
Normalized ALT 29 (17/58) 25 (15/59) 38 (19/50) 43 (23/54) 46 (21/46) 18 (14/76)

47. clinicaloptions.com/hepatitis
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