Zobair M Younossi MD, MPH,

FACP, FACG, FAASLD, AGAF

Chairman and Professor of Medicine

Inova Fairfax Medical Campus, Falls Church, VA

United Sates

The Expanding World of Fatty Liver Disease

Faculty Disclosure: Research Funds and/or Consultants for Gilead Sciences, Intercept, BMS, NovoNordisk, Viking, Terns, Shionogi, Abbvie, Merck, and Novartis.

WHO 2018

The Global Epidemic of Obesity is the Main Driver of Global NASH

WHO 2018

• Since 1975, worldwide obesity has tripled

Younossi Z J of Hepatology 2019

The Rate of Obesity id Growing in Every Country and

This Trend is Expected to Continue …

Organization for Economic Co-operation and Development (OECD 2017)

2016 Global Data

• Adults: >1.9 billion (39%) overweight & >650 million (13%) obese

• Children & adolescents (5-19 yrs): 340 million overweigh or obese

• Most of the world's population live in countries where overweight and obesity kills more people than

underweight.

PHYSIOLOGICAL FACTOR • Energy intake (more than is needed)

• Energy expenditure

• Thrifty Gene

MENTAL & PHYSICAL DISABILITY Mental: Schizophrenia, downs syndrome, mental illness,

learning disabilities, and eating disorders

Physical Disability • Greatly reduced activity levels eg (wheelchair bound) from

physical impairments or age

• Combination of difficulties in regulating food intake &

energy output

ENDOCRINE DISEASES Endocrine diseases

• Hypothyroidism

• Cushing’s syndrome

• Growth hormone deficiency

• PCOS

SOCIAL FACTORS • Reduction in exercise

• Sedentary lifestyle

• TV

• Computer games

• Sedentary jobs

• Fat children become fat adults

• Pregnancy-may eat more or erratically

BEHAVIORAL FACTORS • Consumption of fast food

• Consumption of health unprocessed food

• High sugar and fat diets

• Snacking

• Alcohol consumption

• Weight gain associated with cessation of smoking

• Disorganized eating patterns and eating disorders

GENETIC FACTORS • Prader-willi syndrome

• Other syndromes

• Leptin deficiency

• Other defects and deficiencies

ENVIRONMENTAL FACTORS • Advertising and marketing of high density foods

and soft drinks

• Social deprivation

• Lifestyle changes, more cars etc

• Ethnic tendencies especially if adopting Western

lifestyle

• Steatogenic drugs

• Antiobiotics in food chain

What Drives the Global Epidemic of Obesity? Obesity Is A Complex Disease Related To Genetic And Environmental Factors

OBESITY

NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis

1. Younossi ZM. Hepatology. 2018;68(1):349-360; 2. Chalasani N, et al. Hepatology. 2018;67(1):328-35; 3. Younossi ZM, et al. Hepatology. 2011;53(4):1874-1882;

4. Younossi ZM, et al. Hepatol Commun. 2017;1(5):421-428; 5. Anstee QM, et al. Gastroenterology. 2016;150(8):1728-1744

Steatosis NASH NASH with

advanced fibrosis

Normal

Spectrum of NAFLD

NASH

HCC

NASH in the Context of the Spectrum of NAFLD

Burden

CLINICAL

PRO

ECONOMIC

• Prevalence and incidence

• Liver outcomes or surrogates of mortality

• CVD and other EHM

• Crude death rates

• Life-expectancy, expected years of life lost,

• Symptoms

• HRQOL (Physical, Mental and Social

health)

• Cost of illness

• Budgetary costs

• Indirect and intangible costs

• Resource utilization

• Cost-effectiveness

• Survival

• Patient experience

• Feel

• Resource utilization

• Value

Outcomes Surrogate Endpoints

• Function and WP FUNCTIONAL

• Functional status (disability)

• Absenteeism (WP)

• Presenteeism (WP)

• Days of work missed

• Ability to manage ADL

NASH

1. Younossi ZM, et al. Hepatology. 2016;64(5):1577-1586; 2. Younossi ZM. Clin Gastroenterol Hepatol. 2017;15(8):1144-1147, 3. Younossi Z Hepatology. 2018 Aug 2

What are Different Types of Burden in NASH?

CI, confidence interval; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitisYounossi ZM. et al. Hepatology. 2016;64(1):73-84,

Anderson et al, PLOS One, 2015Argo CK, Caldwell SH. Clin Liver Dis. 2009;13(4):511-531, Schwimmer JB, et al. Pediatrics. 2006;118(4):1388-1393

The Global Epidemic of NAFLD and NASH in Adults

North America

24.1%

Europe

23.7% Asia

27.4%

Middle East

31.8%

South America 30.5%

Africa

13.5%

..

,

• Global prevalence of NAFLD is 25.2%

• Prevalence of NASH in general population is estimated between 1.5% and 6.5%

Prevalence of NAFLD is Higher in Males and Increases with Age

CI, confidence interval; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitisYounossi ZM. et al. Hepatology. 2016;64(1):73-84,

Anderson et al, PLOS One, 2015Argo CK, Caldwell SH. Clin Liver Dis. 2009;13(4):511-531, Schwimmer JB, et al. Pediatrics. 2006;118(4):1388-1393

The Global Epidemic of NAFLD and NASH in Children The Most serious Threat!

6.5% 5.9%

6.8%

5.7%

~25%

10%

..

,

Pre

vale

nc

e

of

NA

FL

D,

%

1.5

8.6 10.2

11.8

0

5

10

15

AfricanAmerican

White Asian Hispanic

NAFLD Prevalence in Children Age 2 to 19 Years per

Race/Ethnicity

• More common in Hispanic boys

• Pathology is different: Zone 1 or 3, Mainly portal,

Portal-periportal fibrosis, Rare ballooning

• Risks: family history, gestational diabetes, T2D

• Prevalence of NAFLD in US children is 2.6-17.3%

• Autopsy study from UCSD (N=742) - Prevalence: 9.6%, rates increasing with age

• Systematic review of 49,419 with diabetes in 22 countries

• Overall global NAFLD prevalence among diabetics is 55.5%

• Overall prevalence of NASH in biopsied diabetics is 67.3%

• Overall prevalence of advanced fibrosis (fibrosis ≥ F3) 17.2%

Younossi ZM. J of Hepatology. 2019

Golabi P, et al. Medicine. 2018;97(13):e0214; Younossi ZM, et al. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20; Ong JP, et al. Obes Surg. 2005;15(3):310-315;

Morita S, et al. Obes Surg. 2015;25(12):2335-2343; Praveenraj P, et al. Obes Surg. 2015;25(11):2078-2087; Younossi ZM et al. Hepatology. 2018 Sep 4. doi: 10.1002/hep.3025

NAFLD in People with Diabetes

Pre

vale

nce (

%)

0

5

10

15

20

25

30

35

40

USA

YOUNOSSI Z

2012

TURKEY

AKYUZ U

2015

KOREA

CHO HC

2016

KOREA

SINN DH

2012

KOREA

KIM HJ

2004

INDIA

DAS K

2010

CHINA

FAN J

2005

HK

WEI JL

2015

JAPAN

NISHIOJI K

2015

JAPAN

EGUCHI Y

2012

NAFLD in Lean Individuals

Disease Burden In Different Subgroups

F1 F2 F3 F4

Normal Non-NASH NASH

NASH with

Fibrosis

NASH with

Advanced

Fibrosis

2.3% per yr

Non-Cirrhotic HCC

Cirrhotic HCC

What Are The Potential Outcomes of NAFLD?

Younossi Z et al. Hepatology 2018, Younossi Z et al. Hepatology 2018, Younossi Z J of Hepatology 2019

0.529% per yr

NAFLD 25%

NASH 1.5% and 6.5%

The Most Common

Cause of Death

GENOTYPE • DNA Sequence ENVIRONMENT

• Diet

• Microbiome

• Xenobiotics

1 0 8 9 10

Fibrolysis Fibrogenesis

What are Some Predictors of Adverse Outcomes in NAFLD?

• Biopsy-proven NAFLD (N=289) with

59.2% biopsy-proven NASH

• After FU 150 months, NASH has

higher risk of liver-related mortality

than non-NASH (P=0.003)

Stepanova M, et al. Dig Dis Sci. 2013;58(10):3017-3023; Ong JP, et al. J Hepatol. 2008;49(4):608-612, Golabi P, Younossi Z, et al. Medicine (Baltimore). 2018;97(13):e0214; Dulai PS,

et al. Hepatology. 2017; Younossi ZM, et al. Hepatology. 2011.

• NHANES III NAFLD cohort (3,613) • Follow-up: December 31st, 2011

• NAFLD with all MS components associated

with overall, CV and liver mortality

• Lower survival with increasing components

of MS (p<0.001)

0.30 0.64

4.28 7.92

23.30

0

5

10

15

20

25

0 1 2 3 4

Mort

alit

y R

ate

(per

1,0

0 P

YF

)

Fibrosis Stage

• Systematic review to include

1495 NAFLD patients

providing 17,452 patient-

years of FU

Presence of NASH Denotes

Progressive Disease

Increasing Components of Metabolic

Syndrome Predicts Mortality

Stage of Fibrosis Predicts

Mortality

Worrisome Pattern and Future Predictions

The Global Burden of NASH

• NHANES 1988-1994 and 1999-2016

• 58,731 adult subjects with CLD

• Yearly trend analyses showed that the

only liver disease with consistently

increasing prevalence was NAFLD

(Kendall tau=0.64, P=0.0123)

• In contrast, a decreasing trend was noted

for CHC (tau=-0.42, p=0.07).

• Drivers of NAFLD: MVA showed that

after adjustment for age, gender, and

ethnicity, obesity – 10.4 (9.5 - 11.3),

T2DM – 3.7 (3.2 - 4.2), hypertension – 2.3

(2.1 - 2.5), hyperlipidemia - 1.8 (1.6 - 2.1))

are major independent predictors of

NAFLD.

The Epidemic of NAFLD is Growing The Changing Face of Chronic Liver Diseases in the United

States in the Past Three Decades

0%

20%

40%

60%

80%

100%

120%

140%

160%

180%

200%

1988-1994 1999-2004 2005-2008 2009-2012 2013-2016

rela

tive t

o 1

988

-1994

ALD CHB CHC NAFLD

Younossi Z et al. Clin Gastro and Hep 20111-587, Younossi Z 2019 (Submitted)

• US National Center for Health Statistics multiple-cause mortality

data

• Between 2007 and 2017 in the U.S, there were 28,132,187

reported deaths with 700,402 LD-related deaths

– Liver Causes of Death (ICD-9 codes)

– Complication of Liver Disease: 373,345 Cirrhosis; 101,132

HCC; 225,925 no cirrhosis or HCC

– Etiology of LD: 240,961 NAFLD; 197,815 ALD; 73,892 CH-

C; 6,375 CH-B; 19,110 other LDs, and 162,249 Unknown.

2007 to 2017 (APC)

Age-standardized-death-

rate-per-100,00

Age-standardized-years-of-

potential-life-lost-per-1000

LD severity 16.71 to 18.48 (1.13) 3.68 to 3.84 (0.63)

Cirrhosis 8.79 to 10.51 (1.99) 1.87 to 2.23 (1.99)

HCC 2.18 to 2.78 (1.93) 0.40 to 0.46 (1.08)

Etiology

NAFLD 5.61 to 6.42 (1.48) 1.11 to 1.18 (0.63)

ALD 4.50 to 5.96 (3.24) 1.16 to 1.54 (3.24)

CH-C 2.01 to 1.19 (-5.04) 0.48 to 0.25 (-6.30)

CH-B 0.23 to 0.13 (-5.35) 0.06 to 0.03 (-6.33)

1 Significantly increasing from 2007 to 2017 (P<.05) 2 Significantly decreasing from 2007 to 2017 (P<.05) 3 Significantly decreasing from 2007 to 2014 (P<.05) and faster

decreasing from 2014 to 2017 (P<.05)

Data markers denote observed rates; lines are fitted rates based

on joinpoint analysis.

Source: National Center for Health Statistics (2007-2017)

NAFLD Related Death is on the Rise Temporal Trends in Liver Deaths in the United States (2007-2017)

Paik J, Younossi ZM DDW 2019

• Markov model

– Incidence of NAFLD based on historical and

projected changes in prevalence of obesity and T2D

Cases of F3 due to NASH

Cases of F4 due to NASH

4.5 M

3.5 M 1.3 M

2 M

NAFLD

NASH

NASH with F3/F4

~25-30% of US Adult Population Have NAFLD

83.1 Million

16.5 Million

3.3 Million

Un

me

t N

ee

d

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Hepatology. 2018 Jan;67(1):123-133.

Future Burden of NASH and Adverse Outcomes in the USA

20% of NAFLD is NASH

27% NAFLD will be NASH

2015 2030

By 2030, there are projected to be

nearly 800,000 excess liver deaths

21.6% 22.9%

25.4%

22.9% 21.9%

17.6% 17.9%

23.6%

26.4%

29.5%

27.6%

24.7%

22.2%

18.8%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

FRANCE GERMANY ITALY SPAIN UK CHINA JAPAN

PR

EV

EL

AN

CE

OF

NA

FL

D

3.6% 4.1%

4.4% 3.9%

4.1%

2.4% 3.0%

5.0% 6.0% 6.3%

5.9% 5.5%

3.4% 3.6%

0.0%

2.0%

4.0%

6.0%

8.0%

FRANCE GERMANY ITALY SPAIN UK CHINA JAPAN

2016 2030

PR

EV

EL

AN

CE

OF

N

AS

H

Future Burden of NAFLD NASH in Europe and Asia: Prevalence

Estimated number with

NAFLD in the USA and

EU: 155.4 million1, 2

Estimated number with

NASH in the USA and

EU: 28.9 million1,2

Estimated number of

F3/F4 fibrosis due to

NASH in the USA and

EU: 5.8 million1,2

1. Estes C, et al. Hepatology 2018;67:123–33 ;

2. Razavi H, et al. Disease Burden Report for Europe 2017

Number of Patients with NAFLD, NASH and Advanced

Fibrosis in USA and EU

Estes et al. J Hepatol 2018;69:896

Future Burden of NASH in Europe and Asia: Adverse Outcomes

Chronic kidney disease

Gallstone disease

Polycystic ovary syndrome

Cerebrovascular disease

Cardiac disease

Vascular disease

Obstructive sleep apnea

Diabetes

Malignancy

Osteoarthritis

NAFLD

Non-Hepatic Diseases Associated with NAFLD

COD, cause of death; CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; SS, simple steatosis

Angulo P, et al. Gastroenterology. 2015;149(2):389-397; Söderberg C, et al. Hepatology. 2010;51(2):595-602; Ekstedt M, et al. Hepatology. 2006;44(4):865-873; Dam-Larsen S, et al. Scand J Gastroenterol. 2009;44(10):1236-1243; Rafiq N, et al. Clin Gastroenterol Hepatol. 2009;7(2):234-238, Hicks. AASLD 2018. Abstr 31

Author N FU (yr)

CVD Death

Findings

Angulo, 2015 619 12.6

38.3% CVD most common COD Fibrosis predicts death

Söderberg, 2010 118 24 30% Death in NASH,

CVD most common COD

Ekstedt, 2006 129 13.

7 16%

CVD death NASH

CVD most common COD in NASH but no SS

Dam-Larsen, 2009 170 20.4

38% No difference between

SS and control

Rafiq, 2009 173 18.5

12.7% CVD most common COD

Patient Characteristic

NAFLD (n=3869)

Control (n=15,209)

Fold Increase

Median age, yrs 53 NR

Women, % 52 NR

Diagnosed with malignancy, n (%)

580 (15) 1521 (10)

Site of malignancy,

incidence/100,000 PY

• Liver

• Stomach

• Pancreas • Lung

26.8

9.8

19.6 34.1

6.6

2.8

7.2 16.9

4

3.5

2.7 2

Younossi ZM et al. Liver Int. 2017; 37(8):1209-1218, Younossi Z et al Liver Int 2018, Younossi Z Clinical Gastro and Hepatology 2019

• NASH with Stage 2–3 fibrosis (N=72):

NASH with Advanced Fibrosis Have Impaired Patient Reported

Outcomes

40

50

60

70

80

90

100

Mean P

RO

score

, 0-1

00 s

cale

Cirrhosis Bridging fibrosis population norm

p<0.05 b/w cirrhosis and bridging fibrosis

• Biopsy proven NASH (N=1667 from STELLAR with PROs

• Economic models to assess burden of

NAFLD using interlinked Markov chains

– Over 64 million people with NAFLD, with

annual direct medical costs of about $103

billion

• Economic burden of NASH

– Markov models (prevalence

and incidence)

– 6.65 million adults with NASH in the and 232

thousand incident cases in the U.S. (2017).

– In the U.S., there are 688 thousand cases of

advanced NASH

– Lifetime direct costs of all NASH will be

$222.6 billion

– Lifetime direct costs of the advanced NASH

population will be $95.4 billion.

Markov Model Structure

HCC LT

PLT

Death

F0 F1 F2 F3 CC DCC

Younossi ZM, et al. Hepatology. 2016;64(5):1577-1586; Younossi ZM, et al. Hepatology. 2018 Sep 4. doi: 10.1002/hep.30254. [Epub ahead of print

NASH with Advanced Fibrosis Have Significant Economic Burden

NASH Patients with Advanced Fibrosis have the Profound Economic Impact

• To address increased CV mortality risk all NAFLD subjects are

candidates for life style modification and treatment of metabolic risk

factors

• To address the increased risk of liver-related mortality, NASH

subjects should be considered treatment candidates

• NASH patients with advanced fibrosis are at most urgent need for

treatment

• How to identify and stage NASH?

• What is the current evidence for treatment of NASH?

Non-alcoholic Steatohepatitis (NASH) Treatment Candidates

NAFLD Sensitivity Specificity

Liver Enzymes

• ALT 45% 85%

• GGT1 63% 65%

Ultrasound2 85% 94%

• Any degree3 61% 100%

• Cutoff ≥ 20%3 CT without contrast4 100% 90%

• Cutoff > 30% 79% 97%

MRI5

• Cutoff PDFF 6.4%, grade ≥1 86% 83%

• Cutoff PDFF 17.4%, grade ≥2 64% 96%

Spectroscopy ~100% ~100%

Liver Biopsy 98% to 100% 100%

1. Alam S, et al. Bangabandhu Sheikh Mujib Med Univ J. 2015;8(1):61-67; 2. Hernaez R, et al. Hepatology. 2011;54(3):1082-1090; 3. Dasarathy S, et al. J Hepatol. 2009;51(6):1061-1067; 4. Rogier J, et al. Liver Transpl. 2015;21(5):690-695; 5. Tang A, et al. Radiology. 2015;274(2):416-425. Younossi ZM, Hepatology. 2017 6. Wong VW et al. Nat Rev Gastroenterol Hepatol 2018;15:461

Diagnostic Tests for NAFLD

Diagnostic Tests for NASH

Wong VW et al. Nat Rev Gastroenterol Hepatol 2018;15:461

NASH Study AUROC AUROC

NASH

• Feldstein, et al. CK-18

• Feldstein, et al. CK-18, sFasL

• Feldstein, et al. oxNASH (13-HODE/LA, age, BMI, AST)

• Younossi, et al. NASH diagnostics

• Poynard, et al. NASH test

• Palekar, et al. HA + clinical

• Loomba, et al. Lipidomic

0.83

0.93

0.83

0.98

0.79

0.76

1.00

0.82

0.79

N/A

0.72

0.78

N/A

N/A

Liver Biopsy

FIB-4

Score

Parameter

Age, years

AST

ALT

Platelet count, cells x 109

BMI

Albumin, g/L

Impaired fasting glucose/DM?

NFS Cutoff

Value1 Stage

<-1.455 F0−F2

-1.455 to 0.676 Indeterminate

>0.676 F3−F4

FIB-4 Cutoff

Value2 Stage

<1.45 F0−F2

1.45 to 3.25 Indeterminate

>3.25 F3−F4

NAFLD Fibrosis Score

APRI: The lower the APRI score (<0.5), the

greater the NPV (and ability to rule

out cirrhosis) and the higher the

value (>1.5) the greater the PPV

(and ability to rule in cirrhosis

1. Angulo P, et al. Hepatology. 2007;45(8):846-854; 2. Sterling RK, et al. Hepatology. 2006;43(6):1317-1325.

Noninvasive Diagnosis of Liver Fibrosis Commonly Used Fibrosis Scores

Technique Visualize liver

Transient

elastography (TE) US

• Liver stiffness expressed in kPa; correlates with liver

fibrosis stage

• Controlled Attenuation Parameter (CAP™) expressed

in dB/meter

• Accurate in detecting advanced fibrosis

• Predicts risk of decompensation

• Correlates well with portal pressure

• Most widely used

Acoustic radiation

force impulse

(ARFI)

US • Employs high intensity acoustic beam to mechanically

excite tissue and monitor tissue displacement response

• No need for an external compression

• Degree of displacement is interpreted into degree of

lightness and darkness

Shear wave

elastography

(SWE)

US • Shear waves are generated from acoustic pulses

forced at five different tissue depth levels and SW

velocity estimated by ultrafast Doppler-like acquisition

of 5,000 frames/sec.

• SW is converted to tissue stiffness as kilopascals

Magnetic

resonance

elastography

(MRE)

MR • Most accurate of the imaging modalities

• Costly, no point-of-care access

• MRI Methods to Estimate Proton Density Fat Fraction

• MRI-PDFF shown to have high correlation to

morphometric fat3

<[VALU

E] 7.25 7.00

9.90 8.75 8.70

0

1

2

3

4

5

6

7

8

9

10

United States Europe France and HongKong

Fibrosis Severity

Median LSM

(range)

Without F3-F4

fibrosis

6.6 kPa

(5.3-8.9)

With F3-F4

fibrosis

14.4 kPa

(12.1-

24.3)

Noninvasive Diagnosis of Liver Fibrosis Radiologic Tests To Measure Liver Stiffness or Elasticity

Median Values

F0 6.93 kPa

F1 7.7 kPa

F2 9.6 kPa

F3 13.95 kPa

F4 23.73 kPa

Stiffness cutoff: 3.63 kPa

- Sensitivity 0.86

- Specificity 0.91

AUC for advanced fibrosis:

0.924

F1 – 1.24 m/s F2 – 1.48 m/s F3 – 1.61 m/s F4 – 1.75 m/s

MRI More Accurate Than Transient Elastography in

Steatosis and Liver Fibrosis • 142 patients with NAFLD (biopsy-proven; BMI 28.1 kg/m2)

• FIB-4 had the highest diagnostic performance to assess

liver fibrosis

• In Japanese patients with NAFLD, MRE had higher diagnostic

accuracy for fibrosis relative to scoring systems and TE

• MRI-PDFF was superior to CAP for steatosis grade

CAP, controlled attenuation parameter; TE, transient elastography. Imajo K, et al. Gastroenterology. 2016;150(3):626-637.

0.80 0.89 0.89

0.97

0.78 0.82 0.88 0.92

0.0

0.2

0.4

0.6

0.8

1.0

1.2

≥1 ≥2 ≥3 ≥4

MRE TE

AU

RO

C

MRE vs TE for Identification of Fibrosis Stagea

0.96 0.90

0.79 0.88

0.73 0.70

0.0

0.2

0.4

0.6

0.8

1.0

1.2

≥1 ≥2 ≥3

MRI-PDFF CAP

AU

RO

C

MRI-PDFF vs CAP for Detection of Steatosis Gradea

MRE

SWE

VCTE/fibroscan

Accu

rac

y

Accessib

ility

Evaluate alcohol consumption

Exclude alternative causes of ALT

Confirmation of NAFLD

Noninvasive risk stratification

Suspected NAFLD Hepatic steatosis on imaging with elevated serum ALT

If noninvasive profile indeterminate, obtain liver biopsy and combine results with noninvasive tests

Intermediate-risk profile •BMI >29.9 •Some metabolic syndrome features •FIB4 <3, APRI <1.5, NFS -1.454-0.676 •Elevated ALT •Fibroscan® 7-10 kPa •Possibly NASH with <F3

High-risk profile •Age >50 years •T2DM •FIB4 >3, APRI >1.5, NFS>0.676 •Elevated ALT •Fibroscan® >10 kPa •Most likely F3-F4 •Consider biopsy if clinical trials

Low-risk profile •BMI <29.9 •Age <40 years •Absent T2DM or metabolic syndrome •Low FIB4, APRI, and NFS •Normal or elevated ALT •Fibroscan® <6 kPa •Most likely steatosis only

NASH

Multi-prong Approach to

Manage Obesity Public Health

Interventions

Integrated Treatment Strategies for NAFLD and NASH

Therapeutic Targets:

• Improving Hepatic

Metabolism

• Improving insulin

sensitivity

• Improving

inflammation

• Improving fibrosis

Patient Target:

• NASH

• NASH with

Advanced

Fibrosis

NASH

Multi-prong Approach to

Manage Obesity Public Health

Interventions

Integrated Treatment Strategies for NAFLD and NASH

Current Therapeutic

Options:

• Weight loss with diet

• Exercise

• Weight loss procedures

• Currently available

medications

Patient Target:

• NASH

• NASH with

Advanced

Fibrosis

aAt least one stage.

N=293 patients with NASH were encouraged to adopt lifestyle changes for weight loss over 52 weeks.

1. Romero-Gómez M, et al. J Hepatology. 2017;67:829–846; 2. Chalasani N, et al. Hepatology. 2018;67(1):328-357.3. Cochrane Database Syst Rev. 2011 Jun 15;(6)

Current Management of NAFLD and NASH Weight Loss: Success and Impact on Fibrosis

• Weight loss

– 3%-5% to improve steatosis, but 7%-10%

to improve the majority of the histologic

features of NASH, including fibrosis

• Sustainability of weight loss:

– Seven trials, total of 373 patients

underwent weight loss programs 1 month

to 1 year

– 15% with “success”, most of these regain

weight.

– No strong evidence of sustained benefit.

• Bariatric surgery and endoscopy

% Weight Loss (WL)

NASH Resolution 10% 26% 64% 90%

Fibrosis Regressiona 45% 38% 50% 81%

Steatosis Improvement 35% 65% 76% 100%

% Patients Achieving WL 70% 12% 9% 10%

5% 7% 10%

Mean weight loss (%)

52 weeks of lifestyle intervention

Probability of improving NASH components

according to weight loss1,2

AASLD Guidance 2018

Weight Loss and Exercise

Weight loss can be effective but hard to achieve and

sustain

Exercise alone may prevent or reduce steatosis, but its ability

to improve other aspects of liver histology remains unknown

MRE-PDFF Pre- and Post-IGB Placement

Current Management of NASH Bariatric Procedures

Post-Bariatric

• NASH (N=21) treated endoscopically with Orbera™

Intragastric Balloon (Apollo Endosurgery, Austin, TX)

• EUS-liver biopsy and MRE at the time of placement

and removal

• Total body weight loss 12.8% (0–32.5)

• NAS ≥2 improvement 73%

• Fibrosis improved in 20%

• MRE and PDFF improved 3 (severe) 1 (mild)

2 (moderate) No NASH

Brunt inflammatory

score

0%

20%

40%

60%

80%

100%

Baseline 1 year 5 years

p˂0.001 ns

Biopsies courtesy of Dr. Prithi Bhathal 2011; EUS, endoscopic ultrasound; IGB, intragastric balloon; MRE, magnetic resonance elastography; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD

Activity Score; NASH, non-alcoholic steatohepatitis; PDFF, proton density fat fraction

Froylich D, et al. Surg Obes Relat Dis. 2016;12(1):127-131; Lassailly G, et al. EASL 2018, Paris, France. #FRI-484; Dixon JB, et al. Obes Surg. 2006;16(10):1278-1286; Bazerbachi F, et al.

DDW 2018. Washington DC, USA. Abstract 795

Pre-Bariatric

• Caspase inhibitors • Ursodeoxycholic acid • Anti-obesity medications • Betaine • N-Acetyl-cysteine • Lecithin • Silymarin • Beta-carotene • Omega 3 Fatty Acid (Pufa, ‘Fish Oil’) • Anti-TNF agents (Pentoxifylline) • ACE inhibitors/ARBs • Metformin • Probiotics (VSL#3) • Lipid Lowering agents (statins)

• GLP-1 Agonist

• SGL2 Inhibitors

• Pioglitazone

• Vitamin E

Current Evidence Does not Support Efficacy

for Treating NASH

Products of Significant Interest but

Evidence is not Available

Not FDA Approved but AASLD

Guidance Supports Use

Pharmacologic Treatment for NAFLD and NASH Currently, No Approved Drug!

Authors N Dose Comparators Outcomes

Arendt 80 1000 IU/d Placebo Improved steatosis (assessed by CT scan)

vs placebo

Sanyal 247 800 IU/d Pioglitazone,

placebo Improved steatosis, inflammation, and

ballooning vs placebo

Lavine 173 800 IU/d Metformin,

placebo Improved steatohepatitis and ballooning vs

placebo

Harrison 45 1000 IU/d Placebo Improved fibrosis vs baseline

Sanyal 20 400 IU/d Vitamin E +

pioglitazone Improved steatosis vs baseline

Dufour 48 800 IU/d UDCA +

placebo Improved steatosis, inflammation, and

ballooning vs baseline

Current Management of NASH Vitamin E

• AASLD Guidance document:

• Vitamin E: At 800 IU/day improves histology in nondiabetic with NASH

• Risks and benefits should be discussed

• Not recommended for NASH in diabetic patients, NAFLD without a liver biopsy,

NASH cirrhosis, or cryptogenic cirrhosis

Current Management of NASH PPAR-γ Agonist

Author N Drug Time

DM

?

Cirrhosi

s

AL

T Fat

Ba

l Infl Fibrosis

Caldwell

2001

10 Troglit

400 mg 3-6

months 1/10 Yes

Ye

s ? No

?Ye

s No

Promrat

2004

18 Pio

30 mg

12

No No Ye

s Yes

Ye

s Yes Yes

Aithal

2008

7

4

Pio

30 mg 12 mo No Yes

Ye

s Yes

Ye

s Yes Yes

Belfort

2006

5

5

Pio

45 mg 6 mo Yes No

Ye

s Yes

Ye

s Yes ---

Ratziu

2008

6

3

Rosi

8 mg 12 mo Yes No

Ye

s Yes --- --- ---

Sanyal

2010

2

4

7

Pio

30 mg 96 wk No No

Ye

s Yes --- Yes ---

Mahady

2011* n/a n/a n/a n/a Yes

Musso G, et al. JAMA Intern Med. 2017;177(5):633-640;

Cusi K. Gastroenterology. 2012;142(4):711-725.

Study or

Subgroup Weight, % Odds Ratio M-H, Random, 95% CI

Aithal et al,

2009 13.2

7.49 (0.37-

151.50)

Belfort et al,

2006 14.0

16.54 (0.89-

308.98)

Cusi et al,

2016 13.8

9.97 (0.52-

190.16)

Sanyal et al,

2004 14.0

1.00 (0.05-

18.57)

Sanyal et al,

2010 45.0

3.28 (0.64-

16.78)

Total (95%

CI) 100.0

4.53 (1.52-

13.52)

0.01 0.1 1 10 100

RCT, randomized controlled trial.

Heterogeneity: Tau2=0.00; Chi2=2.39, df=4 (P=0.66); I2=0%.

Test for overall effect: z=2.72 (P=0.007).

Current Management of NASH Pioglitazone in NASH

N=101 NASH with prediabetes or T2DM. All participants were

placed on a 500 kcal/d deficit diet and randomized to placebo or

pioglitazone

30 mg/day (titrated to 45 mg/d after 2 months) for 18 months.

Cusi K, et al. Ann Intern Med. 2016;165(5):305-315.

• Potential AEs: bone loss, diastolic dysfunction, weight gain?

• Pioglitazone-AASLD 2018 – Pioglitazone improves liver histology in patients with and without T2DM with biopsy-

proven NASH

– Risks and benefits should be discussed with each patient

– Should not be used for NAFLD without biopsy-proven NASH

Current Management of NASH Lipid Lowering Agents

• Patients with NAFLD or NASH are not at higher risk for serious liver injury from statins

• Statins can be used to treat dyslipidemia in patients with NAFLD and NASH

• While statins may be used in patients with NASH cirrhosis, they should be avoided in

patients with decompensated cirrhosis

• No indication for treatment of NASH AASLD Guidance 2018

NASH

Multi-prong Approach to

Manage Obesity Public Health

Interventions

Integrated Treatment Strategies for NAFLD and NASH

Therapeutic Targets:

• Improving Hepatic

Metabolism

• Improving insulin

sensitivity

• Improving

inflammation

• Improving fibrosis

Patient Target:

• NASH

• NASH with

Advanced

Fibrosis

Treatment Targets: Remember the Pathophysiology of NASH Multi-Step Promoters of NASH and Fibrosis Progression

DAMP, danger-associated molecular patterns; ECM, extracellular matrix; IL-1β, interleukin-1beta; PAMP, pathogen-associated molecular patterns; PDGF, platelet-derived growth factor;

TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; TNF-β, tumor necrosis factor-beta.

Benedict M, Zhang X. World J Hepatol. 2017;9(16):715-732; Bedossa P. Liver Int. 2017;37(suppl 1):85-89; Younossi ZM, et al. Hepatology. 2011;53(6):1874-1882.

Bacterial

translocation

(endotoxins)

DAMPs

Kupffer cells

Inflammatory

macrophages

PAMPs

Secondary

Inflammation

and Injury

IL-1ß

TNF

Inflammatory

monocytes

Maturation

Oxidative Stress

Inflammatory Mechanisms

ECM

deposition

(collagen

formation)

Activation/

trans-

differentiation

Hepatic

stellate cells

Activated

myofibroblast Activated

myofibroblasts

Scar

formation/

Fibrosis TGF-ß

PDGF Proliferation

Fibrosis

Endothelial Cell

Dysfunction

Fat accumulation

preceeds injury

Hepatocyte

Visceral Adiposity Insulin

Resistance

Dysbiosis

TARGETS RELATED TO

INSULIN RESISTANCE AND/OR LIPID METABOLISM

TARGETS RELATED TO

LIPOTOXICITY & OXIDATIVE

STRESS

TARGETS RELATED TO

INFLAMMATION AND IMMUNE ACTIVATION

TARGETS RELATED TO CELL DEATH

(APOPTOSIS AND NECROSIS)

TARGETS RELATED TO

FIBROGENESIS & COLLAGEN TURNOVER

PPARγ: Pioglitazone PPARα/∂: Elafibranor

GLP-1: Liraglutide PPARα/∂/γ: IVA337

Semaglutide PPARα/γ: Saroglitazar

MPCi: PXL065 THRβ: MGL-3196

SGLT1/2: LIK066 mTOT: MSDC-0602K

GLP-1/GR: MEDI0382 FXR: OCA,GS-9674,

KHKi: PF-06835919 LIN-452,LMB-763

ACCi: GS-0976, TGR5: INT-767,INT-777

PF-05221304 ASBT: Volixibat

DGAT2i: PF-06865571 FGF19: NGM282

SCD1: Aramchol AMPKi: PXL770

FGF21: BMS-986036 Vitamin E

CCR2/5: Cenicriviroc AOC3: BI 1467335 TLR4: JKB-121 Anti-LPS: IMM-124E

ASK1: Selonsertib Caspases: Emricasan

LOXL2: Simtuzumab Galectin: GR-MD-02

Normal Liver Steatosis without NASH NASH Cirrhosis

Some of New Targets for Treatment of NASH

Regimens in Development for Treatment of NASH

• Many drugs under

evaluation for treatment

of NASH

– >85 clinical trials

(active or planned)

– 4 Phase 3 Clinical Trials

PHASE 2

PHASE 3

MARKETED

U.S. National Institutes of Health. ClinicalTrials.gov. Accessed June 11, 2018:

1. https://clinicaltrials.gov/ct2/show/NCT03028740. Last updated February 13, 2018; 2. https://clinicaltrials.gov/ct2/show/NCT02704403. Last updated

May 14, 2018; 3. https://clinicaltrials.gov/ct2/show/NCT02548351. Last updated May 28, 2018; 4. https://clinicaltrials.gov/ct2/show/NCT03439254. Last

updated May 24, 2018; 5. https://clinicaltrials.gov/ct2/show/NCT03053050. Last updated May 14, 2018;

6. https://clinicaltrials.gov/ct2/show/NCT03053063. Last updated February 26, 2018.

Cenicriviroc (CCR2/CCR5)1

Elafibranor (PPARα/σ)2

Obeticholic acid (FXR)3,4

Selonsertib (ASK-1)5,6

17 12

23

13

21 19

0

10

20

30

40

50

Protocol-defined primary end point Updated definition

Placebo (n=92) Elafibranor 80 mg (n=93) Elafibranor 120 mg (n=89)

GOLDEN 505-Peroxisome Proliferator-Activated Receptors (PPAR α/δ Pathways) Elafibranor

Pa

tie

nts

, %

OR (95% CI) 1.53 (0.70–3.34), P=0.28

OR (95% CI) 2.31 (1.02–5.24), P=0.045

aP<0.05 vs placebo; bP<0.01 vs placebo; *Resolution of NASH without worsening of fibrosis at EOS; **More stringent definition of resolution of NASH recommended by regulatory agencies; ***NASH

confirmed by biopsy ≤6 months before randomization. N=276 (n=274 ITT) patients aged 18–75 with a histologic diagnosis of noncirrhotic NASH were randomized to placebo, elafibranor 80 mg, and

elafibranor 120 mg for 1 year. CI, confidence interval; EOS, end of study; ITT, intention-to-treat; NASH, non-alcoholic steatohepatitis; OR, odds ratio; PPAR, peroxisome proliferator-activated receptor

Ratziu V, et al. Gastroenterology. 2016;150(5):1147-1159; ClinicalTrials.gov. NCT02704403. https://clinicaltrials.gov/ct2/show/NCT02704403

Elafibranor 120 mg

Placebo

Interim analysis

2022 patients with F2-3

202 patients with F1;

All with biopsy-

confirmed NASH

Screen*** 0 Week 18 Week 48 EOS

Study Period (Months)

= biopsy

* **

RESOLVE-IT: Long-Term Evaluation of Elafibranor for NASH

19

16

0

5

10

15

20

25

≥2-Point Improvement in NAS AND No Worsening of Fibrosis

Placebo CVC

Su

bje

cts

, %

N=144

P=0.519

6

10 [VALUE]

20

0

5

10

15

20

25

Complete Resolution of NASHAND No Worsening of

Fibrosis

Improvement in FibrosisStage AND No Worsening of

NASH

Placebo CVC

P=0.494

P=0.023

N=145

Cenicriviroc: CENTAUR and NASH-AURORA studies

86% of patients with baseline F3 who improved maintained benefit at year 2

30

17

3

60

15 11

0

20

40

60

80

≥1 stage fibrosis improvement

≥1 stages fibrosis improvement AND No Worsening of Fibrosis

≥2 stage fibrosis improvement AND No Worsening of Fibrosis

Placebo CVC

Year 1 Results Year 2 Results

N=242 patients with NASH continued to year 2. Patients underwent biopsies at baseline, year 1, and year 2 to assess fibrosis, NASH, and NAS

CVC, cenicriviroc; NASH, non-alcoholic steatohepatitis; NAS, NAFLD Activity Score; QD, once daily

Ratziu V, et al. ILC. April 11-15, 2018. Paris, France. Abstract GS-002; Friedman SL, et al. Hepatology. 2018;67(5):1754-1767; ClinicalTrials.gov. NCT03028740.

https://clinicaltrials.gov/ct2/show/NCT03028740

Biopsy at

Month 12

Placebo QD

CVC 150 mg QD

Placebo QD

CVC 150 mg QD

Screening

Biopsy

Biopsy at

Month 60

NASH-AURORA Study Primary Endpoint at Year 1: improvement in fibrosis AND no worsening of NASH (N 1000)

0

20

40

60

80

Histologicalimprovement

Resolutionof NASH

Improvement infibrosis

Improvement inhepatocyteballooning

Improvements insteatosis

Improvement inlobular inflammation

Obeticholic acid Placebo

Pa

tie

nts

, %

Obeticholic Acid: FLINT and

REGENERATE Studies Improvements in Histology over 72 Weeks

a b,c

a d b d

aP≤0.001; bP<0.05; cResolution of NASH defined as not NAFLD or NAFLD but not NASH; dP<0.01; N=219 adult patients with biopsy-confirmed NASH or borderline NASH and histological NAS of ≥4

were randomized to receive oral obeticholic acid 25 mg once daily or placebo for 72 weeks

NASH, non-alcoholic steatohepatitis; QD, once daily

Neuschwander-Tetri BA, et al. Lancet. 2015;385(9972):956-965

Primary: improvement in fibrosis (with no worsening of NASH) or resolution of

NASHa (with no worsening of fibrosis) at 18 months

Secondary: time to event analysis of composite outcome events at study end

N≈2,400

Biopsy-confirmed NASH

Primarily F2/F3

F1 (≤10%) also evaluated

Obeticholic acid 10 mg QD

Obeticholic acid 25 mg QD

Placebo QD (n=92)

Outcomes Interventions Patients

REGENERATE

Obeticholic Acid: REGENERATE Press Release

Adverse events were generally mild to moderate in severity and the most common

were consistent with the known profile of OCA. • The frequency of serious adverse events was similar across treatment arms (11% in placebo,

11% in OCA 10 mg and 14% in OCA 25 mg) and no SAE occurred in >1% in any treatment arm.

• There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg:

glioblastoma) and none were considered related to treatment.

• The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in

OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to

moderate, with severe pruritus occurring in a small number of patients (<1% in placebo, <1% in

OCA 10 mg and 5% in OCA 25 mg).

• A higher incidence of pruritus associated treatment discontinuation was observed for

OCA 25 mg (<1% in placebo, <1% in OCA 10 mg and 9% in OCA 25 mg). According to the

clinical study protocol, investigator assessed severe pruritus mandated treatment

discontinuation.

• Consistent with observations from previous NASH studies, OCA treatment was associated with

an increase in LDL cholesterol, with a peak increase of 22.6 mg/dL at 4 weeks and

subsequently reversing and approaching baseline at month 18 (4.0 mg/dL increase from

baseline). Triglycerides rapidly and continually decreased in the OCA treatment arms through

month 18.

• There were few and varied serious cardiovascular events and incidence was balanced across the

three treatment arms (2% in placebo, 1% in OCA 10 mg and 2% in OCA 25 mg).

• With respect to hepatobiliary events, more patients (3%) on OCA 25 mg experienced gallstones

or cholecystitis compared to <1% on placebo and 1% on OCA 10 mg.

• While numerically higher in the OCA 25 mg treatment arm, serious hepatic adverse events were

uncommon with <1% incidence in each of the three treatment arms.

http://ir.interceptpharma.com/press-releases. February 19, 2019

Selonsertib: Phase 2 and 3 Clinical Trials

Fibrosis Improvement (≥1 stage from baseline)

Progression to Cirrhosis

43

30 20

0

20

40

60

Selonsertib18 mg±SIM

Selonsertib6 mg±SIM

Simtuzumab

13/30 8/27

2/10

Su

bje

cts

, %

3 7

20

0

10

20

30

Selonsertib18 mg±SIM

Selonsertib6 mg±SIM

Simtuzumab

1/30 2/27

2/10

N=72 patients 18–70 years of age who had either F2 or F3 confirmed by biopsy and at least 3 features of metabolic syndrome were randomized to 6 mg or 18 mg of SEL alone, 6 mg or

18 mg of SEL + SIM, or 125 mg of SIM for 24 weeks

NASH, non-alcoholic steatohepatitis; QD, once daily; SEL, selonsertib; SIM, simzutumab

Loomba R, et al. Hepatology. 2018;67(2):549-559

Histologic Analysis Clinical Efficacy

Endpoint

Liver Biopsy

SEL 18 mg QD

SEL 6 mg QD

Placebo QD

Week 0 Year 5 Week 48

• Double-blind, randomized, placebo-controlled,

Phase 3 trials (N=800 each)

• Key inclusion criteria

– Histologic evidence of NASH and NASH CRN F3/F4

fibrosis

• Primary histologic endpoint

– ≥1 stage improvement in fibrosis without worsening of

NASH

STELLAR-3 (F3) and STELLAR-4 (F4) STELLAR-4 Press Release:

“In the study of 877 enrolled patients who

received study drug, 14.4 percent of patients

treated with selonsertib 18 mg (p=0.56 vs.

placebo) and 12.5 percent of patients treated

with selonsertib 6 mg (p=1.00) achieved a ≥ 1-

stage improvement in fibrosis according to the

NASH Clinical Research Network (CRN)

classification without worsening of NASH after 48

weeks of treatment, compared with 12.8 percent

of patients who received placebo. Selonsertib

was generally well-tolerated and safety results

were consistent with prior studies.”

https://www.businesswire.com/news/home/20190211005738/en/ Febuary 11,

2019

Insulin Sensitivity Hepatic Fibrosis and Inflammation Hepatic Metabolism

Agent Proposed mechanism of

action Agent Proposed mechanism of action Agent Proposed mechanism of action

Lanifibranor

Improved lipid/glucose

metabolism;

anti-inflammatory (PPAR

α/δ pathways)

Emricasan Prevention of caspase activation and

apoptosis (caspase inhibitor) Aramchol

Inhibition of monosaturated fatty

acid synthesis (SCD-1 inhibitor)

MSDC-0602K

Mitochondrial

metabolism and FA

oxidation (mTOT

activator)

GR-MD-02 Inhibition of fibrosis pathways

(Galectin-3 inhibitor) BMS986036

Improvement of lipid/glucose

metabolism; anti-inflammatory

(FGF21 analog)

Saroglitazar

Improved lipid/glucose

metabolism;

anti-inflammatory (PPAR

α/γ pathways)

EDP 305 Regulation of hepatic glucose/lipid

metabolism (FXR agonist) NGM282

Improvement of lipid/glucose

metabolism;

anti-inflammatory (FGF19

analog)

Semaglutide

Improved lipid/glucose

metabolism;

weight loss (GLP-1RA)

GS 9674 Regulation of hepatic glucose/lipid

metabolism (FXR agonist) BI1467335

Amine oxidase/RNAi inhibitor

(VAP-1inhibitor)

Tropifexor Regulation of hepatic glucose/lipid

metabolism (FXR agonist) GS-0976

Inhibition of hepatic de novo

lipogenesis (ACC inhibitor)

Volixbat Inhibition of bile uptake (IBAT inhibitor) IMM-124E Immunomodulation of gut LPS-

related inflammation (anti-LPS)

Simtuzumab Inhibit fibrogenesis by preventing

collagen cross-linkage (anti-LOXL2) MGL-3196

Reduction of hep lipid synthesis

(THR β-selective agonist)

VK2809 Reduction of hep lipid synthesis

(THR β-selective agonist)

Early Phase Clinical Trials in NASH

9/23 14/23 2/23 7/23

aP≤0.05

Armstrong MJ, et al. Lancet. 2016;387(10019):679-690; Dhir G, Cusi K. J

Investig Med. 2018;66(1):7-10.

Current Management of NASH Liraglutide (GLP-1 Agonists): LEAN

Longitudinal Pattern of Weight

Loss with GLP1 Agonists

83% of patients had weight loss >5%

Newsome P, et al. AASLD 2018, San Francisco, USA. #105

19/50 23/54 21/46

Change in body weight

ALT normalization at Week 52

-6.0

-8.6

-11.6 -11.2

-13.8

-2.3

-20.0

-15.0

-10.0

-5.0

0.0

0.05mg 0.1 mg0.2 mg0.3 mg0.4 mg PBO

Esti

mat

ed m

ean

red

uct

ion

in

bo

dy

wei

ght

to W

eek

52

(%

)

29 25

38 43 46

18

0

20

40

60

80

100

0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 mg PBO

Pro

port

ion w

ith n

orm

al A

LT

at

EO

T (

%)

14/76

Effect of semaglutide on liver enzymes in subjects with obesity

and elevated ALT: Data from a randomized Phase 2 trial

Mean ALT ratio: BL to Week 52 Mean ALT ratio: BL to Week 52

Adjusted for weight change

Oral semaglutide: • 44% wt loss >5%

• 2-7% drug D/C due to AEs

• 80% achieve A1c <7%

Diabetes 2018 Jul; 67(Supplement 1)

Lancet vol 392, 10148, p637-649, Aug 2018.

• Semaglutide improves ALT

– Improvement seems to be associated with weight loss

– Histology based studies are ongoing

• GLP-1RAs-AASLD 2018

• It is premature to consider GLP-1 agonists to specifically treat liver disease in patients

with NAFLD or NASH

Mechanism of Action Disease Process/

Pathway Target(s)

ASK1 inhibitor (selonsertib)

and non-steroidal FXR agonist

(GS-9674) and/or ACC inhibitor

(GS-0976)1

Inflammation, fibrosis,

and lipogenesis

Combined PPAR alpha and delta

agonist (elafibranor) and an FXR

agonist2

Inflammation, fibrosis, and

lipogenesis

Chemokine CCR2/CCR5 receptor

blocker (cenicriviroc) in

combination with a FXR agonist3,4

Inflammatory and fibrosis

Targeting Multiple Pathways Combinations with Complementary Mechanisms of Action

ACC, acetyl-CoA carboxylase; ASK-1, apoptosis signal-regulating kinase 1; CCR, chemokine (C-C motif) receptor; FXR, farnesoid X receptor; MRI-PDFF; magnetic resonance imaging proton density

fat fraction; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; SEL, selonsertnib

1. Lawitz E, et al. ILC. April 11-15, 2018; Paris, France. Abstract PS105; 2. Ratziu V, et al. ILC. April 19-23, 2017; Amsterdam, The Netherlands. Abstract LBP-542; 3. Oseini AM, Sanyal AJ. Liver Int.

2017;37 Suppl 1:97-103; 4. Rotman Y, Sanyal AJ. Gut. 2017;66(1):180-190

Combination of an apoptosis signal-regulating

kinase (ASK1) inhibitor (selonsertib) with an

acetyl-CoA carboxylase inhibitor (GS-0976) or

a farnesoid X receptor agonist (GS-9674) in

NASH1

Physical activity Aerobic & Resistance activity

independently: - Reduce liver fat but no evidence for NASH and fibrosis

Dietary composition Modifications of diet without weight loss

- Reduce liver fat but no evidence for NASH and fibrosis

Weight reduction Consistently beneficial

- Steatosis ≥ 5% - NASH ≥ 7% - Fibrosis ≥ 10%

Integrated Treatment Strategies for NAFLD and NASH Multidisciplinary Team

Bariatric Experts (Medical, Endoscopi, Surgical)

Nutrition Experts

Exercise Specialists

DM Experts

Primary Care TeleMedicine

Hepatology/GI

Multidisciplinary Integrated Teams Efficacy Evidence in NASH

Current Medications Vitamin E and pioglitazone Clinical trials

How long to treat? Long term Multidisciplinary team

• NAFLD is the liver complications of obesity and is growing in all refions of the world

• NASH is the progressive form of NAFLD with increasing clinical burden

• NASH in the setting of components of MS can be more progressive

• Patients with NASH and fibrosis are the most urgent need to treatment

• Although liver biopsy is the gold standard to diagnose NASH, a number of non-invasive

tests are being developed

• Prevention of NAFLD must parallel the public health efforts to deal with epidemic of obesity

and DM

• Current SOC treatment for NASH options are limited

• A large number of potential agents are in clinical trials

• The future treatment of NASH will be similar to treatment of T2DM.

• For those with NASH and advanced fibrosis, induction followed by maintenance therapy

may be required

The Expanding World of Fatty Liver Disease