Disclosures · 2020. 12. 10. · 150% 200% relative to 1988-1994 1988-1994 1999-2004 2005-2008...

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Disclosures:

Moderator: Mark W. Russo, MD, MPH, FACGNo Conflicts of Interest.

Speaker: Off Label Use:Zobair M. Younossi, MD, MPH, FACG NoneResearch funding and/or Consultant: Gilead Sciences, Intercept, BMS, NovoNordisk, Viking, Terns, Siemens, Shionogi, AbbVie, Merck, and Novartis.

Zobair M. Younossi, MD, MPH, FACG

President, Inova Medicine Services, Inova Health SystemChairman, Clinical Research, Inova Health System

Chairman and Professor of Medicine, Inova Fairfax Hospital, Falls Church, Virginia, United Sates

NASH: Disease Burden, Diagnosis and Treatment

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2

American College of Gastroenterology

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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, 6. EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402

• Pure steatosis• Steatosis and mild lobular

inflammation

NAFL

HCC

Diagnosis of NAFLD requires•Steatosis in >5% of hepatocytes

•NASH requires specific pathologic criteria

•Exclusion of secondary causes and AFLD

•Associated metabolic risk factors

NASH FibroticF2 fibrosis

FibroticF3 fibrosis

Early F1 fibrosis

CirrhoticF4 fibrosis

The Spectrum of NAFLD

NAFLD and NASH

North America 24.1%

Europe23.7%

Asia27.4%

Middle East31.8%

South America 30.5%

Africa13.5%

Younossi ZM et al. Hepatology. 2016;64:73–84; Argo CK and Caldwell SH. Clin Liver Dis. 2009;13:511–531; Younossi ZM. J Hepatol. 2019;70:531–544.

In T2DM56.8%

In T2DM68.0%

In T2DM30.4%

In T2DM (US) 51.8%

In T2DM67.3%

In T2DM52.0–57.9%

Worldwide prevalence of NAFLD is 25%

Worldwide prevalence of NAFLD among people with T2DM is 55.5%

Prevalence of NASH in general population is between 1.5‐6.5%Prevalence of NASH among T2DM is 37.3% (24.7‐50.0%)

Prevalence of NAFLD and NASH in Adults

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6.5%

5.9%

6.8%

5.7%

~25%

10%

The Global Prevalence of NAFLD in Children

Anderson EL,, et al. PLOS ONE 10(10): e0140908, 2015, Schwimmer JB, et al. Pediatrics. 2006;118(4):1388-1393, Vos M et al. J Pediatr Gastroenterol Nutr. 2017 February ; 64(2): 319–334.

Worldwide prevalence of NAFLD among

Children is about 7‐10%

• Prevalence is higher in boys and increases with higher BMI• U.S. studies have revealed a 4-fold higher risk of hepatic steatosis in Hispanic, compared to non-Hispanic• The prevalence of NAFLD in the US increased 2.7-fold from the late 1980’s to 2010

05

101520253035

Younossi Z et al Hepatology, 69(6):2672‐2682, 2019, Tsukanov V et a AGA 2011 (Abstract Mo2025), Younossi Z et al. Hepatology.;64(5):1577‐1586, 2016 López‐Velázquez JA, Ann Hepatol. 2014;13(2):166‐78, Zelber‐Sagi S et al. Liver Int. 2006;26:856–863; Moghaddasifar I et al. Int J Organ Transplant Med. 2016;7:149; Alswat K et al. Saudi J Gastroenterol. 2018;24:211, Ahmed M et al Gastroenterol Res. 2017;10(5):271‐279 . Deloitte Economic Access. January 2013, Zhou F HEPATOLOGY, Vol. 70, No. 4, 2019

Prevalence of NAFLD in Europe: 20-30% Prevalence of NAFLD in Asia: 29ꞏ62%

48.3%

30.0%33.9%

25.7% 25.0%33.0%

20.0%

8.7%

0%5%10%15%20%25%30%35%40%45%50%

NAFLD %

Prevalence of NAFLD in Latin AmericaPrevalence of NAFLD in the Middle East and Africa

Prevalence of NAFLD and NASH in Different Regions of the World

05

1015202530354045

Adults>50 yrs School Age Children

Prevalence of NAFLD in Australia: 40%

Prevalence of NAFLD in China is 29.2%

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F1 F2 F3 F4

Normal

Natural History of NAFLD and NASH

NASH with fibrosis NASH with advanced fibrosis

Cirrhotic HCC

0.592% per year

2.3% per year

Non‐cirrhotic HCC

Fibrolysis Fibrogenesis

The most common cause of death

HCC, hepatocellular carcinoma.Younossi ZM et al. Hepatology. 2018;68:349–360; Younossi ZM et al. Hepatology. 2018;68:361–371. Younossi ZM. J Hepatol. 2019;70:e17–e32. Jie Li et al. Lancet Gastroenterol Hepatol. May 2019

TimeNon-linear Progression

NASH (7‐30%)

Non‐NASH70‐93%

Stepanova M, et al. Dig Dis Sci. 2013;58(10):3017-3023;, Golabi P, Younossi Z, et al. Medicine (Baltimore). 2018;97(13):e0214; Dulai PS, et al. Hepatology. 2017; Younossi ZM, et al. Hepatology. 2011., Younossi ZM, et al. Hepatology. 2015;62(6):1723-1730, Younossi ZM, et al. Clin Gastroenterol Hepatol. 2018, Younossi Z et al. Clin Gastro and Hep 20111-587, Younossi Z Gut 2020, Paik J, Younossi ZM DDW 2019, Younossi Z AASLD 2019

N=(3,613)0.30 0.64

4.28 7.92

23.30

0

5

10

15

20

25

0 1 2 3 4Mor

talit

y R

ate

(per

1,0

0 PY

F)

Fibrosis Stage

NASH Denotes Progressive Disease

Components of MS Predicts Mortality-NHANES III

Stage of Fibrosis Predicts Mortality

HCC and NAFLD- SEER 2004−2009

LT Candidates in the US (Non-HCC)

Biopsy-proven NAFLD (N=289)

0%

50%

100%

150%

200%

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

tive

to 1

988-

1994

ALD CHB CHC NAFLD

Changes in CLDNHANES 1988-1994 and 1999-2016

Changes in CLD MortalityNational Center for Health Statistics Mortality data

Cox

pro

porti

onal

ha

zard

mod

el

12 months of follow-up after HCC diagnosis

1.0

0.9

0.8

0.6

0.7

0.50 2 8 10 12

0.4

64

HBVHCVNAFLD

N=58,731

Clinical Outcomes: Natural History of NAFLD and NASH

LT Candidates in the US (HCC)

28,132,187 reported deaths with 700,402 LD-related deaths

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Incident decompensated cirrhosis

Incident HCC

Incident liver ‐related deaths

120,000

100,000

80,000

60,000

40,000

20,000

0

Incid

ent cases/deaths

2016 2018 2020 2022 2024 2026 2028 2030

+137%

+178%

+168%

Future burden of NASH and adverse outcomes

By 2030, there are projected to be nearly 800,000 excess liver deaths in the US

Cases of F3 due to NASH

Cases of F4 due to NASH

4.5 M

3.5 M1.3 M

2 M

20% of NAFLD is NASH 27% NAFLD will be NASH2015 2030

HCC, hepatocellular carcinoma; M, million; T2DM, type 2 diabetes mellitus.Estes C et al. Hepatology. 2018;67:123–133. ; Razavi H. Disease burden of non alcoholic fatty liver disease (NAFLD). Center for Disease Analysis. 2017. http://www.elpa.eu/sites/default/files/documents/NAFLD%20Disease%20Burden%20by%20Dr.%20H.%20Razavi_NASH%20NAFLD%20Summit.pdf. Accessed February 2019.

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 JAPAN2016 2030

Prevalen

ce of N

ASH

60

40

20

80

0

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

China, 2015–2030

Inci

dent

cas

es/d

eath

s×

103

18

14

12

10

8

6

4

2

0

16

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

Germany, 2015–2030

0

200

400

600

800

1000

1200

Prev

alen

t NA

SH c

ases

(Tho

usan

ds)

Saudi Arabia, 2015–2030

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

Stage 0 fibrosis Stage 1 fibrosis

Stage 2 fibrosis Stage 3 fibrosis

Cirrhosis, HCC and Liver Transplant

Global Outcomes: Global Burden of Disease (2012-2017)

Paike J and Younossi Z Hepatology 2020

Trends in Incidence Rates (2012-2017) Trends in Mortality Rates (2012-2017)

Changes in Age-standardized Incidence and Death Rates for Cirrhosis and Liver Cancer According to Etiology of Liver Disease

Liver Cancer Cirrhosis Liver Cancer Cirrhosis

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• GBD-2017 was used to assess years lost due to disability (YLD), years of life lost (YLL) and disability-adjusted life-years (DALYs) and temporal trends (2007-2017) for 21 regions and 195 countries.

• In 2017, there were– 6.1 million worldwide incident cases of CLD (15.6% LC and

84.4% cirrhosis),– 2.14 million liver deaths (38.3% LC and 61.6% cirrhosis)– 62.16 million DALYs (33.4% LC and 66.5% cirrhosis).

• The majority of DALYs from CLD was attributed to years of life lost (96.8%) and only 3.2% from years of life lived with disability.

• From 2007-2017, CLD DALYs increased 54.8 to 62.6 million– Increase of 21.4% for LC and 9.8% for cirrhosis.

• Although HBV and HCV accounted for most DALYs in 2017 (21.8 million and 15.3 million; respectively), NAFLD showed the largest increase in DALYs from 2007 to 2017

The Growing Burden of Disability Related to Non-alcoholic Fatty Liver Disease: Data from Global Burden of Disease 2007-2017

Paik J and Younossi Z 2020

Non-Liver Related Outcomes of NAFLDNAFLD is Part of a Multisystem Disorder

Chronic kidney disease OsteoarthritisVascular disease

Obstructive sleep apnea

MalignancySite Fold increase*

Liver 4.0

Stomach 3.5

Pancreas 2.7

Lung 2.0Gallstone disease

NAFLD

*Fold increase in incidence of malignant cancer diagnosis in patients with NAFLD compared to healthy controls. Angulo P et al. Gastroenterology. 2015;149:389–397; Söderberg C et al. Hepatology. 2010;51:595–602; Ekstedt M et al. Hepatology. 2006;44:865–873; Dam‐Larsen S et al. Scand J Gastroenterol. 2009;44:1236–1243; Rafiq N et al. Clin Gastroenterol Hepatol. 2009;7:234–238; Hicks SB et al. Oral abstract presented at the AASLD Liver Meeting; 31; 11 November 2018; San Francisco, USA.

Polycystic ovary syndrome

Diabetes

CV Deaths38.3%30%

16%

38%

12.7%

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Symptom and PRO Burden


Symptoms in NASH: Importance of Fatigue

Cook N et al. Frontier in Medicine 2019

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Fatigue as Symptom and PROHow Common is Fatigue in NASH?

• Highest rate of Fatigue in real world setting was observed in NASH/NAFLD

Younossi Z AASLD 2019, Boston MA

Fatigue PRO in NASH with Advanced Fibrosis

Younossi Z et al AASLD 2018, Younossi Z et al Gastro and Hep 2019

• Biopsy proven NASH from STELLAR 3 and 4 (N=1667) completed 4 PRO questionnaires [SF-36, CLDQ-NASH, EQ-5D, WPAI:SHP] prior to treatment initiation.

• Fatigue and physical health related PRO scores were lower than population norms (all p

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0102030405060708090

100

mea

n PR

O s

core

, 0-1

00

Itch score ≤ 4 Itch score > 4all p

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Economic Burden


• Economic burden of NASH– Markov models (prevalence

and incidence)– 6.65 million adults with NASH in

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

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Pathophysiology and Diagnosis


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/

FibrosisTGF-ß

PDGFProliferation

Fibrosis

Endothelial Cell Dysfunction

NAFLD PathophysiologyPromoters of NASH and Fibrosis Progression

Fat accumulation drives injury

HepatocyteVisceral Adiposity Insulin Resistance

Dysbiosis

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Bio

mar

ker C

ateg

orie

s

Diagnostic

Monitoring

Predictive

Prognostic

Pharmacodynamic

Safety

Susceptibility/Risk

/Response

FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource https://www.ncbi.nlm.nih.gov/books/NBK338448/

Liver Biopsy and Non‐Invasive Tests Across for NAFLD and NASH

• Histology (liver biopsy) is the imperfect gold standard: Invasive Modalities:

Normal Liver Steatosis(NAFL)Steatohepatitis

(NASH) Fibrosis & Cirrhosis

“Dry” (Imaging) Biomarkers

“Wet” Biomarkers

UltrasoundFibroScan™ (CAP)

MR-PDFF

MR Liver MultiScan™ FibroScan™ (VCTE)Ultrasound: SSI, ARFIMR Liver MultiScan™

MR Elastography

“Simple” Scores (FIB4, NFS)Direct Collagen Biomarkers

(ELF Test™, PRO-C3™)NIS4

CK-18NIS4Fatty Liver Index (FLI)

Non‐Invasive Tests & Biomarkers Across the Spectrum of NAFLD

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• FIB-4 Index: – Originally developed to predict advanced fibrosis in

HIV/HCV coinfection– Subsequently studied in 541 patients with NAFLD

(AUROC 0.80)

• APRI:– Meta-analysis of 40 studies– The lower the APRI score (less than 0.5), the

greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis).

• NAFLD Fibrosis Score (NFS):– 733 NAFLD: 480 derivation; 253 validation– Multivariate analysis (Age, hyperglycemia, BMI,

platelet count, albumin, AST/ALT ratio) are independent predictors of advanced fibrosis

NFS Cutoff Value1 Stage

0.676 F3−F4

APRI:The lower the APRI score (1.5) the greater the PPV (and ability to rule in cirrhosis

APRI:The lower the APRI score (1.5) the greater the PPV (and ability to rule in cirrhosis

FIB-4 Cutoff Value2 Stage

3.25 F3−F4

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

Diagnostic Modalities for NAFLD, NASH and Fibrosis

Technique Visualize liverTransient 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 resonanceelastography(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

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Nobilli V, et al. Gastroenterology 2009, Loomba R EASL 2019

Components

• Procollagen III N-terminal peptide (PIIINP)• Hyaluronic acid (HA)• Tissue inhibitor of metalloproteinase 1 (TIMP1)

The Enhanced Liver Fibrosis Test (ELF)

• Patients with NASH and bridging fibrosis (n=219) or compensated cirrhosis (n=258) enrolled in two Phase 2b SIM studies were used to show that ELF can predict progression to cirrhosis and development of liver-related clinical events

• Optimal threshold of baseline ELF: 9.76 (sensitivity 77%, specificity 66%)

Diagnostic Modalities for NAFLD, NASH and Fibrosis

Suggested Algorithm for the Use of NITs for Risk Stratification of Patients With Suspected NAFLD in Clinical Practice

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Suggested Algorithm for the Use of NITs for Risk Stratification of Patients With Suspected NAFLD in Clinical Practice

NASH

Multi-prong Approach to Manage Obesity

Public Health Interventions

Treatment for NAFLD and NASH

Therapeutic Targets:• Improving Hepatic

Metabolism• Improving insulin

sensitivity• Improving inflammation• Improving fibrosis

Patient Target: • NASH• NASH with

Advanced Fibrosis

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Current Evidence for Treatment of NASH

Romero-Gómez M, et al. J Hepatology. 2017;67:829–846; Chalasani N, et al. Hepatology. 2018;67(1):328-357, Cochrane Database Syst Rev. 2011 Jun 15;(6), Gepner Y. Circulation. 2017

• 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

Probability Of Improving NASH Components According To Weight Loss

RCT of 278 sedentary adults with obesity (75%) or DYSL.• Randomized to 18 weeks of isocaloric low-fat or Mediterranean/low-

carbohydrate diet+28 g walnuts/day ± moderate PA (80% aerobic).• All regimens led to the same weight loss and both diets reduced VAT• Exercise enhanced this impact in both diets• Mediterranean diet with exercise led to further reduction of liver fat

Current Treatment of NASH is Very LimitedAvailable Medications

• 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)

Evidence Does not Support Efficacy for Treating NASH

Not FDA Approved but AASLD Supports UsePioglitazone

Pioglitazon 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)

Cusi K, et al. Ann Intern Med. 2016;165(5):305-315. Younossi ZM. Hepatology. 2018 Jul;68(1):361-371

• 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.

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Current Treatment of NASH is Very LimitedAvailable Medications

• 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)

Evidence Does not Support Efficacy for Treating NASH

Not FDA Approved but AASLD Supports UsePioglitazone

Pioglitazon 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)

Cusi K, et al. Ann Intern Med. 2016;165(5):305-315. Younossi ZM. Hepatology. 2018 Jul;68(1):361-371

• 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.

• 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 (Potential AEs: bone loss, diastolic dysfunction, weight gain)

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, placeboImproved 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 + placeboImproved steatosis, inflammation, and ballooning vs baseline

Vitamin E in NASH

• 236 patients with NASH and bridging fibrosis or cirrhosis

• 90 patients took vitamin E 800 IU/day for > 2 years• 90 patients did not take vitamin E

Vitamin E in Patients with Advanced Fibrosis

Vilar-Gomez, V et al, Hepatology 2018; Dec 1. doi: 10.1002/hep.30368.8;

First Event of Hepatic Decompensation Transplant-Free Survival

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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, placeboImproved 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 + placeboImproved steatosis, inflammation, and ballooning vs baseline

Vitamin E in NASH

• 236 patients with NASH and bridging fibrosis or cirrhosis

• 90 patients took vitamin E 800 IU/day for > 2 years• 90 patients did not take vitamin E

Vitamin E in Patients with Advanced Fibrosis

Vilar-Gomez, V et al, Hepatology 2018; Dec 1. doi: 10.1002/hep.30368.8;

First Event of Hepatic Decompensation Transplant-Free Survival

• 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 diabetics, NAFLD without a liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis

SCALE: 3.0 mg/d x 3 yrsWeight Loss in Prediabetics without T2D

Effect of Liraglutide on Body Weight and Liver Histology

LeRoux et al. Lancet. 2017

Wei

ght l

oss

(%)

M. Armstrong et al. Lancet. 2016; C..

Placebo Liraglutide PNASH Resolution 9% 39% 0.02Decreased ballooning 32% 61% 0.05Decreased steatosis 45% 83% 0.01Worse fibrosis 26% 14% 0.04

LEAN: 1.8 mg/d x 48 wksNAFLD with 1/3 T2D

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SCALE: 3.0 mg/d x 3 yrsWeight Loss in Prediabetics without T2D

Effect of Liraglutide on Body Weight and Liver Histology

LeRoux et al. Lancet. 2017

Wei

ght l

oss

(%)

M. Armstrong et al. Lancet. 2016; C..

Placebo Liraglutide PNASH Resolution 9% 39% 0.02Decreased ballooning 32% 61% 0.05Decreased steatosis 45% 83% 0.01Worse fibrosis 26% 14% 0.04

LEAN: 1.8 mg/d x 48 wksNAFLD with 1/3 T2D

• GLP-1RAs-AASLD 2018 • It is premature to consider GLP-1 agonists to specifically treat

liver disease in patients with NAFLD or NASH

Drug MOA Primary Endpoint*

GR-MD-02 Galectin 3inhibitor Reduction of HVPG at 1 y

Resmetirom THR-β agonist Change in hepatic fat fraction assessed by MRI-PDFF at 12 wk

NGM282 FGF19 analog Change in hepatic fat fraction

Emricasan Pancaspase inhibitor Reduction in HVPG in NASH cirrhotic w/pHTN

Aramchol Stearoyl CoA desaturase modulator

Absolute % change from baseline to end of study in liver fat content measured by MRI spectroscopy

VK2809 THR-β agonist Change in hepatic fat

Fircososta Acetyl-CoA carboxylase inhibitor Relative reduction in liver fat from baseline

Semaglutide GLP-1 RA Change in ALT level

Cilofexor FXR Agonist Biochemical and imaging

EDP-305 FXR Agonist Biochemical and imaging

EYP-001 FXR Agonist Biochemical and imaging

LMB-763 FXR Agonist Biochemical and imaging

Tropifexor FXR Agonist Biochemical and imaging

INT-767 FXR Agonist Biochemical and imaging

MET409 FXR Agonist Biochemical and imaging

Partial List of Drugs in Phase 2 and 3 Trials for NASH

Harrison SA, et al. Aliment Pharmacol Ther. 2016;44:1183-1198; Harrison SA, et al. The Liver Meeting ® 2018. Abstract 14; Harrison SA, et al. J Hepatol. 2018;68(suppl 1):S38; Harrison SA, et al. Lancet. 2018;391:1174-1185; Garcia-Tsao G, et al. ILC 2019; Abstract LB-01; Ratziu V, et al. The Liver Meeting ® 2018. Abstract LB-05; Loomba R, et al. EASL 2019. Abstract LBP-20; Alkhouri N, et al. Expert Opin Investig Drugs. 2019 Sep 19:1-7; i. Newsome P, et al. Aliment Pharmacol Ther. 2019;50:193-203., Younossi Z, et al. ILC 2019. Abstract GS-06; ClinicalTrials.gov NCT03439254; c. ClinicalTrials.gov. NCT03028740; ClinicalTrials.gov. NCT02704403.

Drug MOA Trial Primary Endpoint

Obeticholic acid

FXR agonist

REGENERATE

≥1 stage fibrosis improvement with no NASH worsening OR resolution of NASH with no fibrosis worsening

REVERSE

≥1 stage fibrosis improvement AND no worsening of steatohepatitis

CenicrivirocCCR2/CC

R5 antagonist

AURORA

≥1 stage fibrosis improvement AND no worsening of steatohepatitis

Elafibranor PPARα/σ agonist RESOLVE-ITResolution of NASH without fibrosis worsening

Selonsertib ASK-1 Inhibitor STELLAR 3 & 4Improvement of fibrosis without worsening NASHX

X

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17

12

23

13

2119

0

10

20

30

40

50

Protocol-defined primaryend point

Updated definition

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

Patie

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

Ratziu V, et al. Gastroenterology. 2016;150(5):1147-1159; ClinicalTrials.gov. NCT02704403. https://clinicaltrials.gov/ct2/show/NCT02704403, 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, Genfit Press release May 11, 2020

*

RESOLVE-IT: Long-Term Evaluation of Elafibranor for NASHPrimary Endpoint at Year 1: Resolution of NASH no worsening fibrosis

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

GOLDEN 505

ITT (missing biopsy = non-responder) Elafibranor 120mg Placebo P-ValueN % N %

Primary Endpoint

NASH Resolution without worsening of fibrosis 138/717 19.2 52/353 14.7 0.0659

Key secondary Endpoint

Fibrosis improvement of at least one stage 176/717 24.5 79/353 22.4 0.4457

• 1,070 patients (ITT population) with biopsy proven NASH as defined by NAS greater than or equal to 4, fibrosis stage 2 or 3.

• Patients were randomized 2:1 to receive elafibranor 120mg or placebo once daily, with a follow-up liver biopsy at week 72 to evaluate histologic endpoints (resolution of NASH without worsening of fibrosis or fibrosis improvement of at least one stage).

Fibrosis Improvement (≥1 stage from baseline)

Progression to Cirrhosis

4330

20

0

20

40

60

Selonsertib18 mg±SIM


Simtuzumab

13/30 8/27

2/10

Subj

ects

, %

37

20

0

10

20

30



Simtuzumab

1/30 2/272/10

Histologic Analysis Clinical Efficacy Endpoint

Liver Biopsy

SEL 18 mg QDSEL 6 mg QDPlacebo QD

Week 0 Year 5Week 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)

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 weeksNASH, non-alcoholic steatohepatitis; QD, once daily; SEL, selonsertib; SIM, simzutumabLoomba R, et al. Hepatology. 2018;67(2):549-559

Selonsertib: Phase 2 and 3 Clinical Trials

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Fibrosis Improvement (≥1 stage from baseline)

Progression to Cirrhosis

4330

20

0

20

40

60



Simtuzumab

13/30 8/27

2/10

Subj

ects

, %

37

20

0

10

20

30



Simtuzumab

1/30 2/272/10

Histologic Analysis Clinical Efficacy Endpoint

Liver Biopsy

SEL 18 mg QDSEL 6 mg QDPlacebo QD

Week 0 Year 5Week 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)

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 weeksNASH, non-alcoholic steatohepatitis; QD, once daily; SEL, selonsertib; SIM, simzutumabLoomba R, et al. Hepatology. 2018;67(2):549-559

STELLAR‐4 Press Release:“In the study of 877 enrolled patients who received study drug, 14.4% of patients treated with selonsertib 18 mg (p=0.56 vs. placebo) and 12.5% 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% 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

STELLAR‐4 Press Release:In the study of 802 enrolled and dosed patients, 9.3 percent of patients treated with selonsertib 18 mg (p=0.42 versus placebo) and 12.1 percent of patients treated with selonsertib 6 mg (p=0.93) 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, versus 13.2 percent with placebo. Selonsertib was generally well tolerated and safety results were consistent with prior studies.https://www.gilead.com/news‐and‐press/press‐room/press‐releases/2019/April 25th 2019

Selonsertib: Phase 2 and 3 Clinical Trials

Cenicriviroc: CENTAUR and NASH-AURORA

Ratziu V, et al. The International Liver Conference 2018; April 11-15, 2018. Paris, France. Abstract No. GS-002; Friedman SL, et al. Hepatology. 2018;67(5):1754-1767; Martins EB. AURORA: Phase 3 Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH. Clinical Trials.gov Identifier: NCT03028740.

19%16%

0%

5%

10%

15%

20%

25%

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

Placebo (n =144) CVC (n =144)

Subj

ects

, %

6%10%8%

20%

0%

5%

10%

15%

20%

25%

Complete Resolution ofNASH AND No Worsening

of Fibrosis

Improvement in FibrosisStage AND No Worsening

of NASH

Placebo (n = 15) CVC (n = 29)CENTAUR

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

CVC 150 mg QD CVC 150 mg QD

Placebo QD Placebo QD

Screening biopsy Biopsy at month 12 Biopsy at month 60

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0

20

40

60

80

Histologicalimprovement

Resolutionof NASH

Improvement infibrosis

Improvement inhepatocyteballooning

Improvementsin steatosis

Improvement inlobular

inflammation

Obeticholic acid Placebo

Patie

nts,

%

Improvements in Histology over 72 WeeksaP≤0.001; bP

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Sanyal A, et al. Abstract #34 Presented at The Liver Meeting 2019, November 8-12, 2019, Boston, MA.

10.6%15.7%

21.0%

0%

10%

20%

30%

40%

50%

Placebo OCA 10 mg OCA 25 mg

Patie

nts

(%) p = 0.03

p < 0.0001

Fibrosis Improvement ≥1 Stage With No Worsening of NASH: Expanded ITT Population

7.9%11.3%

14.9%

0%

10%

20%

30%

40%

50%

Placebo OCA 10 mg OCA 25 mgPa

tient

s (%

) p = 0.09

NASH Resolution With No Worsening of NASH: Expanded ITT Population

p = 0.0013

n = 407 n = 407 n = 404 n = 407 n = 407 n = 404

Obeticholic Acid: EXPAND-IT ITT

Obeticholic acid [package insert]. FDA.

Placebo(n = 657)

Obeticholic acid10 mg (n = 653)

Obeticholic acid10 mg (n = 653)

Treatment-emergent and serious adverse events

At least one treatment-emergent adverse event 548 (83%) 579 (89%) 601 (91%)

Severity

Mild 160 (24%) 163 (25%) 130 (20%)

Moderate 294 (45%) 323 (49%) 338 (51%)

Severe 87 (13%) 89 (14%) 130 (20%)

Life-threatening 5 (1%) 4 (1%) 2 (

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Fibroblast Growth Factor (FGF) 19 and 21: Phase 2 Studies

NGM 282 (FGF 19) Pegbelfermin (FGF 21) BMS‐986036

• N=74 randomized• 16 weeks duration NAS > 4 allowed• No cirrhosis

• N=82 randomized • 12 weeks duration NAS > 4 allowed• No cirrhosis

Sanyal AJ et al. Lancet. 2019Harrison SA et al, Lancet 2018

Thyroid Receptor β Agonists for NAFLD / NASHResmetirom (MGL-3196): Phase 2 Results

Inclusion/exclusion• 2:1 MGL-3196 to PBO• 125 patients enrolled in U.S.; 18 sites• NASH on liver biopsy: NAS≥4 with F1–3• ≥10% liver fat on MRI-PDFF• Includes diabetics, statin therapy, representative NASH population

Placebo MGL‐3196

Harrison SA, et al. Hepatology. 2018;68(1 suppl):9A.

• Week 36 vs placebo, resmetirom vs placebo• More patients achieved a 2-point NAS improvement (56% vs 32%; P=.02) • More patients achieved NASH resolution (27% vs 6%; P=.02)• Reduced liver fat (MRI PDFF; P

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9/23 14/232/23

7/23

Armstrong MJ, et al. Lancet. 2016;387(10019):679-690;

GLP-1 Agonists in NASHSemaglutide

83% of patients had weight loss >5%

Lancet vol 392, 10148, p637-649, Aug 2018, Newsome P, et al. AASLD 2018, San Francisco, USA. #105.

29 2538 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

Mean ALT ratio: BL to Week 52 Mean ALT ratio: BL to Week 52Adjusted for weight change

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

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, selonsertnib1. 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

Future: Targeting Multiple PathwaysCombinations with Complementary Mechanisms of Action

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• NASH (the progressive form of NAFLD) and its complications are growing globally with the epidemic of obesity

• NASH is a part of multisystemic disease leading to adverse clinical outcomes (hepatic and non‐hepatic)

• Stage of fibrosis is an important predictor of outcomes

• A number of NITs are being developed and validated

• Management of NASH requires a multidisciplinary teams with future regimens to include combination regimens

Treatment: • Life style intervention• Bariatric Experts (Med,

Endoscopic, Surg)• New drug regimens

Hepatology/GI

Multidisciplinary Integrated Teams

Nutrition Experts

DM Experts

Diagnostic Tests: • Clinical agorithms• Non‐invasive serum and

imaging biomarkers• Liver biopsy

Exercise Specialists

Primary Care‐ TeleMedicine


Questions?

Moderator: Mark W. Russo, MD, MPH, FACG

Speaker: Zobair M. Younossi, MD, MPH, FACG

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universe.gi.orgVirtual Grand Rounds

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