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Ruben Living with fibrosis due to NASH
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ACG Virtual Grand RoundsJoin us for upcoming Virtual Grand Rounds!
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Week 12: Gastroparesis: Then, Now, and The FutureHenry P. Parkman, MD, FACG June 11, 2020 at Noon EDT
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NEW!! ACG 2020 ABSTRACT SUBMISSION DEADLINE
EXTENDED 2 WEEKS!
NEW!! DEADLINE: JUNE 15, 2020 11:59pm Eastern
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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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
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
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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
0
5
10
15
20
25
30
35
40
45
Adults>50 yrs School Age Children
Prevalence of NAFLD in Australia: 40%
Prevalence of NAFLD in China is 29.2%
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 P
YF
)
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
port
ion
al
haza
rd m
odel
12 months of follow-up after HCC diagnosis
1.0
0.9
0.8
0.6
0.7
0.5
0 2 8 10 12
0.4
64
HBV
HCV
NAFLDN=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
Incident 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 NASH
2015 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 JAPAN
2016 2030
Prevalence of NASH
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
• 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
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Non-Liver Related Outcomes of NAFLDNAFLD is Part of a Multisystem Disorder
Chronic kidney diseaseOsteoarthritis
Vascular disease
Obstructive sleep apnea
Malignancy
Site Fold increase*
Liver 4.0
Stomach 3.5
Pancreas 2.7
Lung 2.0
Gallstone 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 Deaths
38.3%
30%
16%
38%
12.7%
Symptom and PRO Burden
NASH: Disease Burden, Diagnosis and Treatment
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<0.01)
• Compared to NASH patients with F3, those with cirrhosis (p<0.02) had lower fatigue scores (CLDQ-NASH Fatigue Domain (4.56 vs. 4.77, p=0.002)
• MVA: Independent predictors of lower Fatigue-related PRO scores included female gender, lower albumin and presence of DM and other comorbidities (p<0.01).
40
50
60
70
80
90
100
SF-36:Role
Physical *
SF-36:Vitality
SF-36:PhysicalSummary
*
CLDQ:Activity *
CLDQ:Fatigue *M
ea
n P
RO
sco
re, 0
-10
0 s
cale
Cirrhosis Bridging fibrosis population norm
* p<0.05 b/w cirrhosis and bridging fibrosis
0
10
20
30
40
50
60
70
80
90
100
mea
n P
RO
sco
re,
0-10
0
Itch score ≤ 4 Itch score > 4all p<0.001
• Patients with biopsy-proven NASH (N=1669)
• CLDQ-NASH, SF-36, EQ5D and WPAI
• Clinically significant fatigue and itch were determined as CLDQ-NASH Fatigue and itch domain scores <4
• Clinically significant pruritus in 27%
• NASH with clinically significant pruritus had significant impairment in PROs
Impact of Pruritus and Fatigue on PROs in NASH PatientsPruritus
Younossi Z ADA 2020
Predictor of itch Odds ratio (95% CI) pMale gender (ref: female) 0.75 (0.59 - 0.95) 0.0194Depression 1.53 (1.19 - 1.96) 0.0009Nervous system disorder 1.40 (1.11 - 1.77) 0.0042Skin disorder 1.59 (1.25 - 2.01) 0.0001Albumin, per g/dL 0.56 (0.40 - 0.78) 0.0006
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Younossi Z ADA 2020
• Prevalence of clinically significant fatigue 31%• NASH patients with fatigue vs. no fatigue (p<0.05)
• younger (mean age 56 vs. 59)
• more frequently female (70% vs. 55%)
• White
• Smokers
• cirrhotic (58% vs. 49%)
• diabetic (78% vs. 72%),
• less likely to be employed
• had higher BMI
• more comorbidities
• Patients with fatigue also had lower albumin, higher alkaline phosphatase (ALP), bile acids, fasting glucose, HbA1c, C-reactive protein (CRP), GGT, ELF, Fibrotest, NAFLD Fibrosis Score (NFS), and liver stiffness by transient elastography (p<0.05).
• PRO scores of patients with clinically significant fatigue were lower (mean up to -31.4% of a PRO range size in comparison to patients without fatigue).
0102030405060708090
100
mea
n P
RO
sco
re,
0-10
0
Fatigue score ≤ 4 Fatigue score > 4
all p<0.0001
• In multivariate analysis, predictors of clinically significant fatigue:
• female gender [OR=1.47 (1.15-1.89)• history of depression [2.18 (1.67-2.83)], • nervous system disorders [1.39 (1.10-1.77)]• lower serum albumin (0.40 (0.28-0.59) per g/dL)• younger age, non-Asian race, diabetes, and
other psychiatric comorbidities and some laboratory tests
Impact of Pruritus and Fatigue on PROs in NASH PatientsFatigue
Economic Burden
NASH: Disease Burden, Diagnosis and Treatment
• 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
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Pathophysiology and Diagnosis
NASH: Disease Burden, Diagnosis and Treatment
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
Hepatocyte
Visceral Adiposity Insulin Resistance
Dysbiosis
Bio
mar
ker
Cat
ego
ries
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:
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Normal LiverSteatosis(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
• 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
<-1.455 F0−F2
-1.455 to 0.676 Indeterminate
>0.676 F3−F4
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
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
FIB-4 Cutoff Value2 Stage
<1.45 F0−F2
1.45 to 3.25 Indeterminate
>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 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 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
<7.907.25 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 SeverityMedian LSM
(range)
Without F3-F4 fibrosis
6.6 kPa (5.3-8.9)
With F3-F4 fibrosis
14.4 kPa (12.1-24.3)
Can we use Noninvasive to Estimate Liver Fibrosis?Radiologic Tests To Measure Liver Stiffness or Elasticity
Median ValuesF0 6.93 kPa F1 7.7 kPa F2 9.6 kPaF3 13.95 kPa F4 23.73 kPa
Stiffness cutoff: 3.63 kPa- Sensitivity 0.86- Specificity 0.91AUC for advanced fibrosis: 0.924
F1 – 1.24 m/sF2 – 1.48 m/sF3 – 1.61 m/sF4 – 1.75 m/s
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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
Suggested Algorithm for the Use of NITs for Risk Stratification of Patients With Suspected NAFLD in Clinical Practice
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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
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.
• 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)
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AuthorsN Dose Comparators Outcomes
Arendt 80 1000 IU/d PlaceboImproved steatosis (assessed by CT scan) vs placebo
Sanyal 247 800 IU/dPioglitazone,
placebo
Improved steatosis, inflammation, and ballooning vs placebo
Lavine 173 800 IU/dMetformin,
placeboImproved steatohepatitis and ballooning vs placebo
Harrison 45 1000 IU/d Placebo Improved fibrosis vs baseline
Sanyal 20 400 IU/dVitamin E + pioglitazone
Improved steatosis vs baseline
Dufour 48 800 IU/dUDCA + placebo
Improved 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
We
igh
t lo
ss
(%
)
M. Armstrong et al. Lancet. 2016; C..
Placebo Liraglutide P
NASH Resolution 9% 39% 0.02
Decreased ballooning 32% 61% 0.05
Decreased steatosis 45% 83% 0.01
Worse 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 agonistChange 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
AramcholStearoyl 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
FircosostaAcetyl-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
ElafibranorPPARα/σ agonist
RESOLVE-ITResolution of NASH without fibrosis worsening
SelonsertibASK-1
InhibitorSTELLAR 3 & 4
Improvement of fibrosis without worsening NASHX
X
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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)
Pat
ien
ts, %
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-Value
N % 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
Selonsertib6 mg±SIM
Simtuzumab
13/30 8/27
2/10
Sub
ject
s, %
37
20
0
10
20
30
Selonsertib18 mg±SIM
Selonsertib6 mg±SIM
Simtuzumab
1/30 2/272/10
Histologic Analysis Clinical Efficacy Endpoint
Liver Biopsy
SEL 18 mg QD
SEL 6 mg QD
Placebo 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)
Su
bje
cts,
%
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
Pa
tien
ts, %
Improvements in Histology over 72 Weeks
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 Neuschwander-Tetri BA, et al. Lancet. 2015;385(9972):956-965 Younossi Z, et al. ILC 2019; Presentation GS-06, Younossi Z et al. Lancet 2020
Obeticholic Acid: FLINT and REGENERATE Studies
Positive Results From REGENERATE: A Phase 3 International, Randomized, Placebo-controlled Study Evaluating Obeticholic Acid Treatment for NASH
• OCA 25 mg met the primary endpoint of improvement in liver fibrosis with no worsening of NASH (p=0.0002* vs PBO)
• OCA rapidly decreased ALT, AST and GGT
• Although the additional primary endpoint of NASH resolution with no worsening of fibrosis was not met, OCA improved NASH disease activity based on several key histologic parameters including NAS, hepatocyte ballooning and inflammation
• AEs were mostly mild to moderate in severity and the most common were consistent with the known profile of OCA
*Statistically significant in accordance with the statistical analysis plan as agreed with the FDA. **Per protocol population with available fibrosis data at Month 18/EOT (n=656).
Primary Endpoint (ITT): Fibrosis Improvement by ≥1 Stage With No Worsening of NASH
Regression or Progression of Fibrosis by ≥1 Stage
(Per Protocol With Post‐Baseline Biopsy)**
Younossi Z, et al. EASL 2019, Vienna, Austria. #GS-06, Younossi Z et al. Lancet 2020
Primary Endpoint (ITT): NASH Resolution With No Worsening of Fibrosis
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
Pa
tien
ts (
%) 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 mg
Pa
tien
ts (
%) 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
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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 (<1%)
Death 2 (<1%) 0 1 (<1%)
Leading to treatment discontinuation 41 (6%) 39 (6%) 83 (13%)
Serious adverse events 75 (11%) 72 (11%) 93 (14%)
Obeticholic Acid Safety
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<.0001)• Increased incidence of mild transient diarrhea with resmetirom occurred early in therapy
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9/23 14/232/23
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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 25
3843 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 ActionDisease 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
• 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
NASH: Disease Burden, Diagnosis and Treatment
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Questions?
Moderator: Mark W. Russo, MD, MPH, FACG
Speaker: Zobair M. Younossi, MD, MPH, FACG
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