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TRANSPLANTATIONSZENTRUM
© Universitätsklinikum Leipzig
Thomas BergClinic and Polyclinic for Gastroenterology, Hepatology, Infectiology
and Pneumology
University Clinic Leipzig
New therapies in NAFLD/NASH
Conference on Liver Disease, Kairo, September 2019
http://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiYhsjbjN7eAhUHbVAKHUcRBlwQjRx6BAgBEAU&url=http://www.ukl.vcongress.de/workshop2018&psig=AOvVaw0lv895rn8Vi5Df4lJqwsZH&ust=1542635906122178https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwip6rDojN7eAhUQKVAKHavHDE8QjRx6BAgBEAU&url=https://idw-online.de/de/image3075&psig=AOvVaw1QcFVjwUCmLutBpKAZAt9v&ust=1542635933115531
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NAFLD/NASH: Epidemiology and definition
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World-wide prevalence of non-alcoholic fatty liver disease
Younossi Z and Henry L. Gastroenterology 2016;150:1778Meta-analysis: NAFLD diagnosed by imaging (US, CT, MRI/SPECT; n=45 studies).Younossi. Hepatology. 2016;64:73.
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Definitions of NAFLD, NAFL and NASH
*According to histological analysis or proton density fat fraction or >5.6% by proton MRS or quantitative fat/water-selective MRI;†Daily alcohol consumption of ≥30 g for men and ≥20 g for womenEASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
NAFLD•Excessive hepatic fat accumulation with IR•Steatosis in >5% of hepatocytes*•Exclusion of secondary causes and AFLD†
NASHNAFL
•Pure steatosis•Steatosis and mild lobular inflammation
CirrhoticF4 fibrosis
Fibrotic≥F2 to ≥F3 fibrosis
EarlyF0/F1 fibrosis
HCC
Definitive diagnosis of NASH requires a liver biopsy
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
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Definitions of NAFLD, NAFL and NASH
Nonalcoholic fatty liver disease (NAFLD)
a. Evidence of hepatic steatosis by imaging or histology
b. Lack of secondary causes of hepatic fat accumulation
Nonalcoholic fatty liver (NAFL)
≥5% hepatic steatosis without evidence of hepatocellular
injury in the form of hepatocyte ballooning
Nonalcoholic steatohepatitis(NASH)
≥5% hepatic steatosis and inflammation with hepatocyte injury (eg, ballooning), with or
without any fibrosis
The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from AASLD_Accessed July 2017EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
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Hepatocyte ballooning („ballooning injury“)
none „few“ „prominent“
inter-observer kappa 0.56
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Histologic definition of NASH „Goldstandard: NAS Score“
Kleiner et al. Hepatology 2005NAS ≥ 5: NASH, NAS < 3: no NASH
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Natural history of NAFLD over 8–13 years
de Alwis NMW, Day CP. J Hepatol 2008;48:S104–12Copyright © 2008 European Association for the Study of the Liver Terms and Conditions
Steatosis
NASH F1−F2fibrosis
HCC
Death/LTx Cirrhosis
AdvancedF3fibrosis
12−40%
5−10%
0−50%
8%
13%
25−50%
14%
25%
7%
http://www.elsevier.com/termsandconditions
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NAFLD and NASH - a special concern regarding HCC?
Fan J-G et al. J Hepatol 2017; 67: 862
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Multiple organs are likely to be involved in NAFLD
Nobili, V et al. J Hepatol 2013;58:1218−29 Copyright © 2013 European Association for the Study of the Liver Terms and Conditions
• Pathogenesis of NAFLD probably involves inter-organ crosstalk
– Adipose tissue, pancreas, gut, and liver
Visceral ectopic fat
http://www.elsevier.com/termsandconditions
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Modified according to Slide credit: clinicaloptions.com
NAFLD as a Complex Disease Trait: Genetic and Environmental Modifiers
Genes
Environment
Normal
Steatosis
NASH
CirrhosisPNPLA3TM6SF2MBOAT…
http://www.clinicaloptions.com/oncology
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Therapeutic strategies
Who is „at risk“?
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Fibrosis Stage but not NASH Predicts Mortality and Time to Development of Severe Liver Disease
Ayonrinde OT et al., J Hepatol 2017; 67: 1265
Development of severe liver disease compared to matched controls
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How to detect people at risk?
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Tanaka N et al., World J Gastroenterol 2019
Non-invasive scores predicting ≥ 2 Fibrosis in NAFLD patients
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Identification of patients at risk
Castera L et al., Gastroenterology 2019
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Pre-test likelihood of NASH (with significant fibrosis)
Kornemann MA et al. J Hepatol 2017
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Therapeutic strategies
How should we treat?
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• The management of NAFLD should consist of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and T2DM.
• As patients with NAFLD without steatohepatitis or any fibrosis have excellent prognosis from a liver standpoint, pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis.
AASLD GuidelineWho should be treated with pharmaceuticals
Chalasani N et al., Hepatology 2018
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• Structured programmes aimed at lifestyle changes towards healthy diet and habitual physical activity are advisable in NAFLD
• Patient without NASH or fibrosis should receive counselling for healthy diet and physical activity but no pharmacotherapy
• In overweight/obese NAFLD, a 7-10 % weight loss is the target of most lifestyle interventions, and results in improvement of liver enzymes and histology
• Pharmacotherapy should be reserved for patients with NASH, particularly for those with significant fibrosis (stage F2 and higher). Patients with less severe disease, but at high risk of disease progression could also be candidates for treatment.
Therapy of NAFLD: EASL guidelines
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016
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Life style modifcations and weigth loss medications?
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Romero-Gomez M et al., J Hepatol 2017; 67: 829
Therapy of NAFLD with diet and physical activity:Impact of weight loss
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Pharmacotherapy for weight loss
Weight management medications are commonly underused
• Previous weight loss drugs had poor safety record (fenfluramine, sibutramine, rimonabant)
• Frequent follow-up needed for AE monitoring
• Need for long-term use (Goal ≥ 3% weight loss at 3 mos; ≥ 5% at 1 yr)
• Poor and inconsistent insurance coverage – often costly to patient
• Variable response among patients, including many nonresponders
Slide credit: clinicaloptions.com
http://www.clinicaloptions.com/
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1. Garvey. Endocr Pract. 2016;(suppl 3):1. 2. Harrison. Hepatology. 2009;49:80 3. Wang. Biomed Rep. 2018;9:90. 4. Armstrong. Lancet. 2015;387:679.
Weight management medication
Mean efficacy criterion: significant difference in mean proportion achieving weight loss ≥ 5% drug vs placebo Categorical efficacy criterion: weight loss ≥ 5% in ≥ 35% of participants, with a significant and ≥ 2-fold difference in proportion achieving this in drug vs placebo groups
*Studied in NASH at 1.8-mg dose approved for diabetes, not 3-mg dose approved for weight loss.
Slide credit: clinicaloptions.com
http://www.clinicaloptions.com/
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• Patients with NAFLD should not consume heavy amounts of alcohol
• There are insufficient data to make recommendations with regards to nonheavy consumption of alcohol by individuals with NAFLD
AASLD Guideline
Alcohol Use in Patients with NAFLD and NASH
Chalasani N et al., Hepatology 2018
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Is any alcohol consumption strictly forbidden in NAFLD?
49Lee et al. Clin Gastroenterol Hepatol 2018;16:1404-1406
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48
Does a (very) low alcohol intake safe lives in NAFLD?
N= 4.568 participants of the NHANES III-Survey (1998–2010) with NAFLD (Hepatic Steatosis Index)
Hajifathalian et al. Hepatology 2018;16:1511-1520
< 0.5 drinks/day
0.5-1.4 drinks/day
≥ 1.5 drinks/day
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Therapy of NAFLD with coffee
Romero-Gomez M et al. J Hepatol 2017
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Chen YP et al. Clin Nutr 2018
Dose-response relationship of coffee intake (cups per day) with the risk of occurrence of NAFLD
Therapy of NAFLD with coffee
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Pharmacological treatment of NASH
EASL Clinical practical guideline:No drugs are approved for NASH
No specific therapy can be recommendedAny drug treatment is off label
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402
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Weltweite Häufigkeit der Nicht-alkoholischen Fettleber (NAFLD)Pathopysiological processes in NAFLD as rationale for treatmentstrategies
Courtesy Dr. Q. Anstee
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Fibrosis-stage based treatment algorithm for NAFLD/NASH
Sumida Y et al., J Gastroenterol 2018
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Pioglitazone efficacy in NASH – Meta-analysis of RCT
42Musso et al. Hepatology 2017;65:1058-1061
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• Pioglitazone improves liver histology in patients with and without T2DM with biopsy-proven NASH. Therefore, it may be used to treat these patients. Risks and benefits should be discussed with each patient before starting therapy.
• Until further data support its safety and efficacy, pioglitazone should not be used to treat NAFLD without biopsy-proven NASH.
• Vitamin E may improve steatosis, inflammation and ballooning and resolve NASH in some patients.
• The optimal duration of therapy is unknown; in patients with increased ALT at baseline, treatment should be stopped if there is no reduction in aminotransferases after 6 months of therapy.
Pioglitazone and Vitamin E: Current recommendations
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402; Chalasani N et al. Hepatology 2018
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Armstrong MJ et al., Lancet 2016
Weight (kg) ALT (U/L)
Targeting glucose metabolism: Liraglutide in NASH (LEAN trial)• Long-acting human GLP-1 analogue, t1/2 = 13 h, licensed for glycaemic control in type 2 diabetes• Biopsy-proven NASH, 48 weeks of treatment Liraglutide versus Placebo
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Targeting glucose metabolism: Liraglutide in NASH (LEAN trial)• Long-acting human GLP-1 analogue, t1/2 = 13 h, licensed for glycaemic control in type 2 diabetes• Biopsy-proven NASH, 48 weeks of treatment Liraglutide versus Placebo
Armstrong MJ et al., Lancet 2016
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Selected GLP-1-Analogues: Study data
Drug Mechanism of
Action
Effects on diabetes Effects on NASH Weight loss /
Specials
LiraglutideLong-acting
GLP-1-analogue
Licensed for glycaemiccontrol in overweight
diabeticians
Phase II: 39 % resolution of NASH vs. 9 % Placebo
(LEAN)
Weight loss at 56 wks: Liraglutide 1,8mg:
4,7 %1 ; Liraglutide 3,0 mg: 7,9
– 8,2 %2
SemaglutideLong-acting
GLP-1-analogue
Licensed for glycaemiccontrol in diabetes
mellitus (SUSTAIN trials, Phase IIIa3)
Phase I trial in NAFLD; Phase IIa trials in NASH with fibrosis (F1-F3) and cirrhosis (F4) launched
Oral formulation with similar effects on
lowering HbA1c and weight loss4
DulaglutideLong-acting
GLP-1-analogue
Licensed for glycaemiccontrol in diabetes
mellitus (AWARD trials, Phase III5)
Reduced transaminase activities, reduced liver
stiffness (n = 15)6
Greater weight reduction than
sitagliptin at 104 wks7
1: Mehta A et al., Obes Sci Pract 2017; 2: Pi-Sunyer X et al., NEJM 2015; 3: Aroda VR et al., Diabetes Metab 2019; 4: Bucheit J et al., Diabetes Technol Ther2019; 5: Jendle J et al., Diabetes Metab Res Rev 2016; 6: Seko Y et al., Hepatol Res 2017; 7: Weinstock RS et al., Diabetes Obes Metab 2015;
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Statins• Confidently used to reduce LDL cholesterol and prevent cardiovascular risk• No benefits or harm to liver disease
n-3 polyunsaturated fatty acids• Reduction of both plasma and liver lipids• No data to support their use specifically for NASH
Ezetimibe• Conflicting results, no significant effects on steatosis, only some
improvement of hepatocyte ballooning
Use of lipid-lowering agents in NASH
EASL–EASD–EASO CPG NAFLD. J Hepatol 2016;64:1388–402; Loomba R et al., Hepatology 2015; Nakade Y et al., Hepatol Res 2017
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Should we stop statins in patients with cirrhosis?
Serper M et al. AASLD 2017; Abstract #2106
Adjusted overall survival for patients with cirrhosis
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The „ideal NASH drug“
To qualify for an ideal drug candidate for the treatment of NASH, the drug should
1) positively regulate abnormal lipid metabolism to reduce steatosis, hepatic inflammation, and injury
2) improve underlying insulin resistance; and
3) induce antifibrotic responses
Cayman Currents, Issue 31, Fatty Liver Disease (NAFLD/NASH), Winter 2019
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Targets for treatment based on fibrosis stage
Cayman Currents, Issue 31, Fatty Liver Disease (NAFLD/NASH), Winter 2019
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NASH: Key targets for drugs in phase II and phase III clinical trials
Obeticholic acidElafibranor
Selonsertib Cenicriviroc
Connolly JJ et al., J Clin Transl Hepatol 2018
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PPAR-α
β-oxidation Steatosis
▪ Clinical data in MetS▪ Clinical data in NASH
▪ Adverse events▪ ? Safety concerns
Less effective for NAFLD in humans
PPAR-γ PPAR-α/δ
Steatosis Insulin sensitivity Inflammation
β-oxidation Hepatic steatosis Insulin sensitivity Inflammation Fibrosis Dyslipidemia
Modified according to Slide credit: clinicaloptions.com
PPARs as Targets for NASH
Elafibranor and PPARα/∂/γ (IVA337)
Thiazolidinediones(i.e. pioglitazone)
Fibrates
Gross B, et al. Nat Rev Endocrinol 2016
http://www.clinicaloptions.com/oncology
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Targeting lipid metabolism and inflammation:Elafibranor Phase II results in NASH after 1 year of tx
Ratziu V et al., Gastroenterol 2016
Histologic improvement of NASH• Elafibranor 120 mg: 19 %• Placebo: 12 %
• more pronounced differences in advanced NASH
• Phase III trial ongoing with NASH (F1-F3, NAS ≥ 4)
p = 0.045
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Targeting lipid metabolism and inflammation:Elafibranor in NASH (RESOLVE-IT)
Pts with NASH, NAS ≥ 4 (individual
scores each ≥ 1), stage 1-3 fibrosis
(Planned N = 2000)
Elafibranor 120 mg PO QD
Placebo
Randomized 2:1
Wk 72: Interim analysis
Until accrual of predefined number of events (~ 4 yrs)
ClinicalTrials.gov. NCT02704403.
▪ Randomized, placebo-controlled, double-blind, multicenter phase III study in pts with NASH and fibrosis
Primary endpointsResolution of NASH w/o fibrosis worsening at Wk 72Composite of all-cause mortality, cirrhosis, liver-related clinical outcomes at ~ 4 years
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Targeting inflammation: CCR2/CCR5-signalling pathway
Friedman S et al., Contemp Clin Trials 2016
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Targeting inflammation: Cenicriviroc in NASH Phase II (CENTAUR)
• Cenicriviroc: CCR2/CCR5-Inhibitor, inhibition of monocyte and lymphocyte migration, anti-inflammatory and anti-fibrotic effects
• Phase II results after 1 year of treatment
Friedman S et al., Hepatology 2018• Phase III currently running with NASH and F2-F3 fibrosis
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Targeting Inflammation and Fibrosis:Phase III STELLAR Program for Selonsertib in NASH
Phase 3
ClinicalTrials.gov.
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Phase III Program for Selonsertib in NASH:STELLAR-3 (F3) and STELLAR-4 (F4)
• Week 48 Primary Endpoint
– ≥ 1 stage decrease in fibrosis, with no worsening of ballooning or inflammation
• Clinical Endpoint at Yr5
– Reduction in events of clinical decompensation, transplant, death (F3 and F4 study)
– Reduction in rates of progression to cirrhosis (F3 study)
Selonsertib 18 mg QD
Week 0 Week 48
Selonsertib 6 mg QD
Year 5
Liver biopsy
Histological Analysis Clinical Endpoint
Placebo QD
N=320
N=320
N=160
ClinicalTrials.gov
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Negative Results of the STELLAR Program
Gilead Sciences, Inc., Press releases February 11 and April 25, 2019
Proportion of patients who achieved a ≥ 1-stage improvement in fibrosis without worsening of NASH
The primary endpoint of both studies was not met.
[%]
Placebo Selonsertib 6 mg Selonsertib 18 mg
p = 0.42
p = 0.93
n = 802
[%]
Placebo Selonsertib 6 mg Selonsertib 18 mg
p = 0.56
p = 1.00
n = 877
STELLAR-3 STELLAR-4
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Hepatocyte Lipotoxicity
Combination therapies: Gilead NASH Program
ACC, acetyl CoA carboxylase; ASK1, apoptosis signal-regulating kinase 1; FXR, farnesoid X receptor
Inflammation
Fibrogenesis
ASK1(SEL; GS-4997)
ACC(GS-0976)
FXR(GS-9674)
Combinations of drugs are being evaluated for potential additional therapeutic benefit
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Phase 2 trial investigating combination use of
Semaglutide (GLP-1 receptor agonist)
Cilofexor (FXR agonist)
Firsocostat (ACC inhibitor)
Possible treatment algorithm:
1) Combination of 2 or 3 drugs for 6 to 12 months (improvement in fibrosis, reduction of steatohepatitis)
2) Long-term maintenance therapy
Collaboration Novo Nordisk with Gilead Sciences: NASH project
Novo Nordisk NN9931-4492, Initiation Site 304; Younossi Z, Gastroenterol Hepatol (N Y) 2019
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FXR Central to a Multitude of Key Pathways in Animal Models
↑ Cholesterol
↓ Bile acids
CYP7a1
↓ Fibrosis
↓ Hepatic triglycerides
↑ Glucose toleranceMultiple mechanisms
via ↓ SREPB-1C
RX
R
via ↑ β-oxidation
↓ stellate cell activation
via ↑ iNOS↓ Portal pressure
FXR agonist(eg, obeticholic acid)
1. Cariou B et al. ,Diabetes Metab. 2008;34:685-6912. Calkin AC et al., Nat Rev Mol Cell Biol. 2012;13:213-224
3. Verbeke L et al., Hepatology. 2014;59:2286-98
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55Medical Education Purposes Only
REGENERATE Study Design
The interim analysis was conducted after 931 randomized patients with stage 2 or 3 liver fibrosis had or would have reached their actual/planned Month 18 visit (ITT population).EOS analysis of clinical outcomes to confirm clinical benefit.EOS, end of study; ITT, intent to treat; PBO, placebo; QD, once a day.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
Study success was defined as achievement of one of these two primary endpoints
OCA 10 mg (QD)
OCA 25 mg (QD)
Placebo (QD)
Target ~2400 patients
Randomization 1:1:1
EOS0 18 48Months
Fibrosis Improvement by ≥1 Stage
with No Worsening of NASH
NASH Resolution
with No Worsening of FibrosisOR
Month 18 Interim Analysis
Primary Endpoints
BiopsiesEvent driven
Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019
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56Medical Education Purposes Only
Fibrosis Improvement by ≥1 Stage with No Worsening of NASHPrimary Endpoint: ITT Population, N=931
Primary endpoint definition: fibrosis improvement by ≥1 stage (NASH CRN) with no worsening of NASH (defined as no worsening of hepatocellular ballooning, lobular inflammation or steatosis).Study success was defined as achievement of one of the two primary endpoints evaluated in the Month 18 interim analysis.*Statistically significant in accordance with the statistical analysis plan agreed with the FDA. All other p values are nominal.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
Placebo OCA 10 mg OCA 25 mg0
10
20
30
40
% P
ati
en
ts
17.6%
23.1%
(n=311) (n=308)
*p=0.0002
11.9%
p=0.04
(n=312)
Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019
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57Medical Education Purposes Only
Fibrosis Improvement by ≥1 Stage with No Worsening of NASH Primary Endpoint: Per Protocol Population, N=668
Primary endpoint definition: fibrosis improvement by ≥1 stage (NASH CRN) with no worsening of NASH (defined as no worsening of hepatocellular ballooning, lobular inflammation or steatosis).Per protocol population defined as all patients from the ITT population who completed ≥15 months of treatment and had a Month 18/EOT biopsy, were on treatment for at least 30 days immediately preceding the biopsy, and did not have any major protocol deviation.P values are nominal.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
Placebo OCA 10 mg OCA 25 mg0
10
20
30
40
% P
ati
en
ts
20.8%
27.5%
(n=224) (n=218)
p
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58Medical Education Purposes Only
Fibrosis Improvement by ≥2 StagesPer Protocol Population
P values are nominal.Per protocol population (N=668).Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
Placebo OCA 10 mg OCA 25 mg0
5
10
15
20
% P
ati
en
ts
7.1%
13.3%
(n=224) (n=218)
p=0.0008
4.5%
p=0.22
(n=226)
Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019
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59Medical Education Purposes Only
Placebo (n=220)
OCA 10 mg(n=223)
OCA 25 mg (n=213)
% Patients
30 20 10 0 10 20 30 40
38.0%
28.3%
23.2%
13.1%
16.6%
20.9%
Improved FibrosisWorsened Fibrosis
Regression or Progression of Fibrosis by ≥1 StagePer Protocol Population*
*Per protocol population with available fibrosis stage data at Month 18/EOT (n=656).Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019
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60Medical Education Purposes Only
Changes in Liver Biochemistry Over TimePer Protocol Population
Per protocol population (N=668).SE, standard error.Younossi Z, et al. Presented at EASL, 2019; Vienna, Austria. Oral (GS-06).
0 3 6 9 12 15 1840
60
80
ALT (U/L)
Month
Mean
(S
E)
ULN
0 3 6 9 12 15 1820
40
60
AST (U/L)
Month
Mean
(S
E)
ULN
0 3 6 9 12 15 18
25
50
75
100
GGT (U/L)
Month
Mean
(S
E)
ULN
0 3 6 9 12 15 1860
80
100
120
140
ALP (U/L)
Month
Mean
(S
E)
ULN
Placebo (n=224)
OCA 10 mg (n=226)
OCA 25 mg (n=218)
Younossi Z et al., EASL 2019 Abstract GS-06, J Hepatol 2019
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FXR regulates bile acid metabolims through multiple levelsin the liver and intestine
Calkin and Tontonoz 2012
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A new NASH player: Gut vascular barrier
Mouries J et al. J Hepatol 2019; epub
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Mouries J et al., J Hepatol 2019
A new NASH player: Gut vascular barrier
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• NASH is a growing and common cause of liver-related morbidity and mortality worldwide
• NASH is projected to soon become the leading indication for liver transplantation in the US
• Fibrosis stage is the strongest predictor of liver-related adverse clinical outcomes in patients with NASH
• There are currently no approved pharmacological therapies for NASH
NAFLD and NASH: a major unmet medical need
Angulo P, Gastroenterology 2015; Diehl AM, NEJM 2017; Dulai PS, Hepatology 2017
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Summary I: New Therapies in NAFLD/NASH
• GLP1 analogs and SGLT2 inhibitors are likely to be hepatoprotective in NASH
• Pharmcological treatment of fatty liver should be reserved for patients withNASH, especially with advanced fibrosis
• Patients with advanced NASH should be referred to expertise centers to beevaluated for ongoing clinical studies
• The phase III data in patients with NASH and advanced fibrosis are
– promising for obeticholic acid
– disappointing for selonsertib
– and pending for several other drugs
41,43
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Summary II: New Therapies in NAFLD/NASH
• Probably, bile acid/„enterohepatic“ drugs and anti-diabetic drugs arecompeting in a neck-to-neck race
• Combination therapies with several drugs might show additive effectswith more effective reduction in inflammation and/or fibrosis
• Bariatric surgery is a treatment option in obese individuals who failedlifestyle changes and pharmacotherapy
• Personalised and targeted treatment strategies for NASH arenot established yet
41,43