nonalcoholic fatty liver disease -...

Second Annual Spring Hepatology Update 4/30/2016

1

Nonalcoholic Fatty Liver Disease

Kris V. Kowdley MD, FACP

Director, Liver Care Network

Director, Organ Care Research

Swedish Medical Center

Seattle, WA


2

Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Graphic courtesy of Zobair M. Younossi, MD, MPH, FACG.

NA

FLD

Spectr

um

NASH Is Part of the Spectrum of NAFLD

NASH requires specific

pathologic criteria

• Exclusion of other liver

diseases

• Needed for prognosis


3

Global Epidemiology of NAFLD

• Systematic literature search

– 700+ studies evaluated, 95 studies examined,

53 studies analyzed

• Global prevalence of NAFLD is 21.3%

– Highest prevalence in South America (35.3%) and

the Middle East (31.8%)

– Prevalence in North America 18.5%

• NASH was prevalent in 26.2% of the subjects

with NAFLD

Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Koenig AB, et al. Hepatology. 2015;62(1 suppl):1286A.


4

Metabolic Abnormalities

Associated with NAFLD

Risk Factor1 Incidence (95% CI)

Hyperlipidemia 62.2% (45.3%–76.5%)

Obesity* 47.4% (34.2%–60.9%)

Metabolic syndrome 43.3% (29.4%–58.3%)

Hypertension 38.6% (32.1%–45.7%)

Hypertriglyceridemia 37.3% (25.4%–51.0%)

Diabetes 18% (13.6%–23.5%)

Abbreviation: NAFLD, nonalcoholic fatty liver disease.

1. Koenig AB, et al. Hepatology. 2015;62(1 suppl):1286A. 2. Younossi ZM, et al. Medicine (Baltimore). 2012;91:319-327.

*Although the vast majority of NAFLD patients are overweight or obese, patients with NAFLD may

also be lean.2


5

NAFLD and NASH Natural History

NAFLD

NASH (26%)1NAFL (74%)1

StableFibrosis Progression2

(25%–35% of NASH patients)

Cirrhosis2

(9%–20% of NASH patients)

Liver Failure or HCC2

(40%–60% of cirrhotics over 5–7 y)

OLT or Death2

(22%–33% of cirrhotics)

Abbreviations:

HCC, hepatocellular carcinoma;

NAFLD, nonalcoholic fatty liver disease;

NASH, nonalcoholic steatohepatitis;

OLT, orthotopic liver transplantation.

1. Koenig AB, et al. Hepatology. 2015;62(1 suppl):1286A. 2. Ong JP, et al. Clin Liver Dis. 2007;11:1-16.


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• Patients with NAFLD (N = 432); 26.8% with NASH

• In multivariate analysis, elevated AST and ALT, presence

of diabetes mellitus, male gender, and white ethnicity were

associated with moderate-to-severe fibrosis

(P <.0001)

• Risk increases with increasing metabolic conditions

What Are the Clinical Predictors of

Advanced Fibrosis in NAFLD?

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DM, diabetes mellitus; HTN, hypertension;

NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; VO, visceral obesity.

Hossain N, et al. Clin Gastroenterol Hepatol. 2009;7:1224-1229.

HTN DM HTN + DMHTN + DM

+ VOOR

(95% CI)

1.61 (1.21–2.01)

1.64 (1.13–2.17)

1.69 (1.11–2.28)

1.72(1.13–2.31)

P-value .0374 .0258 .0246 .0205


7

What Is the Association Between

Metabolic Syndrome and NASH?

• Patients with NAFLD, no overt diabetes, and with liver biopsy (N = 304)

• NASH confirmed in 120/304 patients

• Metabolic syndrome* was independently associated with– Histologic NASH

(OR, 3.2; 1.2–8.9)

– Severe fibrosis (OR, 3.5; 1.1–11.2)

88

53

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100

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eta

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S

yn

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(%

) P =.004

NASH Non-NASH

Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio.

Metabolic syndrome was defined as having ≥3 of the following criteria: 1) fasting glucose 110 mg/dL; 2) central obesity;

3) arterial pressure 130/85 mm Hg or pharmacologically treated; 4) triglyceride levels 150 mg/dL or current use of fibrates;

and 5) high-density lipoprotein-cholesterol 40 mg/dL (men) and 50 mg/dL (women).

Marchesini G, et al. Hepatology. 2003;37:917-923.


8

What Are the Clinical Predictors of

Liver-Related Mortality in NAFLD?Multivariate Survival Analysis

Factor aHR (95% CI)

Statistically

significant

predictors

NASH 9.16 (2.10–9.88)

Type 2 diabetes 2.19 (1.00–4.81)

Age 1.06 (1.02–1.10)

Other

Male gender 1.44 (0.62–3.34)

White race 1.85 (0.62–5.47)

Obesity 0.88 (0.38–2.04)

Hyperlipidemia 0.48 (0.19–1.23)

Abbreviations: aHR, adjusted health ratio; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Stepanova M, et al. Dig Dis Sci. 2013;58:3017-3023.


9

Univariate Survival Analyses

What Are the Histologic Predictors of

Liver-Related Mortality in NAFLD?

Abbreviations: HR, hazard ratio; LRM, liver-related mortality; MD, Mallory-Denk; NAFLD, nonalcoholic fatty liver disease.

Younossi ZM, et al. Hepatology. 2011;53:1874-1882.

HR (95% CI)

Portal

inflammation

(grade ≥2)

6.68 (2.20–20.3)P = .0008

Ballooning

(grade ≥2)

5.32 (1.89–14.9) P = .0015

MD bodies

(grade ≥2)

4.21 (1.66–10.7)P = .0024

Portal fibrosis

(grade >2)

14.1 (5.47–36.5)P <.0001

Pericellular

fibrosis (grade >2)

4.86 (1.73–13.7) P = .0027

On multivariate

analysis, only

significant fibrosis

(grade ≥3) was an

independent

predictor of LRM


10

• Several case reports and case series of well-documented

cases of HCC in NAFLD patients1–3

• NAFLD is the 3rd most common cause of HCC1

– Cumulative incidence of HCC in NASH cirrhosis is 2.6% compared

with 4% in HCV2

– Absolute risk for NAFLD-HCC: 3%−6% over 8.2−21 years4

– NAFLD-HCC mortality: 0.25%–2.3% over 7.6–13.7 years4

• Characteristics5

– More common in males (73%), average age 67 years5

– Most often (76%) a single lesion, well to moderately differentiated5

– Larger tumors than metabolic syndrome and other overt causes of

chronic liver disease, including viral hepatitis: 12.8 cm vs 8.8 cm

vs 7.8 cm (P = .001)6

NAFLD and HCC

Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

1. Mittal S, et al. Clin Gastroenterol Hepatol. 2015;13:594-601. 2. Ascha MS, et al. Hepatology. 2010;51:1972-1978. 3. Arase Y, et al. Hepatol Res.

2012;42:264-272. 4. White DL, et al. Clin Gastroenterol Hepatol. 2012;10:1342-1359. 5. Duan XY, et al. Hepatobiliary Pancreat Dis Int. 2012;11:18-

27. 6. Paradis V, et al. Hepatology. 2009;49:851-859.


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• Multicenter, observational, case-control study:

NAFLD-HCC (n = 145), HCV-HCC (n = 611)

• Compared with HCV-HCC, NAFLD-HCC

– Had more metabolic syndrome components

– Had larger tumor volume

– More often had an infiltrative pattern

– More often was found outside surveillance

• Cirrhosis present in 50% of NAFLD-HCC

patients

p=0.017

Clinical Patterns of HCC in

Patients with NAFLD

Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease.

Piscaglia F, et al. Presented at: 50th EASL; April 20-26, 2015; Vienna, Austria. Abstract P0340.


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Trends in NASH-Related Liver

Transplantation Waitlist Registrations

• In 2013, NASH became

2nd indication for LT listing

• OR for waitlist mortality at

90 days

– NASH: 1, reference

– ALD: 0.77; P <.001

– HCV: 0.99; P = .92

• Compared with HCV,

NASH patients had the

lowest chance of getting

transplanted in 90 days

and 1 year

Abbreviations: ALD, alcoholic liver disease; HCV, hepatitis C virus; LT, liver transplantation;

NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio.

Wong RJ, et al. Gastroenterology. 2015;148:547-555.

170

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90

140

190

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ait

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eg

istr

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ts (

%)

Change in Liver Transplantation Waitlist

Registrants, 2004–2013

NASH ALD HCV ALD-HCV


13

Key Diagnostic Challenges

• Lack of disease awareness and potential

severity among clinicians

• Lack of highly sensitive and specific

noninvasive diagnostic tools that are

readily available

• Lack of treatment approved by FDA


14

Predictive Value of Liver

Aminotransferases in NAFLD

• Serum ALT can be normal in up to nearly 60%

of NAFLD patients with NASH1,2

• Serum ALT can be increased in up to 53% of

NAFLD patients with no NASH1,2

• Therefore, serum ALT level alone is not

predictive of NASH or fibrosis level1-3

– Normal ALT cannot rule out progression or NASH

– Increased ALT cannot predict NASH

Abbreviations: ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

1. Fracanzani AL, et al. Hepatology. 2008;48:792-798. 2. Verma S, et al. Liver Int. 2013;33:1398-1405.

3. Torres DM, et al. Nat Rev Gastroenterol Hepatol. 2013;10:510-511.


15

AASLD Practice Guidelines for NAFLD

• “Liver biopsy should be considered in patients with

NAFLD who are at increased risk to have

steatohepatitis and advanced fibrosis”

– “The presence of metabolic syndrome and the NAFLD

Fibrosis Score may be used for identifying patients who

are at risk for steatohepatitis and advanced fibrosis”

• “Liver biopsy should be considered in patients with

suspected NAFLD in whom competing etiologies for

hepatic steatosis and co-existing chronic liver

diseases cannot be excluded without a liver biopsy”

All of the above recommendations are: Strength – 1, Evidence – B.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; NAFLD, nonalcoholic steatohepatitis.

Chalasani N, et al. Hepatology. 2012;55:2005-2023.


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Goals of Liver Biopsy

• Identify histologic features of NASH

– “Defined as the presence of hepatic

steatosis and inflammation with hepatocyte

injury (ballooning) with or without fibrosis”1

• Establish diagnosis

• Stage fibrosis

• Assess prognosis

• Rule out concomitant liver disease

– For example, hemochromatosis Abbreviation: NASH, nonalcoholic steatohepatitis.

1. Chalasani N, et al. Hepatology. 2012;55:2005-2023.


17

Red Flags for Risk of Progression to

Advanced Fibrosis in Patients with NASH

• Older age (>45 years)1

• Obesity1,2

• Diabetes1

• AST/ALT ratio >11

• Metabolic syndrome, particularly features of

hypertension and insulin resistance3

• Hispanic > non-Hispanic white > black4

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; NASH, nonalcoholic steatohepatitis.

1. Angulo P, et al. Hepatology. 1999;30:1356-1362. 2. Ratziu V, et al. Gastroenterology. 2000;118:1117-1123.

3. Dixon JB, et al. Gastroenterology. 2001;121:91-100. 4. Williams CD, et al. Gastroenterology. 2011;140:124-131.


18

Histologic Features Associated with

Disease Progression and Mortality

Hierarchy of

Mortality Risk

1. Fibrosis

2. Portal

inflammation

3. Diagnosis of

NASH

4. Ballooning

degeneratio

n

Abbreviations: CI, confidence interval; HR, hazard ratio; NASH, nonalcoholic steatohepatitis.

Loomba R, et al. Gastroenterology. 2015;149:278-281.

Stage 95% CI of HR

1 1.18, 2.81

2 1.20, 3.03

3 1.16, 3.12

4 3.35, 12.04

Risk of Mortality by

Fibrosis Stage

Stage 95% CI of HR

1 0.63, 8.91

2 2.26, 24.94

3 4.35, 43.65

4 11.94, 188.61

Risk of Liver-

Related Events by

Fibrosis Stage


19

Noninvasive Tests for Liver Fibrosis

• Clinical or laboratory tests

– NAFLD Fibrosis Score

– FIB-4 index

– BARD

– AST/ALT ratio

• Imaging modalities

– Shear-wave elastography

• Supersonic imaging, Fibroscan, ARFI

• MRE

– MRI-based

• Liver MultiScan

Abbreviations: ALT, alanine aminotransferase; ARFI, acoustic radiation force impulse; AST, aspartate aminotransferase;

MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease.


20

NAFLD Fibrosis Score

• Derivation and validation of the scoring system

• 733 NAFLD patients: 480 derivation; 253 validation

• Multivariate analysis

– Age, hyperglycemia, BMI, platelet count, albumin,

AST/ALT ratio are independent predictors of

advanced fibrosis

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; NAFLD, nonalcoholic fatty liver

disease; NPV, negative predictive value; PPV, positive predictive value.

Angulo P, et al. Hepatology. 2007;45:846-854.

Cutoff Point GroupPredictive Value for

Advanced Fibrosis

Low cutoff point:

<–1.455

Derivation NPV 93%

Validation NPV 88%

High cutoff point:

>0.676

Derivation PPV 90%

Validation PPV 82%


21

Formula1 Online calculator2

–1.675 + (0.037 x age [years])

+ (0.094 x BMI [kg/m2]) +

(1.13 x IFG/diabetes

[yes =1, no = 0]) +

(0.99 x AST/ALT ratio) –

(0.013 x platelet [109/L]) –

(0.66 x albumin [g/dL])

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index;

IFG, impaired fasting glucose; NAFLD, nonalcoholic fatty liver disease.

1. Angulo P, et al. Hepatology. 2007;45:846-854.

2. NAFLD Fibrosis Score Online Calculator. http://nafldscore.com/.

Calculating the

NAFLD Fibrosis Score

Measures:

– Age

– BMI (kg/mL)

– IGF/diabetes

– AST

– ALT

– Platelets

– Albumin

Available at: http://nafldscore.com


22

FIB-4 Index

• Originally developed to predict advanced

fibrosis in HIV/HCV coinfection1

• Subsequently studied in 541 patients with

NAFLD2

– AUROC 0.80

Abbreviations: AUROC, area under receiver operating characteristic curve; HCV, hepatitis C virus; HIV, human immunodeficiency

virus; NAFLD, nonalcoholic fatty liver disease; NPV, negative predictive value; PPV, positive predictive value.

1. Sterling RK, et al. Hepatology. 2006;43:1317-1325. 2. Shah AG, et al. Clin Gastroenterol Hepatol. 2009;7:1104-1112.

Cutoff PointPredictive Value for

Advanced FibrosisInterpretation

Low cutoff point:

<1.30

PPV 43%

NPV 90%

Absence of

advanced fibrosis: F0–1

High cutoff point:

>2.67

PPV 80%

NPV 83%

Presence of

advanced fibrosis: F3–4


23

Formula1

Online calculator2

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

1. Sterling RK, et al. Hepatology. 2006;43:1317-1325.

2. Hepatitis C Online. http://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4.

Calculator image used with permission from Hepatitis C Online.

Calculating the FIB-4

(Age [years] x AST [U/L])

(Platelet [x109] x √ALT [U/L])


24

Transient Elastography

• Measures velocity of a low-frequency (50 Hz) elastic

shear wave propagating through the liver1

• Allows painless and simultaneous measurement of 2

quantitative parameters

– Liver stiffness expressed in kPa: correlates with fibrosis stage2

• Correlated to liver fibrosis stage2

– Controlled attenuation parameter expressed in dB/meter:

correlates with steatosis3

• Volume of liver tissue is 100 times bigger than biopsy4

• False positives: recent meal ingestion, acute hepatitis,

extrahepatic cholestasis, and congestion1

• Low applicability: obesity, ascites, operator inexperience1

1. Castera L, et al. Nat Rev Gastroenterol Hepatol. 2013;10:666-675. 2. Friedrich-Rust M, et al. Gastroenterology. 2008;134:960-974.

3. Sasso M, et al. J Viral Hepat. 2012;19:244-253. 4. Gómez-Domínguez E, et al. Aliment Pharmacol Ther. 2006;24:513-518.


25

Magnetic Resonance ElastographySimple

Steatosis

Inflammation

But No Fibrosis Fibrosis

Graphics courtesy of Rohit Loomba, MD, MHSc.


26

MRE—Accuracy in Predicting and

Identifying Fibrosis

Prospective study of ability of MRE to predict fibrosis in NAFLD

patients1

• AUROC 0.924

Individual participant data pooled analysis of ability of MRE to detect

fibrosis in NAFLD patients2

• AUROC for stage ≤1, 0.86; stage ≥2, 0.87; stage ≥3, 0.90; stage 4, 0.91

Cross-sectional analysis of a prospective cohort to compare

performance of MRE vs clinical prediction rules (CPR) for predicting

advanced fibrosis3

• AUROC for MRE, 0.957

• AUROC for CPRs, 0.796–0.861

Abbreviations: AUROC, area under receiver operating characteristic curve; MRE, magnetic resonance elastography;

NAFLD, nonalcoholic fatty liver disease.

1. Loomba R, et al. Hepatology. 2014;60:1920-1928. 2. Singh S, et al. Eur Radiol. 2015 Aug 28. [Epub ahead of print].

3. Cui J, et al. Aliment Pharmacol Ther. 2015;41:1271-1280.


27

NASH Pathogenesis—

Multiple-Hit Hypothesis

1st Hit

Increased lipolysis and increased delivery of FFA to liver

Results in steatosisand accumulation of liver fat

2nd Hit

Oxidative stress from mitochondrial ROS and CYP-450 enzymes

Alternative 2nd hit: adipokines associated with obesity and factors associated with apoptotic pathway

Results in inflammation and necrosis

Abbreviations: DM, diabetes mellitus; FFA, free fatty acids; IR, insulin resistance; NASH, nonalcoholic steatohepatitis;

ROS, reactive oxygen species.

Mishra P, et al. Non-alcoholic Fatty Liver Disease. Practical Management of Liver Diseases. Cambridge University Press; 2008.

NASHFibrosis and

progression

of disease

Obesity

IR

Type 2 DM


28

Key Concepts in the

Pathogenesis of NASH

Browning JD, et al. J Clin Invest. 2004;114:147-152.

From Dr. Loomba:

Delete if cannot get

permission to use.


29

Lifestyle change

• Foundation of any treatment plan

• Difficult to achieve and sustain

• Not enough for morbidly obese patients


30

RCT Intensive Lifestyle Change and Weight

Loss

48 weeks

Responders:

NAS reduction

of > 3

Promrat Hepatol 2010;51:121


31

Class Drug Status

Farnesoid X receptor agonist Obeticholic acid III; Breakthrough*

Fatty acid/bile acid modifier Aramchol IIb; Fast Track*

Dual inhibitor of CCR2 and CCR5 Cenicriviroc IIb; Fast Track*

Dual peroxisome proliferator-

activated receptor alpha/delta

agonist

Elafibranor

(GFT505)

IIb; Fast Track*

Anti-lysyl oxidase-like 2

monoclonal antibody

Simtuzumab IIb

Apoptosis signal-regulating kinase

1 inhibitor

GS-4997 II

Galectin-3-inhibitor GR-MD-02 II; Fast Track*

Niemann–Pick C1-like 1 protein

selective blocker

Ezetimibe II

*FDA.

Therapies in Phase II/III Testing for NASH


32

Abbreviations: FXR, farnesoid X receptor; NASH, nonalcoholic steatohepatitis; RXR, retinoid X receptor.

Kuipers F, et al. Nat Rev Endocrinol. 2014;10:488-498. Ratziu V. Nat Rev Gastroenterol Hepatol. 2013;10;676-685.

Zhang Y, Edwards PA. FEBS Lett. 2008;582:10-18. Graphic courtesy of Anne S. Henkel, MD.

Farnesoid X Receptor and Its Role in

NASH

Cholesterol

CYP7a1

DecreaseFibrosis

Hepatic

Stellate Cell

RXR

FXR

Glucose Intolerance

Hepatic Triglycerides

Bile Acids

?

Hepatocyte


33

Elafibranor (GFT505)—

Mechanism of Action• Dual PPAR alpha/delta agonist1

• Improves lipid and glucose metabolism in prediabetic patients2

• Improves hepatic and peripheral insulin sensitivity in obese

patients3

• Improves steatohepatitis and fibrosis in mouse NASH models1

• Antifibrotic and anti-inflammatory effect1

PPAR-α PPAR-δ

Expression1 Hepatocytes Ubiquitous

Action1 Lipid and lipoprotein

metabolism

Anti-inflammatory

Mitochondrial function,

fatty acid oxidation, and

insulin sensitivity

Anti-inflammatory

Abbreviations: NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor.

1. Cariou B, et al. Expert Opin Investig Drugs. 2014;23:1441-1448. 2. Cariou B, et al. Diabetes Care.

2011;34:2008-2014. 3. Cariou B, et al. Diabetes Care. 2013;36:2923-2930.


34

Phase IIb, 72-week, randomized, double-blind, placebo-

controlled study to assess efficacy and safety of OCA in

patients with NASH; planned interim analysis before end

of treatment

Arms

Patients283 patients ≥18 years of age

Histologic evidence of NASH based on a liver biopsy

obtained ≤90 days prior to randomization; NAS ≥4

Endpoints

Primary

Histologic improvement in NAS from baseline, with no

worsening in fibrosis; decrease in NAS of ≥2 points

Secondary

Resolution of NASH; change in NAS, hepatocellular

ballooning, steatosis, lobular/portal inflammation; change in

liver enzymes, insulin resistance, weight-related measures,

and QOL

Abbreviations: NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; OCA, obeticholic acid; QOL, quality of life.

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

Design

1) OCA 25 mg/day

2) Placebo

OCA—Phase IIb FLINT Trial


35

FLINT Primary Endpoint—Improved

Liver Histology at Week 72

Histologic response =

• ≥2-point

improvement in NAS

– NAS = steatosis

grade (0–3) +

inflammation grade

(0–3) + ballooning

grade

(0–2)

• No worsening of

fibrosisAbbreviations: NAS, NAFLD activity score; OCA, obeticholic acid.


P =.0002

21

45

0

10

20

30

40

50

60

Placebo OCA 25 mg

Pa

tie

nts

(%

)

(n = 109) (n = 110)

Histologic Response Rate


36

3538

31

19

53

61

46

35

0

10

20

30

40

50

60

70

80

Lobularinflammation

Steatosis Hepatocellularballooning

Fibrosis

Pa

tie

nts

wit

h Im

pro

ve

me

nt

(%)

P <.01

FLINT—Improved Secondary

Histologic Outcomes at Week 72

P = .001

Abbreviation: OCA, obeticholic acid.


P <.05

P <.01

Placebo (n = 109)

OCA 25 mg (n = 110)


37

Elafibranor (GFT505)—Phase IIb

GOLDEN TrialPhase IIb, 1-year, international, multicenter, randomized,

double-blind, placebo-controlled trial to assess the safety

and efficacy of elafibranor in noncirrhotic patients with NASH

Arms1,21) Elafibranor 80 mg

2) Elafibranor 120 mg

3) Placebo

Patients1,2

274 patients ≥18 years of age

Histologic evidence of NASH based on a liver biopsy;

treatment with vitamin E, polyunsaturated fatty acids, or

ursodeoxycholic acid discontinued 3 months prior to biopsy

Endpoints1

Primary

Resolution of NASH with no worsening of fibrosis

Secondary

Change in NAS, fibrosis, liver enzymes, lipid parameters,

metabolic markers, safety markers

Abbreviations: NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis.

1. ClinicalTrials.gov. NCT01694849. https://clinicaltrials.gov/ct2/show/NCT01694849.

2. Ratziu V, et al. Hepatology. 2015;62(suppl 1):262A.

Design1


38

GOLDEN—Preliminary Findings

• Primary endpoint was not met in

initial assessment

– Elafibranor was not better than

placebo in resolving NASH

– After controlling for baseline

heterogeneity of severity and center

effect, the primary endpoint was met

• Main caveats

– High placebo response due to

inclusion of milder disease

– Subset analysis: NAS >5 shows

significant improvement in elafibranor

120-mg group vs placebo

Abbreviations: ELF, elafibranor; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; PBO, placebo.

Ratziu V, et al. Hepatology. 2015;62(suppl 1):262A.

27.5

14.8

19.5

00

10

20

30

40

Re

sp

on

se

Ra

te (

%)

ELF 120 mg

PBO

NAS 4–5 NAS >5


39

Conclusions

• Nonalcoholic fatty liver disease (NAFLD) has

tremendous clinical, economic, and patient-reported

outcome burden to patients and to society

– This burden is growing globally

• Nonalcoholic steatohepatitis (NASH) is the progressive

form of NAFLD

• Histologic fibrosis (stage 2 or more) predicts

liver-related mortality

• Pathogenesis of NASH is complex, requiring multiple hits

• Biomarkers should be based on pathogenetic pathways

• Treatment targets to be carefully chosen

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