NASH Treatment Approaches:

Now and in the Future

Stephen A. Harrison, MD,

COL (Ret.), FAASLD
Visiting Professor of Hepatology
Radcliffe Department of Medicine
University of Oxford
Oxford, United Kingdom

This program is supported by an educational grant from Intercept

Pharmaceuticals, Inc.
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Faculty Disclosures

Quentin M. Anstee, BSc, MB BS, PhD, MRCP(UK), FRCP, has

disclosed that he has received consulting fees paid to his institution from
Acuitas Medical, Genfit, Intercept, Inventiva, Janssen, Lilly, NewGene,
Pfizer, Raptor Pharmaceuticals, and Tobira and funds for research
support paid to his institution from AbbVie and GlaxoSmithKline.
Stephen A. Harrison, MD, COL (Ret.), FAASLD, has disclosed that he
has received consulting fees from Bristol-Myers Squibb, the Chronic
Liver Disease Foundation, FibroGen, Genfit, Intercept, Medivation,
Merck, NGM Biopharmaceuticals, and Pfizer; fees for non-CME/CE
services received directly from a commercial interest or their agents (eg,
speaker bureaus) from AbbVie, Alexion, Gilead Sciences, and Merck;
and funds for research support paid to his institution from Bristol-Myers
Squibb, Conatus, Galectin, Galmed, Gilead Sciences, Immuron,
Intercept, Madrigal, Merck, NGM Biopharmaceuticals, and Tobira.
Mary E. Rinella, MD, has disclosed that she has received consulting fees
from Amarin, BioPharma, Echosens, Enanta, Immuron, Intercept, NGM
Biopharmaceuticals, and NuSirt.
Outline

 Current Best Practices in NASH Management

– Lifestyle Changes
– Pharmacologic
– Surgical Management Strategies
 Investigational Therapies
– Phase III
– Phase II
 Lifestyle Changes in NAFLD

 Foundation of any treatment plan

 Difficult to achieve and sustain
 Not enough for morbidly obese pts

Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
Weight Loss Correlates to Frequency of
Clinic Visits

1/100 of 1 percent

Minutes in 1 yr = 525,960
Minutes discussing weight loss and lifestyle with HCP
(assuming 4 visits of 15 mins each)
Slide credit: clinicaloptions.com
 Percentage of Weight Loss Associated
With Histological Improvement in NAFLD
 Analysis of data from 4 randomized studies
Weight loss ≥ 10%
Fibrosis
regression
(45% of pts)
Weight loss ≥ 7%
NASH resolution
(64% to 90% of pts)*

Weight loss ≥ 5%
Ballooning/inflammation
(41% to 100% of pts)*

Weight loss ≥ 3%
Steatosis
(35% to 100% of pts)*

*Depending on degree of weight loss.

Hannah WN, et al. Clin Liver Dis. 2016;20:339-350. Slide credit: clinicaloptions.com
Effect of Diet in NAFLD

 Limiting total caloric intake is ideal and more

important than aiming for a specific nutrient
composition
 My diet recommendation: limit processed carbs!
– White/brown bread, rice
– White/orange potatoes
– Flour/corn tortillas
– Pizza/pasta
– Chips
– Fructose-containing sodas and juices
Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
Effect of Exercise on NAFLD

 Physical inactivity linked to

– Increased body weight
– Central adiposity
– Insulin resistance
– Increased risk of metabolic syndrome
– NAFLD
– Severity of NASH

Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
 Exercise by METs

Physical Activity METs

Light intensity <3
 Sleeping
 Watching TV
 Writing, desk work, typing
 Walking, 1.7 mph (2.7 km/h), level ground, strolling, very slow
 Walking, 2.5 mph (4 km/h)
Moderate intensity 3 to 6
 Bicycling, stationary, 50 watts, very light effort
 Walking, 3.0 mph (4.8 km/h)
 Calisthenics, home exercise, light or moderate effort, general
 Walk, 3.4 mph (5.5 km/h)
 Bicycling, < 10 mph (16 km/h), leisure, to work or for pleasure
 Bicycling, stationary, 100 watts, light effort
Vigorous intensity >6
 Jogging, general
 Calisthenics (eg, pushups, sit-ups, pullups, jumping jacks), heavy, vigorous effort
 Running/jogging in place
 Rope jumping

Allina Health System Press, Helping Your Heart, cvs-ahc-90648 (5/05),

third edition, ISBN 1-931876-11-8. Slide credit: clinicaloptions.com
 Lack of Exercise Is Common in NAFLD

 Pts engage in less physical activity

– < 20% meet recommended physical activity guidelines
 Adults with NAFLD (N = 813)[1]
– 54% of pts reported NO physical activity
– Vigorous-intensity exercise (≥ 6 METs for 75 min/wk)
associated with decreased odds of NASH
– OR: 0.65 (95% CI: 0.43-0.98; P = .04)

1. Kistler KD, et al. Am J Gastroenterol. 2011;106:460-468. Slide credit: clinicaloptions.com

 What Is the Right Prescription for Exercise
in Pts With NAFLD?
 Data limited by small sample sizes, poor statistical
power, and lack of correlation with histopathology
 Exercise associated with a reduction in hepatic fat
even in the absence of weight loss
 Small studies suggest resistance training reduces
hepatic fat, improves other metabolic parameters

Hashida R, et al. J Hepatol. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

 Evidence for Exercise in NAFLD

 No head-to-head trials of aerobic exercise vs

resistance training for efficacy in NAFLD
– No data to suggest superiority of one exercise regimen
vs another
 Current evidence reinforces utility of aerobic or
resistance exercise for improving steatosis

Chocolate Chunk Muffin: 440 calories

Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
My Recommendation

Hypocaloric diet Moderate

Sustained
(daily reduction
by 500-1000 kcal)
+ intensity = weight loss
exercise

Slide credit: clinicaloptions.com

Outline

 Current Best Practices

– Lifestyle Changes
– Pharmacologic
– Surgical Management Strategies
 Investigational Therapies
– Phase III
– Phase II
Current Status of Pharmacologic
Treatments for NASH
 No FDA-approved therapies for NASH
 Currently available therapeutics with proven efficacy
– Vitamin E
– Pioglitazone
 More limited data
– Pentoxifylline
– Liraglutide

Slide credit: clinicaloptions.com

Vitamin E
 PIVENS: Histologic Resolution of NASH at
Wk 96 With Vitamin E vs Pioglitazone
 Double-blind, placebo-controlled, randomized, phase III trial in adults
with biopsy-proven NASH and no diabetes or cirrhosis (N = 247)
100
Pts With Resolved NASH (%)

80
P = .001
60 P = .05
47
40 36

21
20
n/N = 29/80 15/72 33/70
0
Vitamin E Placebo Pioglitazone
800 IU/day 30 mg/day
Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685. Slide credit: clinicaloptions.com
 PIVENS: No Significant Improvement in
Fibrosis at Wk 96 for Vitamin E or Pioglitazone

60 P = .19 P = .1
Pts With Change in Fibrosis

Improved

40

20 Δ grade Δ grade Δ grade

Score (%)

-0.3 -0.1 -0.4

0
Worsened

-20

-40

-60
Vitamin E Placebo Pioglitazone
800 IU/day 30 mg/day

Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685. Slide credit: clinicaloptions.com

 Why Not Empirically Treat Suspected
NASH With Vitamin E?
 ~ 50% of pts do not respond to vitamin E[1]
– Liver enzymes are not reliable to assess quiescence or
progression
 Increased risk of hemorrhagic stroke[2]
 Prostate cancer risk?
– Absolute increase 1.6/1000 PY; synthetic form[3]
– No effect on prostate cancer risk (n = 11,000)[4]
 Long-term safety?
– Remains unknown though likely safe
– Doses > 400 IU/day may be associated with increased mortality
but data limited by small studies[5]
References in slidenotes. Slide credit: clinicaloptions.com
Pioglitazone
 PIVENS: Histologic Improvement at
Wk 96 With Vitamin E vs Pioglitazone
100
Pts With Improvement* (%)
P = .001
80
P = .04
60 NNT = 4.2
43 NNT = 6.9
40 34

19
20

n= 84 83 80
0
Vitamin E Placebo Pioglitazone
800 IU/day 30 mg/day
*Histologic improvement: ≥ 1-point improvement in hepatocellular ballooning score, no increase in
fibrosis score, and either a decrease in NAS to ≤ 3 or a ≤ 2-point decrease in NAS plus ≥ 1-point
decrease in either the lobular inflammation or steatosis score.
Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685. Slide credit: clinicaloptions.com
 Pioglitazone in Diabetes: Improvement or
Resolution of NASH at 18 Mos
 Randomized, placebo-controlled, double-blind phase IV
trial of pts with NASH and prediabetes or type 2 diabetes
mellitus (N = 101)[1]
Placebo (n = 42)
– Secondary outcome Pioglitazone (n = 40)

Pts With Improvement (%)

100
analysis of histologic P < .001
scores included pts 80 P = .001
65
with paired biopsies from 60 58
before/after tx (n = 82)
40
19 21
20

0
≥ 2-Point Reduction Resolution
in NAS of NASH
(No Worsening
of Fibrosis)
1. ClinicalTrials.gov. NCT00994682.
2. Cusi K, et al. Ann Intern Med. 2016;165:305-315. Slide credit: clinicaloptions.com
 Pharmacologic Treatment Options Studied
in NASH
Agent Good Evidence Limited or AASLD
for Use[1] Insufficient Evidence NAFLD/NASH
for Use[1] Recommendation[2]
NASH without NASH with diabetes or NASH without
Vitamin E
diabetes cirrhosis diabetes
NASH with or Can be used for
Pioglitazone NASH with cirrhosis
without diabetes steatohepatitis
No significant effect
Metformin on liver histology[2] Not recommended

Needs further study to

Pentoxifylline determine ideal
subpopulation

1. Rinella ME, et al. Gastroenterol Hepatol. 2014;10: 219-227.

2. Chalasani N, et al. Hepatology. 2012;55:2005-2023. Slide credit: clinicaloptions.com
Surgical Management Strategies
 Bariatric Surgery Improves Clinical
Parameters
 Prospective study following bariatric surgery in pts who are
severely obese (N = 381) with ≥ 1 comorbidity, no excessive
drinking < 2 yrs, no chronic liver diseases
– Liver biopsies assessed by 2 blinded reviewers for fibrosis (F0-4),
NAFLD scoring to determine NASH (≥ 3, probable or definite; ≥ 5,
definite)
Parameter Before Surgery After 5 Yrs P Value
Diabetes mellitus, n (%) 94 (24.8) 24 (10.8) .00001
Arterial hypertension, n (%) 185 (48.8) 85 (37.0) .0005
Serum triglycerides, mean (g/L) 1.67 1.06 .00001
Fasting glucose, mean (g/L) 1.18 0.94 .00001
Insulin resistance index, mean 3.2 2.83 .00001
ALT, mean (IU/L) 30.1 22.8 .00003
GGT, mean (IU/L) 39.9 29.2 .00001

Mathurin P, et al. Gastroenterology. 2009;137:532-540. Slide credit: clinicaloptions.com

 Bariatric Surgery Improves Fibrosis in Pts
With NASH
 Prospective study of bariatric surgery in pts who are morbidly
obese with biopsy-validated NASH, ≥ 1 comorbidity factor for
> 5 yrs, no chronic liver disease (N = 109)
Distribution of Fibrosis METAVIR Scores Wilcoxon signed-
2.5 rank paired t test
100 3.75
7.5 7.5 P < .003
80 21.25 13.75
Fibrosis METAVIR Score
Pts (%)

60 32.5 F4
40 F3
40 F2
20 43.75 F1
27.5 F0
0
Baseline After 1 Yr

Lassailly G, et al. Gastroenterology. 2015;149:379-388. Slide credit: clinicaloptions.com

Outline

 Current Best Practices

– Lifestyle Changes
– Pharmacologic
– Surgical Management Strategies
 Investigational Therapies
– Phase III
– Phase II
 Key NASH Therapies: Improvement in
Steatosis
 Results from separate studies, not head to head
– Time points and populations may differ between studies
Active drug
100 P = .009
P < .001 Placebo
P = .005 83
80 P = .001
69
61
60 54
Pts (%)

P = .10
45
40 38 35
31 31 P = .52

20 18 19
16
n/N = 43/80 22/72 48/70 22/72 19/23 10/22 62/102 37/98 11/31 7/39 23/145 27/144
0
Vitamin E Pioglitazone Liraglutide Obeticholic Elafibranor Cenicriviroc
800 IU/day[1] 30 mg/day[1] 1.8 mg/day[2] Acid 25 120 mg/day [4] 150 mg/day[5]
mg/day[3]
 In bariatric surgery study, median steatosis improved from 60% at baseline to
10% at 1 yr[6]
References in slidenotes. Slide credit: clinicaloptions.com
 Key NASH Therapies: Resolution of NASH

 Results from separate studies, not head to head

– Time points and populations may differ between studies Active therapy
Placebo
100
85
80
P = .001
60 P = .019
Pts (%)

P = .05 47
P = .08 P = .01 P = .49
39
40 36 29
21 21 9 22 8 6
5
20 2/ 13
2/ 8/
29/ 15/ 33/ 15/ 9/ 22 22/ 13/ 9/ 11/ 70/
n/N = 39 144
80 72 70 72 23 102 98 31 145 82
0
Vitamin E Pioglitazone Liraglutide Obeticholic Elafibranor Cenicriviroc Bariatric
800 30 mg/day[1] 1.8 mg/day[2] Acid 25 120 mg/day[4] 150 mg/day[5] Surgery[6]
IU/day[1] mg/day[3]

References in slidenotes. Slide credit: clinicaloptions.com

 Key NASH Therapies: Improvement in
Fibrosis
 Results from separate studies, not head to head
– Time points and populations may differ between studies Active therapy
Placebo
100

80

P = .24 P = .12
60
Pts (%)

P = .004
41 44
P = .46 P = .02
40 31 31 35 34
26
19 20
20 14 10
33/ 22/ 31/ 22/ 6/ 3/ 36/ 19/ 29/ 15/ 27/
n/N = No data
80 72 70 72 23 22 102 98 145 144 80
0
Vitamin E Pioglitazone Liraglutide Obeticholic Elafibranor Cenicriviroc Bariatric
800 IU/d[1] 30 mg/d[1] 1.8 mg/d[2] Acid 25 120 mg/d[4] 150 mg/d[5] Surgery[6]
mg/d[3]

References in slidenotes. Slide credit: clinicaloptions.com

 Emerging Treatments in NASH: Phase III

Drug Mechanism of Study Trial Primary

Action Population Endpoint(s)
Resolution of NASH
PPAR α/δ NASH with
Elafibranor RESOLVE-IT[2] w/o fibrosis
agonist[1] fibrosis
worsening
Improvement in
fibrosis w/o NASH
Obeticholic FXR agonist NASH with worsening;
REGENERATE[4,5]
acid (bile acid)[3] fibrosis improvement in
NASH w/o fibrosis
worsening

1. Ratziu V, et al. Gastroenterology. 2016;150:1147-1159.

2. ClinicalTrials.gov. NCT02704403.
3. Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.
4. ClinicalTrials.gov. NCT02548351.
5. Ratziu V, et al. EASL 2016. Abstract THU-488. Slide credit: clinicaloptions.com
 Emerging Treatments in NASH: Phase II

Drug Mechanism of Study Population Trial Primary Endpoint(s)

Action
Inhibitor of NASH with liver Improvement in NAS
Cenicriviroc CENTAUR*[1,2]
CCR2/CCR5 fibrosis w/o fibrosis worsening
Monoclonal Morphometric
Liver fibrosis
Simtuzumab antibody to NCT01672866*[4] quantitative collagen
secondary to NASH
LOXL2[3] change; EFS
Fatty acid–bile Change in liver
Aramchol NASH Aramchol_005*[6]
acid conjugate[5] triglycerides by NMRS
Resolution of NASH w/o
Liraglutide GLP-1 analogue Overweight NASH LEAN[7,8]
fibrosis worsening
Liver fibrosis and
Galectin-3
GR-MD-02 portal hypertension NASH-CX[10] Improvement in HVPG
inhibitor[9]
in NASH cirrhosis
NASH with liver Improvement in fibrosis
Emricasan Caspase inhibitor ENCORE-NF[11]
fibrosis w/o NASH worsening
*Phase IIb.

References in slidenotes. Slide credit: clinicaloptions.com

 Emerging Treatments in NASH: Phase II

Drug(s) Mechanism(s) of Study Trial Primary Endpoint(s)

Action Population
NASH with F2-
Selonsertib ASK1 inhibitor GS-US-384-1497[1,2] Safety and tolerability
F3 liver fibrosis
Safety and tolerability;
JKB-121 TLR-4 antagonist NASH Pro00062677[3] change in ALT, hepatic
fat; TTP
NGM-282 FGF-19 agonist[4] NASH 15-0105[5] Change in hepatic fat
Safety and tolerability;
BMS-986036 FGF-21 agonist NASH MB130-045[6]
change in hepatic fat
GS-0976 ACC inhibitor NASH GS-US-426-3989[7] Safety and tolerability
FXR agonist
GS-9674, (bile acid) NAFLD GS-US-384-3914[8] Safety and tolerability
GS-0976
ACC inhibitor
Improvement in NAS
Volixibat ASBT inhibitor NASH NCT02787304[9]
w/o fibrosis worsening

References in slidenotes. Slide credit: clinicaloptions.com

Agents in Phase III:
Obeticholic Acid
Elafibranor
 Obeticholic Acid: FXR Agonist and Bile
Acid Analogue
CDCA OCA (6-ECDCA)
chenodeoxycholic acid obeticholic acid
O O
Me Me
OH OH
Me Me

HO OH HO OH
6α ethyl substitution

~ 90 x increased potency

FXR EC50 = 8.7 µM FXR EC50 = 99 nM

 In vitro/in vivo studies do not necessarily correlate with

clinical response
Pellicciari R, et al. J Med Chem. 2002;45:3569-3572. Slide credit: clinicaloptions.com
 FXR Central to a Multitude of Key
Pathways in Animal Models
Multiple mechanisms
↑ Glucose tolerance

via ↓ SREPB-1C
↓ Portal via ↑ iNOS ↓ Hepatic

RXR
pressure via ↑ β-oxidation triglycerides
↓ Bile acids

↑ Cholesterol
CYP7a1

↓ Fibrosis FXR agonist

(eg, obeticholic acid)
↓ stellate cell
activation

References in slidenotes. Slide credit: clinicaloptions.com

 FLINT: Obeticholic Acid in Noncirrhotic
Pts With NASH
 Double-blind, placebo-controlled, randomized,
multicenter phase IIb trial
Primary Endpoint:
Wk 72 Improvement
in NAS ≥ 2 Points Wk 72
Stratified by clinical center and Wk 72 With No Worsening Improvement
diabetes status at baseline of Fibrosis in Fibrosis

Pts with NASH or Obeticholic acid 25 mg PO QD 45% 35%

borderline NASH (n = 141) (50/110) (36/102)
confirmed by entry
biopsy, NAS ≥ 4
(individual scores
Placebo
21% 19%
each ≥ 1), no cirrhosis
(n = 142) (23/109) (19/98)
(N = 283)

P = .0002 P = .004

Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965. Slide credit: clinicaloptions.com

 REGENERATE: Long-term Evaluation of
Obeticholic Acid for NASH and Fibrosis
 Double-blind, placebo-controlled, randomized,
multicenter phase III trial
Final
Mo 18 interim Mo 48 interim
analysis
analysis analysis
(~ 6 yrs)

Obeticholic acid
25 mg/day
Pts with biopsy-
Until accrued 264
confirmed NASH, outcome events in OCA
stage 2-3 fibrosis Obeticholic acid
25 mg/day and placebo
(Planned N = 10 mg/day
treatment arms
2065) (estimated 6 yrs)

Placebo

Ratziu V, et al. EASL 2016. Abstract THU-488. Slide credit: clinicaloptions.com

 REGENERATE: Interim and Final Analysis
Endpoints
 Mo 18 (interim analysis) coprimary endpoints
– Fibrosis improvement ≥ 1 point without NASH worsening

– NASH resolution without fibrosis worsening

 Final analysis comparing time to adjudicated events

– Progression to cirrhosis

– Uncontrolled ascites

– Hospitalization (bacterial peritonitis, hepatic encephalopathy, variceal

bleed)

– Hepatocellular carcinoma

– Liver transplant or transplant eligibility

– Death
Ratziu V, et al. EASL 2016. Abstract THU-488. Slide credit: clinicaloptions.com
 Dual PPARa/d Agonist
Elafibranor

PPARa PPARd

• Fatty acid oxidation • Lipoprotein metabolism

• TG lowering • Glucose homeostasis
• HDL raising • Energy metabolism
• Inflammation • Inflammation

Liver
Slide courtesy of Bart Staels, MD. Slide credit: clinicaloptions.com
 GOLDEN-505: Elafibranor for 52 Wks

 Double-blind, placebo-controlled, randomized, international

phase IIb trial
Wk 52
Stratified by Protocol-Defined Modified
diabetes status Primary Definition of
Outcome* Response†

Elafibranor 80 mg PO QD 23% 13%

(n = 93) (21/93) (12/93)
Pts with
histologic 21% 19%
Elafibranor 120 mg PO QD
diagnosis of (19/89) (17/89)
(n = 91)

P = .045
P = .28
noncirrhotic
NASH (N = 276)
17% 12%
Placebo
(16/92) (11/92)
(n = 92)
*Disappearance of steatosis, †Disappearance of ballooning and disappearance
ballooning, or lobular inflammation. or mild persistence of lobular inflammation.

Ratziu V, et al. Gastroenterology. 2016;150:1147-1159. Slide credit: clinicaloptions.com

 GOLDEN-505: Correlation Between NASH
Histology and Fibrosis at 52 Wks
 Changes in hepatocyte ballooning and lobular inflammation correlated
with changes in fibrosis stage (P = .04 and P < .001, respectively)
 Changes in steatosis did not correlate with changes in fibrosis stage
Fibrosis improvement Fibrosis worsening
100

80 Fisher test, P < .001

N = 237
60
Pts (%)

40

20

0
≤ -3 -2 -1 0 1 ≥2
Changes in Lobular Inflammation Plus Ballooning Scores
Ratziu V, et al. AASLD 2016. Abstract LB-37. These data are available in unpresented
abstract format only, and will be presented in full during the AASLD meeting. We encourage
you to review the presented data before making any conclusions. Slide credit: clinicaloptions.com
 RESOLVE-IT: Long-term Evaluation of
Elafibranor for NASH
 Randomized, placebo-controlled, double-blind, multicenter phase III
study in pts with NASH and fibrosis
Wk 72: Interim
analysis
Randomized 2:1

Pts with NASH, Elafibranor 120 mg PO QD

Until accrual of
NAS ≥ 4 (individual
predefined
scores each ≥ 1),
number of
stage 1-3 fibrosis
events (~ 4 yrs)
(Planned N = 2000) Placebo

 Primary endpoints
– Resolution of NASH w/o fibrosis worsening at Wk 72

– Composite of all-cause mortality, cirrhosis, liver-related clinical outcomes

at ~ 4 yrs
ClinicalTrials.gov. NCT02704403. Slide credit: clinicaloptions.com
Agents in Phase II:
Liraglutide
Aramchol
Cenicriviroc
Selonsertib
 LEAN: Liraglutide for 48 Wks

 Randomized, double-blind phase II trial of overweight pts with NASH

100 Liraglutide (n = 23)
Placebo (n = 22)

80 P = .019 P = .05 P = .65 P = .46 P = .04

61
60 55
Pts (%)

48
39
40 36
32
26
20 14
9 9
n/N = 9/23 2/22 14/23 7/22 11/23 12/22 6/23 3/22 2/23 8/22
0
Resolution Improved Improved Improved Worsened
of NASH Ballooning Inflammation Fibrosis Fibrosis
Armstrong MJ, et al. Lancet. 2016;387:679-690. Slide credit: clinicaloptions.com
 Aramchol in NAFLD: Liver Imaging
Results at 3 Mos
 Double-blind, placebo-controlled, 50 Aramchol 300 mg/day (n = 20)
randomized phase II trial in Aramchol 100 mg/day (n = 20)
adults with biopsy-confirmed 40 Placebo (n = 20)
NAFLD (N = 60), some with 30

in Liver Fat Content (%)

NASH (n = 6)[1] P = .353
20

Relative Change
 Unclear if imaging changes 10 6.39
accompanied by changes in
inflammation or injury[1] 0
-2.89
– No improvement in liver -10
enzymes -12.57
-20
 Similar phase IIb study -30 P = .020
underway with aramchol 400
and 600 mg/day in pts with NASH[2] -40
– Will include histologic endpoints -50

1. Safadi R, et al. Clin Gastroenterol Hepatol. 2014;12:2085-2091.

2. ClinicalTrials.gov. NCT02279524. Slide credit: clinicaloptions.com
 CENTAUR: Cenicriviroc Results at 52 Wks

 Randomized, double-blind phase IIb trial of pts with NASH, NAS ≥ 4, liver
fibrosis, and diabetes or metabolic syndrome (N = 289)
100
Cenicriviroc 150 mg/day
Placebo
80

60
Pts (%)

P = .02
40 P = .52
P = .49
19 20
20 16
10
23/ 27/ 8 6 29/
n/N = 145 144 11/145 8/144 145 15/144
0
Improvement in NAS Resolution of NASH Improvement in Fibrosis
≥ 2 Points With No
Worsening of Fibrosis
Sanyal AJ, et al. AASLD 2016. Abstract LB-1. These data are available in unpresented
abstract format only, and will be presented in full during the AASLD meeting. We
encourage you to review the presented data before making any conclusions. Slide credit: clinicaloptions.com
 Selonsertib: Short-term (24-Wk) Results
 Open-label, randomized phase II trial of pts with biopsy-confirmed NASH,
NAS ≥ 5, F2-F3 liver fibrosis (N = 72)

100
Selonsertib 18 mg/day ± simtuzumab
80 Selonsertib 6 mg/day ± simtuzumab
Simtuzumab
60
Pts (%)

43
40
30
20 20
20
7
n/N = 3
13/30 8/27 2/10 1/30 2/27 2/10
0
Improvement in Fibrosis Progression to Cirrhosis

Loomba R, et al. AASLD 2016. Abstract LB-3. Slide credit: clinicaloptions.com

Take-Home Points

 Lifestyle changes are the foundation of any treatment

plan
– Weight loss ≥ 3% to 10% associated with histologic
improvement in NAFLD
 AASLD guidance cites evidence for vitamin E (NASH
without diabetes), pioglitazone (NASH with or without
diabetes), bariatric surgery
 Preliminary evidence for improvement in fibrosis with
some investigational therapies

Slide credit: clinicaloptions.com

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