NASH Treatment Approaches:

Now and in the Future

 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
 Percentage of Weight Loss
Associated With Histological
Improvement
Weight loss ≥ 10% in NAFLD
• Analysis of data from 4 randomized
Fibrosis
studies
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
Hannah WN, et al. Dig Dis Sci. 2016;61:1365-1374. Slide credit: clinicaloptions.com
– Pizza/pasta
 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
Allina Health System Press, Helping Your Heart, cvs-ahc-90648 (5/05),
•Rope
third jumping
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
Hashida R, parameters
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
Chocolate reinforces
Chunk Muffin: 440utility
caloriesof
aerobic or resistance exercise for improving
steatosis
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
• Double-blind, placebo-controlled, randomized, phase III trial
E vs Pioglitazone
in adults with biopsy-proven NASH and no diabetes or
cirrhosis (N100
Pts With Resolved NASH (%)

= 247)
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
References in slidenotes. Slide credit: clinicaloptions.com
Pioglitazone
 PIVENS: Histologic Improvement at
Wk 96 With Vitamin E vs
100
Pioglitazone
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
Placebo (n = 42)
phase IV trial of pts with NASH andPioglitazone (n = 40)

Pts With Improvement (%)

100
prediabetes or type 2 diabetes Pmellitus
< .001 (N P== .001
80
101)[1] 65
58 60
– Secondary outcome
40
analysis of histologic 19 21
20
scores included pts
with paired biopsies from 0 ≥ 2-Point Reduction Resolution
in NAS of NASH
before/after tx (n = 82) (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
Agent
Options
Good
Studied in
Limited or
NASH
AASLD
Evidence for Insufficient NAFLD/NASH
Use[1] Evidence for Use[1] Recommendation[2
]

NASH without NASH with NASH without

Vitamin E
diabetes diabetes or cirrhosis diabetes
NASH with or
Pioglitazon NASH with Can be used for
without
e cirrhosis steatohepatitis
diabetes
No significant effect
Metformin on liver histology[2] Not recommended

Needs further study

Pentoxifylli
to determine
1. Rinella ME, et al. Gastroenterol Hepatol. 2014;10: 219-227. ideal
2.ne
Chalasani N, et al. Hepatology. 2012;55:2005-2023. Slide credit: clinicaloptions.com
subpopulation
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
Parameter Before Surgery After 5 Yrs P Value
Diabetes–mellitus,
Livernbiopsies
(%) assessed by 2 blinded 24
94 (24.8) reviewers
(10.8) for .00001
fibrosis (F0-4),
Arterial hypertension, n (%) NAFLD scoring to determine
185 (48.8) 85 (37.0) NASH.0005
(≥
3, probable
Serum triglycerides, mean or definite; ≥ 5, definite)
1.67 1.06 .00001
(g/L)
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
Mathurin P, et al.(IU/L) 39.9
Gastroenterology. 2009;137:532-540. 29.2 .00001
Slide credit: clinicaloptions.com
 Bariatric Surgery Improves
Fibrosis in Pts With NASH
• Prospective study of bariatric surgery in pts who
are morbidly obese
Distribution withMETAVIR
of Fibrosis biopsy-validated NASH,
Scores Wilcoxon signed-
≥ 1 100
comorbidity factor 3.75
for 2.5 rank paired t test
7.5 P < .003
> 5 yrs,
80
no chronic liver
7.5 disease
13.75
(N = 109)
21.25
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
P = .009
Active drug
100 Placebo
– PTime
= .005
P < .001
points and populations may differ between studies
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]

References in slidenotes. Slide credit: clinicaloptions.com

 Key NASH Therapies:
Resolution of NASH
Active therapy
100
• Results from separate studies, not head to head Placebo

– Time points and populations may differ between studies 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
Active therapy
100
• Results from separate studies, not head to head Placebo

– Time points and populations may differ between studies

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:
Drug Mechanism of
Phase
Study
III Trial Primary
Action Population Endpoint(s)
Resolution of
Elafibrano PPAR α/δ NASH with
RESOLVE-IT[2] NASH w/o fibrosis
r agonist[1] fibrosis
worsening
Improvement in
fibrosis w/o NASH
Obeticholi FXR agonist NASH with REGENERATE[4,5 worsening;
c 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:
Drug
Phase II
Mechanism of Study Population Trial Primary Endpoint(s)
Action
Cenicriviro Inhibitor of NASH with liver Improvement in NAS
CENTAUR*[1,2]
c CCR2/CCR5 fibrosis w/o fibrosis worsening
Monoclonal Liver fibrosis Morphometric
Simtuzuma
antibody to secondary to NCT01672866*[4] quantitative collagen
b
LOXL2[3] NASH change; EFS
Fatty acid–bile Change in liver
Aramchol NASH Aramchol_005*[6]
acid conjugate[5] triglycerides by NMRS
Resolution of NASH
Liraglutide GLP-1 analogue Overweight NASH LEAN[7,8]
w/o fibrosis worsening
Liver fibrosis and
Galectin-3
GR-MD-02 portal hypertension NASH-CX[10] Improvement in HVPG
inhibitor[9]
in NASH cirrhosis

*Phase IIb. Improvement in

Caspase NASH with liver
Emricasan ENCORE-NF[11] fibrosis w/o NASH
inhibitor fibrosis
worsening
References in slidenotes. Slide credit: clinicaloptions.com
 Emerging Treatments in NASH:
Drug(s)
Phase II
Mechanism(s) of Study Trial Primary Endpoint(s)
Action Population
NASH with
GS-US-384-
Selonsertib ASK1 inhibitor F2-F3 liver Safety and tolerability
1497[1,2]
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
BMS- Safety and tolerability;
FGF-21 agonist NASH MB130-045[6]
986036 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]
References in slidenotes. w/o fibrosis
Slide credit: worsening
clinicaloptions.com
Agents in Phase III:
Obeticholic Acid
Elafibranor
 Obeticholic Acid: FXR Agonist
and Bile Acid Analogue
CDCA OCA (6-ECDCA)
obeticholic acid
chenodeoxycholic 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,
Primary Endpoint:
Wk 72
randomized, multicenter phaseImprovement
IIb trial
in
NAS ≥ 2 Points
Stratified by clinical center and Wk 72
With No Wk 72
diabetes status at baseline
Worsening of Improvemen
Fibrosis t in Fibrosis
Pts with NASH or Obeticholic acid 25 mg PO QD
borderline NASH (n = 141)
confirmed by entry 45% 35%
biopsy, NAS ≥ 4 (50/110) (36/102)
(individual scores
each ≥ 1), no cirrhosis Placebo
(N = 283) (n = 142) 21% 19%
(23/109) (19/98)
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,
Final
randomized, multicenter
Mo 18 interim
analysis phase
Mo 48 interim
analysis III trial
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)
Pts with
(21/93) (12/93)
histologic 21% 19%
Elafibranor 120 mg PO QD
diagnosis of
(n = 91) (19/89) (17/89)

P = .045
P = .28
noncirrhotic
NASH (N = 276)
17% 12%
Placebo
(n = 92) (16/92) (11/92)
*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
Fibrosis with Fibrosis
improvement changes in fibrosis stage
worsening
(P =100.04 and P < .001, respectively)
80
• Changes in steatosis did notFisher test, P < .001
correlate
N = 237
with changes in
60 stage
Pts (%)

fibrosis
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
 Randomized, placebo-controlled, double-blind, multicenter phase III study in
pts with NASH and fibrosis NASH
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