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
– Pizza/pasta
– Chips
– Fructose-containing sodas and juices
 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
 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
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
 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
 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
 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
 Outline
• Current Best Practices
– Lifestyle Changes
– Pharmacologic
– Surgical Management Strategies
• Investigational Therapies
– Phase III
– Phase II
 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

 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

Agents in Phase II:
Liraglutide
Aramchol
Cenicriviroc
Selonsertib