Outline

  1. Future trends in the treatment of non-alcoholic steatohepatitis
  2. Non-alcoholic fatty liver disease, a growing pandemia
  3. Pathogenesis of NASH
  4. Glucagon-like peptide 1 (GLP-1) analogues dipeptidyl peptidase 4 (DPP-4) inhibitors
  5. Dual and pan-PPAR agonists
  6. Agonists of bile acid activated receptors
  7. Selective FXR agonists
  8. Selective GPBAR1 agonists
  9. Dual GPBAR1 and FXR agonists
  10. Fibroblasts growth factors (FGF) 19 and 21 analogues
  11. Inhibitor of intestinal transporters: apical sodium-dependent bile acid transporter (ASTB/ SLC10A2) and sodium-glucose cotransporter 1 and 2 (SGLT1 and 2)
  12. Agents that target lipotoxicity
  13. Stearoyl-CoA desaturase (SCD)-1 inhibitors
  14. Acetyl-coA carboxylase (ACC) inhibitor
  15. Diacylglycerol acyltransferase- (DGAT)-1inhibitor
  16. Agents targeting liver inflammation and fibrosis
  17. CCR2/CCR5 antagonist
  18. Lysyl oxidase-like 2 (LOXL2) inhibitor
  19. Apoptosis signal-regulating kinase 1 (ASK-1) inhibitor
  20. Pan-caspase inhibitors
  21. Galectin-3 inhibitor
  22. Other anti-inflammatory agents
  23. Agents that target classical hormone receptors
  24. Mineral corticoids
  25. Growth hormone-releasing hormone (GHRH) analog
  26. β-Selective thyroid hormone receptor (THR) agonist (MGL-3196)
  27. Leptin analog
  28. Adenosine (A)3 receptor antagonist
  29. Gut microbiota
  30. Miscelaneous agents
  31. Conclusions
  32. Conflict of interest
  33. References
  34. Glossary
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Contents
lists
available
at
ScienceDirect
Pharmacological
Research
journal
homepage:
www.elsevier.com/locate/yphrs
Review
Future
trends
in
the
treatment
of
non-alcoholic
steatohepatitis
Stefano
Fiorucci
a,
⁎
,1
,
Michele
Biagioli
a
,
Eleonora
Distrutti
b
a
University
of
Perugia,
Department
Surgical
and
Biomedical
Sciences,
Perugia,
Italy
b
Azienda
Ospedaliera
di
Perugia,
Perugia,
Italy
ARTICLE
INFO
Keywords:
Steatohepatitis
Liver
Intestine
Nuclear
receptors
FXR
GPBAR1
PPARs
Lipids
Fibrosis
Apoptosis
Inflammation
ABSTRACT
With
an
estimated
prevalence
of
≈25%
in
Western
and
Asian
countries,
non
alcoholic
fatty
liver
disease
(NAFLD),
caused
by
chronic
excessive
caloric
intake,
is
the
emerging
as
the
most
prevalent
liver
disorder
worldwide.
NAFLD
exists
in
two
clinical
entities,
non-alcoholic
fatty
liver
disease
(NAFL),
a
relative
benign
disease
that
carry
on
minimal
risk
of
liver-related
morbidity
but
significant
risk
of
cardiovascular
complications,
and
non-alcoholic
steatohepatitis
(NASH),
a
progressive
liver
disorder
with
a
significant
risk
for
development
of
liver-related
morbidities
and
mortality.
While,
liver
injury
in
NASH
is
contributed
by
lipid
overload
in
hepa-
tocytes,
lipotoxicity,
the
main
determinant
of
disease
progression
is
an
inflammation-driven
fibrotic
response.
Here,
we
review
the
landscape
of
emerging
pharmacological
interventions
in
the
treatment
of
NAFL
and
NASH.
A
consensus
exists
that,
while
treating
the
liver
component
of
NASH
requires
development
of
novel
pharma-
cological
approaches,
the
future
therapy
of
NASH
needs
to
be
tailored
to
the
single
patient
and
most
likely
will
be
a
combination
of
agents
acting
on
specific
pathogenic
mechanisms
at
different
disease
stage.
1.
Non-alcoholic
fatty
liver
disease,
a
growing
pandemia
Excessive
deposition
of
lipids
in
the
liver,
due
to
excessive
caloric
intake
in
individual
with
no
risk
for
excessive
alcohol
consumption,
leads
to
progressive
hepatocytes
injury
and
represents
the
cause
of
fatty
liver
disease,
also
known
as
non-alcoholic
fatty
liver
disease
(NAFLD).
NAFLD
is
a
highly
prevalent
human
disorder,
that
exists
in
two
main
clinical
subtypes:
non-alcoholic
fatty
liver
(NAFL)
and
non-alcoholic
steatohepatitis
(NASH)
(Fig.
1).
Paralleling
the
global
pandemia
of
diabetes
and
obesity,
the
prevalence
of
NAFLD
has
increased
stably
in
the
last
two
decades
worldwide,
reaching
the
highest
prevalence
in
South
America
(31%)
and
the
Middle
East
(32%),
followed
by
Asia
(27%),
the
USA
(24%)
and
Europe
(23%)
[1,2].
NASH
prevalence
in
the
general
population
is
1.5–6.5%,
and
increase
dramatically
in
patients
subgroups,
including
NAFLD
patients
who
had
liver
biopsy
for
a
“clinical
indication ”
of
fatty
liver
(≈60%),
obese
patients
(>
95%),
type
II
diabetes
and
dyslipidemic
patients
(>
50%)
[3].
Despite
NAFL
is
a
relative
benign
liver
disease
with
a
minimal
risk
for
liver
disease
progression,
patients
with
NAFL
have
increased
overall
mortality
in
comparison
with
the
general
population,
mostly
because
cardiovascular
diseases
(CVD).
In
contrast,
NASH
is
a
progressive
liver
disease,
with
increased
risk
of
liver-related
mortality
due
to
develop-
ment
of
liver
cirrhosis
and
hepatocellular
carcinoma.
In
2018,
NASH
is
already
the
second
most
common
indication
for
liver
transplantation
in
the
USA
[1– 3]
and,
due
to
development
of
effective
anti−HCV
thera-
pies,
will
become
the
first
indication
in
the
next
decade.
More
than
lipotoxicity,
the
most
important
independent
predictor
of
long-term
outcome
of
NASH
patients
is
the
severity
of
liver
fibrosis,
and
specific
approaches
aimed
at
accurate
staging
and
treatment
of
fibrosis
are
currently
under
evaluation
[ 4–7].
While
adopting
a
safe
life-style
effectively
reduce
the
severity
of
steatosis
and
some
existing
drugs
could
be
repurposed
to
help
to
treat
co-morbidities
(8–18),
current
treatments
are
largely
unsatisfactory
when
the
liver
component
of
NASH
is
taken
into
consideration.
Given
that
patients
with
NAFL
without
liver
fibrosis
have
excellent
prognosis,
and
that
the
disease
burden
is
largely
related
to
development
of
CVD,
pharmacological
treatments
directed
at
the
treatment
of
cardiovascular
and
metabolic
comorbidities
such
as
obesity,
hyperlipidemia
and
type
II
diabetes
are
recommended
(8–18).
In
contrast,
a
consensus
exists
that
“pharmacological
treatments
aimed
primarily
at
improving
liver
dis-
ease
should
generally
be
limited
to
those
with
biopsy-proven
NASH
and
fibrosis”
[4–7].
There
are
several
available
pharmacological
and
non-pharmacolo-
gical
approaches
that
are
recommended
for
treating
patients
with
NAFL/NASH
[8–18].
Because
these
agents
are
not
specifically
designed
to
target
the
liver
component
of
the
disease
and
are
well
known
for
https://doi.org/10.1016/j.phrs.2018.07.014
Received
19
June
2018;
Received
in
revised
form
11
July
2018;
Accepted
13
July
2018
⁎
Corresponding
author.
1
www.gastroenterologia.unipg.it.
E-mail
address:
stefano.fiorucci@unipg.it
(S.
Fiorucci).
Pharmacological Research 134 (2018) 289–298
Available online 17 July 2018
1043-6618/ © 2018 Elsevier Ltd. All rights reserved.
T
Previous PDF in this issue
their
pharmacological
activity
in
other
areas,
the
readers
are
redirected
to
currently
available
guidelines
and
many
excellent
reviews
in
these
fields
[4–7].
Finally,
because
searching
for
NASH
on
PubMed
retrieves
more
than
14.000
article,
we
are
aware
that
many
excellent
articles
will
not
be
included
in
this
review
and
apologize
to
the
authors
for
these
exclusions.
The
focus
of
the
present
review
is
limited
to
future
phar-
macological
approaches
that
will
specifically
target
the
liver
disease
in
NASH.
2.
Pathogenesis
of
NASH
NAFLD
(Fig.
1)
is
due
to
the
pathological
accumulation
of
lipids
in
hepatocytes,
a
process
that
involves
either
an
increased
uptake
or
an
increased
synthesis
of
lipids
that
exceeds
the
ability
of
hepatocytes
to
export
or
utilize
lipids
for
metabolic
purposes
[2].
When
lipid
accu-
mulation
exceed
the
protective
mechanisms,
hepatocytes
become
in-
jured,
a
process
known
as
lipotoxicity,
that
represent
a
well
defined
therapeutic
target
in
NASH
(Fig.
2).
In
the
human
liver,
lipotoxicity
manifests
histologically
as
hepatocellular
ballooning
and
the
presence
and
magnitude
of
ballooning
are
used
for
histological
grading
and
staging
of
NASH.
The
triacylglycerols
(TG)
are
the
main
lipid
compo-
nent
detected
in
ballooned
hepatocytes,
however,
TG
are
not
directly
hepatotoxic
per
se
and
therefore
lipotoxicity
is
due
to
other
lipids,
such
as
fatty
acids
(FAs),
diacylglycerol,
oxysterols,
cholesterol
and
phos-
pholipids
[19–21
].
FAs,
are
potent
hepatotoxic
lipids,
released
from
adipocytes
in
condition
of
energy
surplus.
A
high
caloric
intake
shifts
the
adipocytes
phenotype
from
small
to
large,
a
cell
subtype
char-
acterized
by
reduced
secretion
of
adiponectin
and
increased
production
of
TNFα
and
resistin.
These
changes
prevent
further
FAs
storage
and
promote
their
release
as
free
FA
(FFA),
that
are
then
delivered
to
he-
patocytes
(Figs.
1
and
2).
Increased
FFA
uptake
and
their
accumulation
by
hepatocytes
propels
TG
synthesis,
a
mechanism
that
will
help
to
dispose
FA.
Thus,
the
mutual
relation
between
FFA
uptake
and
TG
synthesis
will
determine
whether
or
not
lipotoxicity
will
manifest.
Lipotoxicity
is
mediated
by
different
cellular
mechanisms
including
direct
damage
to
peroxisomes
and
mitochondria
[19–21].
The
damaged
mitochondria
lost
their
membrane
polarization
and
become
unable
to
efficiently
perform
β-oxidation
and
energy
metabolism
further
exacer-
bating
FA
accumulation.
The
injured
hepatocytes
release
a
number
of
inflammatory
mediators
including:
1)
sonic
hedgehog,
which
activates
the
hedgehog
signaling,
a
pathway
that
is
essential
for
liver
repair
and
regeneration
but
if
persistently
activated
might
induce
fibrosis
[21],
2)
pro-apoptotic
factors
such
as
caspase
9;
and
3)
cell
damage-associated
molecular
patterns
(DAMPs),
such
as
high-mobility
group
box
1,
heat
shock
proteins,
nuclear
and
mitochondrial
DNA,
histones,
purine
nu-
cleotides
(ATP,
UTP)
that
are
recognized
by
cell
surface
pattern
re-
cognition
receptors,
such
as
the
Toll-like
receptor
2,
4,
and
cytosolic
receptors,
such
as
Toll-like
receptor
7–9,
expressed
by
cells
of
innate
immunity
dictating
their
activation
(Fig.
3
and
4).
Further
on,
bal-
looned
hepatocytes
are
characterized
by
excessive
activation
of
the
stress
kinase
c-Jun
N-terminal
kinase
(Fig.
3)
that
also
contributes
to
recruitment
of
inflammatory
cells.
Ultimately,
hepatocytes
will
become
apoptotic
or
necrotic
(if
severe
mitochondrial
membrane
depolarization
results
in
a
complete
cessation
of
mitochondrial
electron
transport
and
ATP
synthesis).
In
progressively
deteriorating
hepatocytes,
FA
worsen
insulin
re-
sistance
propelling
inflammation
[21–26]
and
fibrosis
[27–29],
which
further
contribute
to
hepatocytes
injury.
Inflammasomes,
cytokines
and
chemokines
and
their
receptors,
together
with
cells
of
innate
(neu-
trophils,
macrophages,
NK
cells,
and
NKT
cells)
and
adaptive
immunity
(T
and
B
cells)
contribute
to
liver
inflammation
(Fig.
3)
and
are
ther-
apeutic
targets
in
NASH
[22–25].
Hepatic
macrophages
consist
of
re-
sident
macrophages
known
as
Kupffer
cells
(KCs)
and
macrophages
that
enter
the
liver
from
systemic
circulation
[23].
Macrophages
isolated
from
the
liver
of
NASH
models
are
biased
toward
an
M1,
proin-
flammatory,
phenotype,
while
NASH
resolution,
associates
with
ac-
quisition
of
a
M2,
regulatory,
phenotype
(thought
these
subsets
are
not
so
clear
cut
in
human
NASH).
KCs
and
afferent
macrophages
along
with
hepatic
NK
and
NKT
cells
and
dendritic
cells
are
the
first
sensor
of
products
generated
by
the
intestinal
microbiota
[22–26].
An
intestinal
dysbiosis
characterized
by
an
enrichment
in
Prevotella
and
Porphyr-
omonas
reduction
in
Bacteroidetes,
is
considered
to
be
a
contributing
factor
promoting
progression
from
NAFLD
to
NASH
(the
so-called
second
hit)(
Fig.
3)[
26].
One
consequence
of
liver
inflammation
is
the
activation
of
tissue
repair
mechanisms
aimed
at
replace
injured
hepatocytes
by
activation
of
the
staminal
compartment
and
stimulation
of
hepatocytes
pro-
liferation,
and
remodeling
of
extracellular
matrix
(ECM).
If
inflamma-
tion
persists
over
time,
this
will
lead
to
recruitment
and
activation
of
ECM-forming
cells
with
excessive
deposition
of
a
distorted
ECM,
ulti-
mately
leading
to
liver
fibrosis
[Figs.
1,
3
and
4].
Liver
fibrosis
[23,27–29],
is
a
late
contributor
to
NASH
pathogenesis
and
involves
the
transdifferentiation
and
activation
of
specific
cell
subtypes
that
are
ne-
cessary
to
build
up
a
newly
formed
ECM.
Although
many
cell
types
contribute
ECM
components,
the
majority
of
ECM-forming
cells
origi-
nate
from
hepatic
stellate
cells
(HSC),
and
to
lesser
extent
from
portal
fibroblasts
or
bone
marrow
derived
mesothelial
cells
[reviewed
in
ref.
28].
In
the
normal
liver,
HSC
known
also
as
perisinusoidal
fat-storing
cells
or
Ito
cells,
are
a
subset
of
non-parenchymal
cells
located
in
the
space
of
Disse
highly
enriched
in
vitamin
A
[28].
Upon
liver
injury,
hepatocytes
and
non-parenchymal
liver
cells
(i.e.
sinusoidal
endothelial
cells,
macrophages,
NK
cells,
and
lymphocytes)
release
profibrogenetic
mediators
such
as
the
platelet-derived
growth
factor
(PDGF)
and
transforming
growth
factor
beta
(TGF-β)[
27–29](
Fig.
4)
that
binds
to,
Fig.
1.
Progression
of
non-alcoholic
fatty
liver
disease
(NAFLD).
NAFLD
exists
in
two
clinical
entities:
NAFL,
non-alcoholic
fatty
liver,
and
NASH,
non-alco-
holic
steatohepatiotis.
Progression
from
healthy
liver
to
NAFL,
is
due
to
fat
deposition
in
parenchymal
liver
cells,
hepatocytes,
and
is
contributed
by
chronic
excessive
caloric
intake
and
sedentary
lifestyle.
Several
metabolic
dis-
orders
associates
with
development
of
NAFL
including
metabolic
syndrome,
dyslipidemia,
diabetes
and
obesity.
Genetic
polymorphisms
have
been
shown
to
contribute
to
development
of
NAFL
and
NASH,
including
SNPs
in
the
PNPLA3
gene
(Patatin-like
phospholipase
domain-containing
protein
3
and
TM6FSF2
(transmembrane
6
superfamily
member
2).
In
contrast,
the
rs72613567:TA
in
HSD17B13
(Hydroxysteroid
17-Beta
Dehydrogenase
13)
is
considered
to
be
protective.
NAFL
is
defined
by
appearance
of
lipid
droplets
within
the
cyto-
plasm
of
hepatocytes
(steatosis)
in
more
than
5%
of
hepatocytes.
NASH
is
considered
to
be
a
progressive
form
of
NAFLD
and
develop
when
lipids
other
than
the
triacylglycerol,
essentially
fatty
acids,
released
from
adipocytes,
be-
come
toxic
for
hepatocytes
(a
phenomenon
called
lipotoxicity).
To
cope
with
progressive
hepatocytes
injury
and
death,
the
liver
activates
inflammatory/
immune
response
and
regenerative
pathways
leading
to
extensive
extracellular
matrix
remodeling
and
fibrosis
that
might
progress
to
liver
cirrhosis.
Several
factors
including
adipocytes
functionality
and
intestinal
microbiota
contribute
to
liver
injury.
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
290
and
activate,
HSCs.
This
process
of
transdi
fferentiation
is
characterized
by
the
loss
of
the
vitamin
A
droplets,
and
acquisition
of
a
myofibroblast-
like
phenotype
characterized
by
high
levels
of
expression
of
α-smooth
muscle
actin
(SMA),
a
migratory
phenotype
and
contraction
properties,
along
with
ability
to
release
ECM
components
[28].
In
the
next
sections,
we
will
review
the
landscape
of
agents
that
are
currently
under
development
for
the
treatment
of
NASH,
with
emphasis
on
drug
that
are
undergoing
clinical
trials
and/or
transition
from
pre-
clinical
to
clinical
stages.
Fig.
2.
Pharmacological
approaches
that
target
metabolism
and
lipotoxicity
in
the
treatment
of
NAFL
and
NASH.
1)
Agents
that
target
lipido-
genic
pathways
in
the
liver.
This
group
in-
cludes
inhibitors
of
acetyl-coA
carboxylase
(ACC)
such
as
PF-05221304
and
GS-0976.
Inhibitors
of
stearoyl-CoA
desaturase
(SCD)-1,
such
as
aramchol,
and
inhibitors
of
diacylgly-
cerol
acyltransferase-
(DGAT)-1,
pradigastat.
These
agents
inhibits
the
endogenopus
synth-
esis
of
fatty
acids
(FA).
2.
Ligands
for
the
far-
nesoid-x-receptor
(FXR),
the
first
in
class
being
obeticholic
acid
(also
known
as
6-ethyl-CDCA).
FXR
agonists
(obeticholic
acid,
GS-9674,tropi-
fenor
(LIN452),
LMB763,
BAR502
and
INT767)
modulate
various
steps
in
lipid
and
glucose
metabolism
in
the
liver
and
might
release
of
FGF19
(a
FXR-regulated
factor)
from
en-
terocytes.
FGF19
reach
the
liver
through
the
portal
circulation
and
binds
to
FGFR4
acti-
vating
the
βkloto
pathway.
These
effects
leads
to
a
SHP
(small
heterodimer
partner)-depen-
dent
repression
of
SREPB1c
and
FAS
(fatty
acid
synthase),
leading
reduction
of
endogenous
synthesis
of
FA
and
triacyglycerols.
In
addition
FXR
agonists
modulate
liver
inflammation
and
fibrosis.
NGM282
is
FGF19
analog
that
is
cur-
rently
tested
in
NASH
patients.
3)
GLP-1
ana-
logues
(semaglutide
and
exenadine)
and
DDP-4
inhibitors
(sitagliptin)
impact
on
lipid
and
glucose
metabolism
by
promoting
insulin
release
from
pancreatic
β-cells
and
insulin
sensitivity.
GLP-1
is
released
from
intestinal
“L”
cells
and
its
synthesis
and
secretion
is
regulated
by
GPBAR1
a
bile
acid
activated
receptor.
BAR501
and
BAR502
are
selective
and
non-selective
GPBAR1
ligands
that
act
on
this
pathway.
4)
Peroxisome
Proliferator
Activated
Receptors
(PPARs)
are
a
family
of
receptors
with
potent
regulatory
activity
on
lipid
and
glucose
metabolism.
The
PPARαδ
agonist,
elafibranor,
promotes
FA
oxidation
and
exerts
anti-fibrotic
activities
(Fig.
4).
5)
Inhibitors
of
intestinal
transporter
such
as
SCL10A2
and
SLGT1
and
2
interfere
with
intestinal
bile
acid
uptake
and
intestinal
and
kidney
glucose
uptake.
6)
β-
Selective
Thyroid
Hormone
Receptor
(THR)
agonist
(MGL-3198).
Fig.
3.
Pharmacological
approaches
that
target
inflammatory
and
immunity
dysfunction
in
the
treatment
of
NASH.
Abbreviation.
ASK-1,
Apoptosis
signal-regulating
kinase
1;
A3AR,
Adenosine
3
receptor;
IMM-124
E,
hyper-
immune
bovine
colostrum;
JKB-121
is
a
Toll
like
receptor
antagonists;
SSAO/VAP-1,
semi-
carbazide-sensitive
amine
oxidase/vascular
adhesion
protein
1.
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
291
3.
Glucagon-like
peptide
1
(GLP-1)
analogues
dipeptidyl
peptidase
4
(DPP-4)
inhibitors
GLP-1
is
a
gastrointestinal
incretin
released
from
the
“ L
”
type
en-
docrine
cells
most
abundant
in
the
distal
ileum
[17,18,
30].
GLP-1
exerts
beneficial
effects
on
glucose
metabolism
by
inducing
insulin
biosynth-
esis
and
release
from
pancreatic
β
cells
and
increasing
insulin
sensi-
tivity.
GLP-1
induces
satiety
by
central
and
peripheral
effects
[30].
GLP-
1
has
a
short
half-life
and
undergoes
rapid
degradation
by
DiPeptidyl
Peptidase-4
(DPP4)
[17,18,30].
GLP-1
analog
and
DDP-4
inhibitors-
gliptin-
[28,29
]
are
currently
available
for
treating
diabetes,
but
their
role
in
treating
NASH
is
still
unclear
[4,5].
Sitagliptin,
a
DDP-4
in-
hibitor,
has
been
tested
in
NASH
patients
showing
some
efficacy,
on
steatosis
score,
but
failing
to
reduce
progression
of
liver
fibrosis
[31].
Long-lasting
GLP-1
analogues,
semaglutide
(NCT02970942)
[
32]
and
exenadine,
(NCT02303730)
[33]
are
currently
undergoing
clinical
trials
in
NASH
patients.
In
summary,
the
fact
that
agents
that
target
GLP-1/
DDP-4
pathway
have
shown
some
efficacy
in
the
treatment
of
NAFLD,
but
impact
of
these
new
treatments
on
liver
fibrosis
remain
un-
satisfactory.
However,
GLP-1
analogues
and
gliptins
might
find
appli-
cation
in
the
management
of
diabetic
patients
with
NASH.
4.
Dual
and
pan-PPAR
agonists
Peroxisome
proliferator-activator
receptors
(PPARs)
are
a
group
of
nuclear
receptors
expressed
in
the
liver
and
other
metabolic
tissues,
that
transcriptionally
regulate
metabolic
processes
including
lipid
β-
oxidation,
insulin
secretion
and
insulin
sensitivity
in
the
liver,
adipose
tissues
and
skeletal
muscles.
There
are
three
PPAR
(α,
β/ δ
and
γ)
which
have
different
body
distribution
and
target
different
cell
systems.
Thiazolidinediones,
such
as
rosiglitazone
and
pioglitazone,
are
a
class
of
selective
PPAR-
γ
ligands
with
broad
effects
on
glucose
and
lipid
metabolism,
as
well
as
on
vascular
biology
and
inflammation
[11,12,15,16].
Rosiglitazone
is
no
longer
available
for
its
CVC
side
ef-
fects.
Pioglitazone
(BPX
2),
has
been
tested
in
patients
with
NASH,
alone
or
in
combination
with
diet
and
vitamin
E,
and
found
effective
in
reversing
steatosis
but
not
fibrosis
[11,12].
In
contrast
to
rosiglitazone,
pioglitazone
is
protective
against
cardiovascular
events
and
is
currently
recommended
for
treatment
of
patients
with
biopsy-proven
NASH
[4,5].
In
contrast,
fibrates,
a
family
of
PPAR α
agonists,
have
been
tested
in
patients
with
NASH,
showing
no
efficacy
in
reversing
inflammation
and
fibrosis
[4,5].
PPARα/δ
agonists
have
been
developed
and
are
currently
trialed
in
patients
with
NASH.
Elafibranor
is
the
first
in
class
of
dual
PPARα/δ
agonist
that
was
shown
effective
in
reducing
liver
damage
(steatosis,
inflammation
and
fibrosis)
in
preclinical
models
of
NASH
[34
].
Results
from
a
Phase
2b,
randomized
double-blind
placebo-controlled
trial
(GOLDEN-505
study),
have
been
published
recently
[35].
In
intention-
to-treat
analysis,
there
was
no
significant
difference
between
the
ela-
fibranor
and
placebo
groups
in
the
protocol-defined
primary
outcome
i.e.
resolution
of
NASH
without
fibrosis
worsening.
In
post
hoc
re-
analysis,
however,
it
was
found
that
in
patients
with
NAFLD
disease
activity
score
(NAS)
≥4,
elafibranor
at
dose
of
120
mg/day
resolved
NASH
in
a
larger
proportion
of
patients
than
placebo
(20%
vs
11%;
odds
ratio
=
3.16;
P
=
.018)
[35].
A
subgroup
analysis
further
de-
monstrated
that
in
patients
in
whom
elafibranor
was
effective
in
re-
ducing
the
steatosis
score,
it
also
ameliorated
fi
brosis
[35].
Elafibranor
was
well
tolerated
improved
patients’
cardiometabolic
risk
profile,
but
increased
serum
creatinine
which
led
to
a
reported
renal
impairment/
failure
in
7
patients
[35].
In
summary,
efficacy
of
elafibranor
needs
to
be
further
investigated
since
positive
eff
ects
on
the
steatosis
score
were
identified
only
in
a
subgroup
of
patients
and
on
a
post-hoc
analysis
and
the
improvement
was
relatively
minor
(Fig.
5).
A
Phase
3
trial
designed
to
evaluate
the
efficacy
and
long-term
safety
of
elafibranor
versus
placebo
in
NASH
patients
is
ongoing
(NCT02704403).
Saroglitazar
is
a
dual
PPARα/γ
agonist,
which
has
been
approved
for
treatment
of
diabetic
dyslipidemia
in
India
[36,37
].
Saroglitazar
was
found
effective
in
reducing
steatosis
and
fibrosis
in
preclinical
models
of
NASH
[36,37]
and
ameliorated
the
glycemic
and
lipid
control
in
patients
with
biopsy-proven
NASH
in
a
Phase
2
trial.
Finally,
IVA-
337,
a
new
pan-PPAR
agonist,
has
been
found
effective
in
pre-clinical
models
and
is
undergoing
evaluation
in
clinical
trials
for
its
efficacy
in
Fig.
4.
Pharmacological
approaches
that
target
liver
fi
brosis
in
the
treatment
of
NASH.
LOXL2.
Lysyl
oxidase-like
2.
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
292
NASH
[38].
The
data
on
these
two
later
agents
are
too
preliminary
to
forecast
a
role
in
the
treatment
of
NASH.
5.
Agonists
of
bile
acid
activated
receptors
Bile
acids
derivatives
have
been
the
first
to
be
developed
to
speci-
fically
target
the
liver
component
of
NASH
[39,40
].
These
orally
active
agents
target
the
two
main
bile
acid
activated
receptors,
i.e.
the
far-
nesoid-x-receptor
(FXR)
and
G
protein
bile
acid
activated
receptor
(GPBAR)1
(also
known
as
TGR5).
6.
Selective
FXR
agonists
FXR
is
a
nuclear
transcription
factor
expressed
in
entero-hepatic
tissues,
where
it
regulates
major
steps
in
lipid
and
glucose
metabolism
along
with
bile
acid
synthesis,
and,
by
different
mechanisms,
in-
flammation
and
fibrosis
[39].
In
the
liver
(Fig.
2),
FXR
induces
the
transcription
of
the
nuclear
receptor
SHP,
small
heterodimer
partner,
an
atypical
nuclear
receptor
that
lacks
the
DNA
binding
domain,
and
functions
as
a
corepressor
for
several
genes,
including
SREPB1,
a
ne-
gative
regulator
of
fatty
acid
synthase
(FAS).
Activation
of
liver
FXR
reduces
TG
synthesis
and
gluconeogenesis.
FXR
promotes
insulin
re-
lease
from
pancreatic
β
cells
and
ameliorates
insulin
sensitivity
in
the
liver
and
muscles
[40].
In
the
intestine,
activation
of
FXR
is
involved
in
transcriptional
regulation
of
FGF-19
which,
in
its
turn,
represses
bile
acid
synthesis
and
ameliorates
insulin
sensitivity
and
FA
βoxidation
in
hepatocytes,
adipose
tissues
and
muscles
(Fig.
2).
Obeticholic
acid
(OCA)
previously
known
as
6-ethyl-CDCA
or
INT-747
[40],
is
a
semi-
synthetic
bile
acid,
synthesized
by
adding
a
ethyl
group
to
the
position
6
of
CDCA
[40].
CDCA
is
a
primary
bile
acid
used
in
the
past
for
the
treatment
of
gallbladder
stones,
in
combination
with
ursodeoxycholic
acid
(UDCA),
and
then
abandoned
for
lack
of
efficacy
and
liver
toxicity.
OCA
has
been
approved
for
the
treatment
of
primary
biliary
cholangitis
(PBC)
in
2016.
In
a
Phase
2
trial
(FLINT
study)
carried
out
in
biopsy
proven
non-cirrhotic
NASH
patients
[
41],
treatment
with
OCA,
25
mg/
day,
resulted
in
higher
proportion
of
patients
(62%
vs
31%)
showing
histological
improvement,
including
amelioration
of
steatosis
score
and
no
progression
of
liver
fi
brosis,
in
comparison
to
placebo
(Fig.
5)[
41].
A
Phase
3
trial
is
currently
ongoing
(NCT02548351)
[42].
An
important
limitation
of
OCA
are
severity
of
side
effects.
In
the
FLINT
study
(41),
OCA
caused
intense/severe
pruritus
in
23%
of
patients
and
dis-
continuation
of
the
medication
in
some
cases,
and
worsened
the
lipid
profile
(reduced
HDL)
which
may
require
closer
monitoring
to
exclude
development
CVD
[41].
Further
on,
in
post-marketing
surveillance
the
use
of
OCA
has
been
associated
with
development
of
major
side
e ff
ects,
including
liver
decompensation
requiring
liver
transplantation
and
deaths
(63
patients
up
December
2017)
in
cirrhotic
patients
receiving
a
dose
of
5
mg/day
[43].
These
cluster
of
events
has
caused
a
warning
by
FDA
and
EMEA
[43]
relatively
to
the
use
of
OCA
in
patients
with
ad-
vanced
liver
disease
(F4
fibrosis).
In
those
patients,
the
starting
dose
of
OCA
should
not
exceed
5
mg/week,
i.e.
a
dose
that
is
dramatically
lower
than
that
tested
in
the
FLINT
study
(25
mg/day)
[41].
These
events
make
unlikely
that
OPCA
could
be
used
in
patients
with
NASH
and
advanced
fi
brosis
or
cirrhosis
(Fig.
5).
GS-9674
is
a
synthetic
non-steroidal
FXR
agonist
generated
from
the
isoxazole
structure
of
GW4064,
a
highly
potent
and
selective
FXR
li-
gand,
originally
developed
at
Glaxo
Smith
Kline
currently
used
for
re-
search
purposes
[40].
GS-9674,
currently
under
development
by
Gilead
Fig.
5.
Results
from
some
PhaseII-
III
clinical
trials
with
anti-NASH
agents.
Drugs
we
have
obtained
favorable
results
in
Phase
II
trials
and
have
entered
phase
III
trials
are
shown.
Abbreviations.
ITT,
intention
to
treat;
MRI-PDFF,
magnetic
resonance
with
proton
density
fat
fraction;
MRE,
magnetic
resonance
elastography;
NAS,
NAFLD
activity
score.
Data
on
relative
efficacy
of
single
agents
can
not
be
compared
because
extracted
from
difefrent
trials
that
used
different
methodologies
and
endpoints.
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
293
[44],
and
has
been
shown
effective
in
reducing
steatosis
and
fibrosis
in
preclinical
models
of
diet-induced
obesity
by
several
mechanisms
[45].
A
Phase
2
trial,
comparing
GS-9674
at
doses
of
30
mg
or
100
mg/day
to
placebo
for
24
weeks,
has
been
completed
in
January
2018
[46].
In
addition,
efficacy
of
GS-9674
in
combination
with
selonsertib,
a
small-
molecule
inhibitor
of
apoptosis
signal-regulating
kinase
1
(ASK1)
and
each
agent
individually
has
been
investigated
in
patients
with
NASH
(Fig.
5).
The
results
of
these
studies,
however
demonstrate
no
additive
effects
among
selonsertib
and
GS-9674
on
steatosis
and
fibrosis,
as
as-
sessed
by
magnetic
resonance
(MR)
techniques
(see
below-selonsortib).
Tropifexor,
also
known
as
LJN452,
and
LMB763,
are
steroidal,
non-
bile
acid,
agonists
of
FXR,
firstly
described
in
2017,
and
both
are
un-
dergoing
clinical
trials
[47
–49].
7.
Selective
GPBAR1
agonists
GPBAR1
also
known
as
TGR5,
is
a
G-protein
coupled
receptor,
ac-
tivated
by
secondary
bile
acids
[40].
GPBAR1
is
expressed
in
the
in-
testine,
adipose
tissues
(white
and
brown)
and
non-parenchymal
liver
cells,
particularly
KCs
and
liver
sinusoidal
endothelial
cells,
but
not
hepatocytes.
In
the
intestine,
secondary
bile
acids
generated
by
the
intestinal
microbiota,
activate
GPBAR1
in
“L”
cells,
causing
the
release
of
GLP-1
(Fig.
2).
The
receptor
is
highly
expressed
by
monocytes
and
macrophages
and
its
activation
counter-regulates
the
innate
immune
response
in
the
intestine
and
liver
[50,51].
GPBAR1
increases
energy
expenditure,
but
it
also
function
as
itching
receptor
I
the
holding
po-
tential
for
side
effects
[40].
BAR501
is
a
non
bile
acid,
selective
GPBAR1
ligand
that
has
been
shown
eff ective
in
reducing
steatosis,
inflammation
and
fibrosis
in
preclinical
models
of
NASH
[50,51],
and
is
current
under
development
for
treatment
of
NASH
(Table
1).
8.
Dual
GPBAR1
and
FXR
agonists
BAR502,
is
a
recently
described
dual
FXR
and
GPBAR1
ligand,
that
has
been
shown
effective
in
reducing
liver
steatosis
and
fibrosis
in
mice
feed
a
high
caloric
diet
and
fructose
[52],
and
that
is
currently
under-
going
pre-clinical
toxicology
(Table
1).
In
summary,
FXR
agonists
represent
the
largest
group
of
novel
drugs
undergoing
evaluation
for
the
treatment
of
NASH.
OCA,
the
first
in
class
of
these
agents
has
been
shown
effective
in
reducing
steatosis
and
fi
-
brosis
in
a
Phase
2
trial
in
NASH
patients,
but
its
use
associates
with
severe
side
effects
that
might
limit
its
clinical
utility
(Fig.
5).
Other
FXR
agonists
have
shown
a
better
safety
profile
(GS-9674),
but
efficacy
re-
mains
unclear.
A
combination
strategy
in
which
a
FXR
ligand
(GS-9674)
was
combined
with
selonsertib
(an
ASK1
inhibitor)
has
failed
to
fulfill
expectations
(Fig.
2).
9.
Fibroblasts
growth
factors
(FGF)
19
and
21
analogues
FGF19
is
an
hormone
released
by
the
terminal
ileum
in
response
to
food
ingestion
[53]
with
a
plasmatic
peak
occurring
≈3
h
after
a
meal.
In
enterocytes,
the
release
of
FGF19
(or
its
orthologue
FGF-15
in
the
mouse)
is
under
the
transcriptional
regulation
of
FXR
[54].
FGF19
reaches
the
liver
though
the
portal
circulation
and
then
binds
to
the
FGFR4/β-klotho
receptor
complex
on
hepatocytes
(Fig.
2),
eliciting
a
series
of
regulatory
functions
that
include
the
repression
of
bile
acid
synthesis
and
gluconeogenesis
and
activation
of
glycogen
storage
[53].
Since,
FGFR4
activation
might
have
cancer-promoting
effects
[55],
non-tumorigenic
variants
of
FGF-19
have
been
developed
to
target
the
liver
in
metabolic
disorders,
with
some
success
in
initial
studies
[56].
NGM-282
is
a
FGF19
analogue
that
has
shown
efficacy
in
reducing
hepatic
steatosis
in
a
Phase
2
trial
in
liver
biopsy-confirmed
NASH
patients
[56].
FGF21
(Fig.
2)
is
a
member
of
the
FGF
subfamily
which
includes
FGF23
and
FGF15/19
[53].
FGF21
is
released
from
hepatocytes
under
condition
of
feeding
and
overfeeeding
[53,57]
and
stimulates
glucose
uptake
by
adipocytes
and
ameliorates
insulin
sensitivity
[53,57].
In
preclinical
studies,
FGF21
reduced
body
weight
and
improved
glucose
tolerance
in
rodents
models
of
obesity
and
diabetes.
BMS986036
is
an
investigational
pegylated
analogue
of
human
FGF21,
endowed
with
long
half-live
that
has
been
found
effective
in
reducing
steatosis
score
and
fibrosis
in
74
patients
with
biopsy
proven
NASH
[58].
While
ago-
nists
the
FGFs
family
hold
some
promise,
long
term
safety
remains
a
concern.
10.
Inhibitor
of
intestinal
transporters:
apical
sodium-dependent
bile
acid
transporter
(ASTB/
SLC10A2)
and
sodium-glucose
cotransporter
1
and
2
(SGLT1
and
2)
ASBT
(SLC10A2)
is
a
transmembrane
protein,
primarily
expressed
in
enterocytes,
that
mediates
the
uptake
of
bile
acids
in
the
distal
ileum
and
colon
participating
to
the
enterohepatic
recirculation
of
these
Table
1
Ligands
for
nuclear
receptors
and
nuclear
receptor
targets
currently
in
devel-
opment
for
treating
NAFLD.
Pharmacological
target
Agent
name
PPARs
agonists
Dual
PPAR-a/y
agonist
Saroglitazar
Dual
PPAR-a/d
agonist
agonist
Elafibranor
Pan
peroxisome
agonist
PPAR-a/d/y
IVA337
Bile
acid
activated
receptors
agonists
FXR
agonists
–
semi-synthetic
bile
acid
derivatives
Obeticholic
acid
(also
known
as
6-ECDCA
and
INT-747)
FXR
agonist
non-steroidal
GS-9674
(also
known
as
PX-
104)
FXR
agonist
steroidal
non-bile
acid
Tropifexor
(also
known
as
LJN452)
LMB763
GPBAR1
agonist
BAR501
Dual
non
bile
acids
FXR
and
GPBAR1
agonists
BAR502
FGF-19
and
FGF21
agonist
NGM282
(FGF19)
Recombinant
pegylated
FGF-21
BMS986036
(FGF21)
Drugs
acting
on
Intestinal
transporters
Apical
sodium
dependent
bile
acid
transporter
(ASBT/SLC10A2)
inhibitor
Volixibat
Sodium
glucose
cotransporter
(SGLT)
1
and
2
antagonist
LIK066
Ipagriflozin
Anti-lipemic
agents
Stearoyl-CoA
desaturase
(SCD)-1
inhibitor
Aramchol
Acetyl-coA
carboxylase
(ACC)
inhibitor
PF-05221304,
GS-0976
Diacylglycerol
acyltransferase(DGAT)-1
inhibitor
Pradigastat
Anti-inflammatory
and
anti-fibrotic
CCR2/CCR5
antagonist
Cenicriviroc
Lysyl
oxidase-like
2
(LOXL)2
Simtuzumab
(GS-6624)
Apoptosis
signal-regulating
kinase
(ASK)-1
Selonsertib
(GS4997)
Pancaspase
inhibitor
Emiricasan
Galectin
3
inhibitor
GR-MD-02
Leukotriene
receptor
antagonist
Tipelukast
Toll
like
receptor
antagonists
JKB-121
Agents
that
target
classical
endocrine
receptors
Nonsteroidal
antimineralocorticoid
Aparenone
(MT3995)
GHRH
analog
Tesamorelin
β-Selective
Thyroid
Hormone
Receptor
(THR)
agonist
MGL3196
Leptin
analog
Metreleptin
Adenosine
3
receptor
antagonist
CF102
Agents
that
target
the
intestinal
microbiota
Macrolides
Solithromycin
Hyperimmune
bovine
colostrum
IMM-142E
Fecal
transplantation
Others
VAP-1/(AOC3/SSAO
inhibitor
B1467335
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
294
steroids.
Uptake
of
bile
acids
by
the
distal
ileum
is
essential
to
maintain
bile
acid
homeostasis
and
lipid
absorption
(Fig.
2).
Volixibat
(SHP-626)
is
an
ASTB
inhibitor
that
has
been
shown
safety
in
diabetic
patients
and
was
granted
the
Fast
Track
designation
by
FDA
in
2016
for
an
in-
vestigational
treatment
of
adult
patients
with
NASH
with
liver
fibrosis
[59].
The
trial
(NCT02787304)
is
ongoing
and
no
further
data
are
available.
Because
this
agent
inhibits
bile
acid/lipid
absorption,
a
common
side
effect
is
diarrhea.
The
sodium-dependent
glucose
cotransporters
(SGLTs)
are
a
family
of
glucose
transporter
expressed
in
by
enterocytes
of
the
small
intestine
(SGLT1)
and
the
proximal
tubule
in
the
kidney
(SGLT1
and
2).
In
these
tissue,
SGLTs
contribute
to
intestinal
and
renal
glucose
reabsorption
(Fig.
2).
LIK066
is
a
dual
SGLT1
and
2
inhibitor
that
is
currently
evaluated
in
Phase
2
trial
by
Novartis
[60].
In
contrast,
ipraglifozin
is
a
selective
SGLT2
inhibitor
that
has
shown
efficacy
in
small
clinical
trials
in
patients
with
NASH
and
is
currently
approaching
Phase
2
[61,62].
Both
SLC10A2
and
SGLTs
inhibitors
prevent
nutrient
absorption
acting
on
the
distal
ileum
and
could
be
combined
with
other
agents
to
reduce
diarrhea.
11.
Agents
that
target
lipotoxicity
11.1.
Stearoyl-CoA
desaturase
(SCD)-1
inhibitors
SCD-1
(Fig.
2)
is
an
enzyme
that
catalyzes
a
rate-limiting
step
in
the
synthesis
of
monounsaturated
fatty
acids
such
as
oleic
acid
[63].
SCD-1
gene
deficient
mice
develop
less
liver
injury
in
response
to
a
high
fat
diet
and
decreased
insulin
resistance,
highlighting
the
potential
of
this
target
in
the
treatment
of
NAFLD.
Aramchol
[
64],
is
a
fatty
acid–bile
acid
conjugate
generated
by
the
combination
of
cholic
acid
with
ara-
chidonic
acid,
endowed
with
robust
SCD-1
antagonist
activity.
In
an-
imal
models,
SCD-1
inhibition
carry
on
a
pro-atherogenic
risk
[
63].
However,
in
addition
to
fact
that
aramchol
is
a
weak
inhibitor
of
SCD-1,
this
agent
also
activates
cholesterol
efflux
by
stimulating
the
ABCA1
transporter,
a
widely
expressed
cholesterol
export
pump.
Aramchol
has
been
granted
a
Fast
Track
designation
status
by
the
FDA
for
the
treat-
ment
of
NASH.
In
a
3-months
study,
at
the
dose
of
300
mg/day,
ara-
mchol
was
well
tolerated,
without
significant
side
eff
ects,
and
found
effective
in
reducing
hepatic
steatosis
as
measured
by
magnetic
re-
sonance
spectroscopy
[64].
A
multicenter
Phase
2b
trial
(NCT02279524)
in
NASH
patients
is
ongoing
[65].
11.2.
Acetyl-coA
carboxylase
(ACC)
inhibitor
ACC
(Fig.
2)
catalyzes
the
irreversible
carboxylation
of
acetyl-CoA
to
produce
malonyl-CoA
and
is
involved
in
FA
synthesis
in
the
liver
[66].
PF-05221304
[67]
and
GS-0976
[68]
are
two
small
molecules
ACC
inhibitors
in
clinical
trials
in
patients
with
NAFLD
and
NASH,
respectively.
GS-0976
has
been
investigated
either
alone
or
as
a
apart
of
combination
therapy
with
other
Gilead
’s
proprietary
agents
such
as
selonsertib.
Results
from
a
Phase
2
trials
were
reported
in
April
2018
[68].
All
patients
cluded
in
this
proof-of-conceptstudy
were
diagnosed
with
NASH
and
liver
fi
brosis
stages
F2
to
F3
using
liver
biopsy
or
magnetic
resonance
elastography
(MRE),
while
steatosis
was
assessed
by
MRI
proton
density
fat
fraction
(MRI-PDFF).
Results
of
this
trial
demonstrate
that
the
association
of
selonsertib,
18
mg,
with
GS-0976,
20
mg,
for
12
weeks
was
more
effective
than
selonsertib
alone
in
re-
ducing
liver
fat
content
or
obtaining
a
reduction
>
30%
of
liver
fat
content
as
measured
by
MRI-PDFF.
However,
the
combination
of
se-
lonsertib
with
GS-0974
was
less
effective
than
GS-0976
alone
[68].
The
trial
also
included
two
harms
with
GS9674
(a
FXR
agonist).
Again,
co-
treating
NASH
patients
with
selonsertibin
combination
with
GS-9674,
failed
to
achieve
better
results
than
the
FXR
agonist
alone.
Finally,
none
of
the
treatment
was
effective
in
reducing
liver
fibrosis
(measure
as
liver
stiffness
by
MRE)
[68].
The
results
of
this
study
question
the
clinical
benefit
of
these
combinations,
but
the
study
was
clearly
underpowered
(only
10
or
20
patients
per
group)
to
drive
firm
con-
clusions.
11.3.
Diacylglycerol
acyltransferase-
(DGAT)-1inhibitor
DGATs
(Fig.
2
)
are
enzymes
that
catalyze
the
final
step
of
trigly-
ceride
synthesis,
i.e.
attachment
of
fatty
acyl-CoA
to
diacylglycerol
(DAG).
There
are
two
DGAT
isoforms
DGAT1
and
2.
Pradigastat
[69],
also
known
as
LCQ908,
is
a
orally
active
DGAT-1
inhibitor,
that
is
currently
undergoing
a
clinical
trial
in
the
treatment
of
NAFLD
[70].
Only
preliminary
data
are
available.
11.4.
Agents
targeting
liver
inflammation
and
fibrosis
Since
the
severity
of
liver
fibrosis,
is
the
strongest
predictor
of
morbidity
and
mortality
in
patients
with
NASH
[ 4,5],
there
is
a
major
interest
for
developing
therapeutics
that
specifically
target
this
process
(Fig.
4).
Some
of
the
agents
mentioned
above,
such
as
OCA
[71]
and,
to
some
extent,
elafibranor
[34],
reduce
liver
fibrosis,
while
others
are
currently
developed
to
selectively
target
pro-
fibrogenetic
pathways
[22–28].
11.5.
CCR2/CCR5
antagonist
Cenicriviroc
is
a
CCR2/CCR5
antagonist
(
Fig.
3
and
4)
is
an
anti-
fibrotic
agents
that
was
shown
effective
in
attenuating
liver
and
kidney
fibrosis
in
rodents
[72].
Cenicriviroc
and
was
trialed
in
a
Phase
2b
trial
in
NASH
patients
(CENTAUR
study)
[73,74
].
At
year
1,
the
prespecified
primary
endpoint
was
not
meet,
and
a
similar
proportion
of
subjects
(19%
vs.
16%)
receiving
placebo
or
cenicriviroc,
150
mg/day,
achieved
the
primary
endpoint
of
hepatic
histological
improvement
in
NAS
(more
than
2
points
and
no
worsening
of
fibrosis
stage)
(Fig.
5).
Several
secondary
endpoints
however
were
meet
[74],
including:
amelioration
of
a
combined
stages
2
and
3
liver
fibrosis
in
comparison
to
baseline
fibrosis
stage
(28.0%
vs
15.5%,
P
=
0.049)
and
amelioration
of
grade
2
ballooning
at
histology
(28.1%
vs
8.7%,
p
=
0.0056).
The
results
of
the
CENTAUR
study
demonstrated
that
cenicriviroc
is
well
tolerated,
but
its
efficacy
is
modest
(Fig.
5).
11.6.
Lysyl
oxidase-like
2
(LOXL2)
inhibitor
LOXL2
(Fig.
3
and
4)
is
a
key
component
in
the
assembly
and
sta-
bilization
of
extracellular
matrix.
LOXL2
promotes
the
liver
fi
brosis
via
the
cross-linkage
of
collagen
fibers
after
these
are
released
by
HSCs
or
other
myofibroblasts
[22–28].
Simtuzumab
(GS-6624)
is
a
monoclonal
antibody
that
binds
and
inhibit
LOXL2
[75].
Results
from
a
Phase
2
trials
in
patients
with
NASH
with
advanced
fibrosis
or
cirrhosis
(stages
F3-F4)
demonstrated
that
simtuzumab
was
well
tolerated
but
exerted
no
benefit
in
comparison
with
placebo
[75].
11.7.
Apoptosis
signal-regulating
kinase
1
(ASK-1)
inhibitor
Selonsertib
inhibits
ASK-1
and
MAP3
kinase,
two
putative
targets
that
promote
hepatic
steatosis
and
fibrosis
[76].
The
safety
and
efficacy
of
selonsertib
alone
is
currently
investigated
in
Phase
3
trials
(STELLAR
3
and
4)
[77–79].
As
mentioned
above
in
a
Phase
2
trials
released
in
2018
[68],
selonsertib
alone
was
trialed
against
GS-0976
(an
ACC
in-
hibitor)
and
GS-9674
(an
FXR
agonist)
each
agent
alone
or
in
combi-
nation
[68].
In
this
study
(Fig.
5)
selonsertib
alone
failed
to
meet
any
endpoint
and
the
association
of
selonsertib
with
GS-0976
or
CS-9674
was
less
effective
than
two
agent
alone.
All
agents
failed
to
reduce
liver
stiffness
(fibrosis)
[68].
11.8.
Pan-caspase
inhibitors
Emiricasan
(IDN-6556)
(Fig.
4)
is
a
pan-caspase
inhibitor
and
anti-
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
295
apoptotic
agent
[80]
that
has
shown
efficacy
in
murine
models
of
liver
fibrosis.
Emricasan
(Conatus
Pharmaceuticals
Inc)
was
granted
the
fast
track
designation
by
the
FDA
for
the
development
of
NASH
and
cir-
rhosis,
and
is
currently
evaluated
in
Phase
2
trials
in
patients
NASH
and
fibrosis
[81].
The
POLT−HCV-SVR,
was
a
Phase
2b
multicenter,
double-blind,
trial
in
which
emricasan
was
tested
for
efficacy
in
subjects
who
had
hepatitis
C
Virus
(HCV)
reinfection
and
liver
fibrosis
following
orthotopic
liver
transplantation
treated
successfully
with
anti−HCV
therapies
[82].
As
April
2018,
it
has
been
reported
that
emricasan
has
failed
to
reach
primary
endpoints
(improving
fibrosis)
in
this
study.
11.9.
Galectin-3
inhibitor
Galectin-3
is
a
protein
expressed
predominantly
in
immune
cells
(Fig.
3)
that
recognizes
and
binds
to
galactose
residues
and
is
an
es-
sential
protein
in
liver
fibrogenesis
[22–29].
GR-MD-02
is
a
galectin-3
inhibitor,
that
is
currently
undergoing
a
two
Phase
2b
trial
(NASH-CX
trial)
in
NASH
patients
with
fibrosis/cirrhosis
(NCT02462967).
The
interim
analysis
of
this
study
released
by
April
2018
[83],
suggest
that
treating
cirrhotic
patients
with
GR-MD-02,
8
mg/kg,
resulted
in
a
sta-
tistically
significant
improvement
in
portal
pressure
and
a
reduction
in
the
development
of
newly
formed
esophageal
varices
at
the
end
of
the
one-year
study.
11.10.
Other
anti-inflammatory
agents
Tipelukast,
also
known
as
MN-001,
is
a
orally
bioavailable
small
molecule
leukotriene
receptor
antagonist
that
exerts
anti-fibrotic
and
anti-inflammatory
activity
in
preclinical
models
of
NASH.
A
Open
label
study
is
currently
ongoing
with
this
agent
[
84].
JKB-121
(Fig.
4)i
sa
Toll
like
receptor
antagonists
[22–28,85]
and
a
clinical
trial
in
NASH
patients
is
currently
running
(NCT02442687).
12.
Agents
that
target
classical
hormone
receptors
12.1.
Mineral
corticoids
Aparenone
(MT3995)
is
small
molecule
antagonist
of
aldosterone
and
is
currently
advanced
to
Phase
2
trial
in
patients
with
diabetic
nephropaty
and
NASH
[86,87].
Results
are
pending.
12.2.
Growth
hormone-releasing
hormone
(GHRH)
analog
Tesamorelin
[88–90],
is
a
long-lasting
GHRH
analogue,
that
was
shown
effective
in
attenuating
visceral
fat
and
lipodistrophy
in
HIV-
infected
individuals
taking
highly
active
anti-retroviral
therapy
(HAART).
As
May
2018,
Theratechnologies
(www.theratech.com)
has
announced
that
tesamorelin
will
enter
a
Phase
2b
trial
in
patients
with
in
the
current
year.
12.3.
β-Selective
thyroid
hormone
receptor
(THR)
agonist
(MGL-3196)
Since
the
beneficial
effects
of
thyroid
hormone
on
lipid
levels
are
primarily
linked
to
action
on
the
thyroid
hormone
receptor
β
(THR-β)
in
the
liver
(Fig.
2),
while
adverse
effects,
including
cardiac
effects,
are
mediated
by
THR-
α,
selective
THRβ
agonist
have
been
developed
to
target
metabolic
disorders.
MGL-3196
[91]
is
a
orally
active
THR-β
agonist,
that
diminish
hepatic
lipid
accumulation
in
rodents
fed
a
high
fat
diet
and
is
currently
developed
for
treating
NASH.
In
a
Phase
2
trial
in
patients
with
biopsy-proven
NASH
[91],
MGL-3196
has
meet
all
the
primary
endpoints
reducing
the
hepatic
fat
content
and
liver
fibrosis
as
measured
by
MRI-PDFF.
12.4.
Leptin
analog
Metreleptin,
a
leptin
analogue
approved
by
FDA
for
the
treatment
of
generalized
lipodystrophy,
a
rare
condition
characterized
by
leptin
deficiency.
Metreleptin
has
also
been
tested
for
its
effects
on
lipid
ac-
cumulation
in
lipodistrophic
patients
[92].
A
small
pilot
trial
(Clin-
icalTrials.gov
Identifier:
NCT01679197)
carried
out
on
23
patients,
of
whom
18
completed
one
year
follow
up,
has
shown
some
signals
of
steatosis
improvement.
It
is
unclear
whether
development
will
be
continued.
12.5.
Adenosine
(A)3
receptor
antagonist
CF102,
also
known
as
namodenoson,
is
a
small
orally
bioactive,
highly
selective
agonist
for
the
A3
adenosine
receptor
(A3AR).
This
agent
[93]
exert
anti-fibrotic
and
anti-inflammatory
activity
in
rodent
models
of
NASH
and
liver
fibrosis,
partially
by
targeting
NKT
cells
(Fig.
3
and
4).
CF102
is
currently
investigated
in
a
Phase
2
trial
in
patients
NASH.
The
trial
is
ongoing
and
enrollment
is
expected
to
finish
in
2018.
12.6.
Gut
microbiota
Intestinal
dysbiosis
is
considered
a
causative
mechanisms
of
NASH,
at
least
in
animal
models
[26].
A
recent
meta-analysis
has
demonstrated
a
putative
relation
between
intestinal
dysbiosis
and
NAFLD/
NASH
[94],
and
patients
are
known
to
develop
a
signature
microbiota
that
might
predict
the
severity
of
liver
fibrosis
[95].
Probiotic
and
fecal
microbiota
transplantation
have
shown
beneficial
effects
in
rodent
models
of
NASH
[96,97],
suggesting
that
modulation
of
gut
microbiota
through
probiotics
and/or
symbiontics
(that
target
protozoa)
could
provide
a
beneficial
effect
in
NASH
patients.
The
macrolide
antibiotic,
solithromycin
[98],
has
been
tested
with
some
results
in
a
pilot
study
and
is
currently
in
a
phase
II
trial
(NCT02510599).
Similarly,
IMM-124
E,
a
hyperimmune
bovine
colostrum
[99],
that
modulates
the
gut-liver
axis,
is
currently
evaluated
in
Phase
2
trial
in
patients
with
NASH.
Finally,
several
ongoing
trials
are
currently
running
to
test
ef-
ficacy
of
probiotic
and
fecal
microbiota
transplantation
in
NASH
pa-
tients
(NCT02469272,
NCT02868164,
NCT02721264,
NCT01680640,
NCT02568605,
NCT02642172).
12.7.
Miscelaneous
agents
The
semicarbazide-sensitive
amine
oxidase/vascular
adhesion
pro-
tein
1
(SSAO/VAP-1)
is
an
homodimeric
glycoprotein
adhesion
mole-
cule
that
is
widely
expressed
in
the
vascular
system.
During
in-
flammation
(Fig.
4)
this
complex
facilitates
leukocyte
recruitment
through
its
SSAO
component
and
its
activation
promotes
liver
in-
flammation
and
fibrosis
[100
].
BI
1,467,335
(formerly
known
as
PXS-
4728
A)
is
a
SSAO/VAP-1
inhibitor
that
was
shown
e ffective
in
reducing
liver
injury
in
rodents
[100].
A
Phase
2
clinical
trials
in
patients
with
NASH
was
started
in
2017
[101].
13.
Conclusions
Liver
accumulation
of
lipids
(NAFL/NASH),
occurring
in
the
context
of
systemic
metabolic
disorders
(diabetes,
dyslipidemia
and
obesity)
or
chronic
high
caloric
intake
and
sedentary
lifestyle
is
a
growing
health
care
concerns
in
modern
world.
NASH
is
a
potentially
progressive
liver
disease,
and
the
liver
component
contributes
signifi
cantly
to
the
disease
burden.
It
is
now
widely
accepted
that
specific
treatments
need
to
be
developed
to
treat
NASH.
Several
classes
of
novel
therapeutics
that
target
key
pathogenic
mechanisms
are
under
development
for
treating
NASH.
Agonists
for
the
nuclear
receptors
PPARαδ
and
FXR,
elafibranor
and
obeticholic
acid,
are
advancing
fast
in
their
regulatory
track
currently
undergoing
Phase
3
pre-registration
trials.
These
agents
have
the
advantage
to
act
on
multiple
targets
and
have
shown
effective
in
Phase
2
trials
in
reducing
liver
fat
deposition
and
to
some
extent
fibrosis.
The
FXR
agonist
S.
Fiorucci
et
al.
Pharmacological Research 134 (2018) 289–298
296
obeticolic
acid,
however,
has
attracted
attention
for
its
liver
toxicity
in
cirrhotic
patients,
and
its
role
in
treating
NASH
patients
with
severe
fibrosis
(i.e.
those
patients
for
whom
there
is
a
real
medical
need)
is
difficult
to
predict.
In
addition,
other
side
effects,
including
some
time
severe
pruritus
are
highly
prevalent
with
this
agent.
On
the
other
hand,
the
rate
of
response
to
elafibranor
is
unclear
and
needs
to
be
further
assessed
(Fig.
5).
GLP-1,
FGF19
and
FGF21
analogues
and
DDP-4
inhibitors
hold
promise
in
specific
NASH
subsets
particularly
in
diabetic
patients.
While
novel
anti-fibrotic
agents
such
as
anti−CCR2/CCR5
antagonist
(genicriviroc)
and
the
ASK-1
inhibitor
(selonsertib)
have
been
shown
signals
of
efficacy
in
attenuating
liver
fibrosis
in
NASH
patients.
Similarly,
novel
lipid-lowering
agents,
targeting
SCD-1
(aramchol)
and
ACC
(GS-0976
and
PF05221304)
have
shown
efficacy
in
Phase
2
trials.
Finally,
therapies
that
target
the
intestinal
microbiota
are
currently
under
evaluation.
While,
the
lack
of
specific
biomarkers,
do
not
allow
to
reach
the
diagnostic
accuracy
that
is
ideally
required
to
fully
develop
a
patient-
tailored
approach,
our
knowledge
of
NASH
pathogenesis
has
been
greatly
advanced
through
basic
and
translational
investigations
in
re-
cent
years
and
will
be
further
driven
by
development
of
more
predictive
preclinical
models
along
with
identification
of
better
biomarkers.
The
current
landscape
suggest
that
we
will
never
discover
a
universal
therapy
for
NASH.
As
for
other
multifactorial
disorders,
the
ideal
management
needs
to
be
tailored
to
the
single
patient
(see
outstanding
questions),
and,
most
likely,
will
emerge
from
combination
of
agents
that
target
specific
pathogenic
mechanisms
at
different
disease
stage.
Conflict
of
interest
The
authors
have
no
conflict
of
interest.
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298
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