Journal of Physiology and Biochemistry (2023) 79:869–879

https://doi.org/10.1007/s13105-023-00954-4

REVIEW

Metabolic dysfunction–associated fatty liver disease (MAFLD):

an update of the recent advances in pharmacological treatment
Paloma Sangro1 · Manuel de la Torre Aláez1 · Bruno Sangro1,2 · Delia D’Avola1,2

Received: 24 November 2022 / Accepted: 28 February 2023 / Published online: 28 March 2023
© The Author(s) 2023

Abstract
Metabolic dysfunction–associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic
syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a
wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious
complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms
underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have
been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the
last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major
components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a
large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD
at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced
clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.

Keywords MAFLD · NAFLD · NASH · Drug therapies · Clinical trials

Introduction
Key Points • For the time being, there is no specific treatment
for NASH to avoid disease progression into hepatic fibrosis or to
Definition and epidemiology
reduce established fibrosis.
• As pathophysiology of NASH is very complex and not- Metabolic dysfunction–associated fatty liver disease
completely well understood, identification of biological drug (MAFLD) has become one of the most relevant forms of
targets is challenging.
chronic liver disease worldwide due to the progressively
• Many clinical trials are under development to try to identify
drugs to diminish hepatic inflammation/fibrosis. A synthesis of increased in obesity rates over the past 30–40 years [1].
the results of the most advanced clinical trials for the treatment of Obesity is defined as a body mass index ≥ 30 kg/m2 and the
NASH is presented in this review. World Health Organization estimates that over 13% of the
world population (> 600 million people) suffer from it, with
Paloma Sangro, Manuel de la Torre Aláez Shared equal authorship.
more prevalent rates among children and adolescents [2].
* Paloma Sangro The metabolic syndrome includes three out of the follow-
[email protected] ing conditions: abdominal obesity, hypertriglyceridemia,
* Manuel de la Torre Aláez low HDL cholesterol, arterial hypertension, and/or hyper-
[email protected] glycemia. MAFLD is not only associated to those comor-
Bruno Sangro bidities but also to insulin resistance. Indeed, the nomencla-
[email protected] ture of non-alcoholic fatty liver disease (NAFLD) has been
Delia D’Avola updated to MAFLD. This term describes better the liver dis-
[email protected] ease associated with known metabolic dysfunction. In fact,
1 the new definition of MAFLD refers to hepatic steatosis in
Liver Unit Clínica, Universidad de Navarra, Madrid, Spain
addition to one of the following three criteria: overweight/
2
Centro de Investigación Biomédica en Red de Enfermedades obesity, presence of type 2 diabetes mellitus, or evidence of
Hepáticas y Digestivas, Pamplona, Spain

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870 P. Sangro et al.

metabolic dysregulation. The exclusion of other liver dis- a significant association of a variant in “patatin-like phos-
eases including alcoholic, autoimmune, or viral hepatitis is pholipase domain-containing 3” (PNPLA3) gene on chromo-
not a prerequisite for the diagnosis of MAFLD [3]. some 22 leading to modifications in retinol metabolism [12];
Within the general population, the overall global preva- or in “transmembrane 6 superfamily member 2” (TM6SF2)
lence of NAFLD (defined using imaging criteria) is esti- gene on chromosome 19 leading to an impaired lipid trans-
mated to be 25% [4]. However, important variability was porter, have been associated with fatty liver disease [13].
observed according to geographic regions, being up to 31.8% Polymorphism in “ectoenzyme nucleotide pyrophosphate
in the Middle East, 30.4% in South America, and 13.5% phosphodiesterase 1” (ENPP1 or PC1) and in “insulin recep-
in Africa [4]. NAFLD incidence has rarely been measured. tor substrate-1” (IRS1) genes, which are related to insulin
Given the common risk factors between NAFLD and resistance, have also been described in NAFLD patients
cardiovascular risk factors, cardiac-related death is one of [14]. Even, a polymorphism in “membrane bound O-acyl-
the leading causes of death for NAFLD patients [5]. Other transferase domain-containing 7” (MBOAT7-TMC4) gene,
causes include liver-related death, malignancy, or other involved in oxidative stress, increases the risk of fibrosis in
causes such as infections, type 2 diabetes mellitus, or pul- patients with NAFLD [15]. Genetic variants in “glucokinase
monary embolism. regulatory protein” (GCKR) gene [16], “solute carrier family
NAFLD is defined as the presence of steatosis in > 5% 2-member 1” (SLC2A1) gene [17], and “17-beta hydroxys-
of hepatocytes in the absence of other competing chronic teroid dehydrogenase 13” (HSD17B13) gene [18], have also
liver diseases and without significant alcohol consumption been identified in patients with fatty liver disease.
(< 20 g/day in women and < 30 g/day in men). NAFLD NASH is the result of multiple intracellular signals
includes non-alcoholic fatty liver (NAFL) and non-alcoholic derived either from proinflammatory molecules and con-
steatohepatitis (NASH), the latter being more severe as it tact with immune cells and/or from external stimulation
includes hepatocyte damage with the risk of subsequent through visceral adipose tissue and gut microbiome, the
development of significant fibrosis, cirrhosis, and/or hepa- last two conditioned by diet. The outcome of these interac-
tocellular carcinoma [6]. In this context, NASH has become tions on hepatocytes includes modified insulin signaling,
one of the leading causes of cirrhosis in adults in the USA lipogenesis, mitochondrial dysfunction, and activation or
and NASH-related cirrhosis is currently the second indica- abnormal functioning of nuclear receptors such as bile acid
tion of liver transplantation in the USA [7]. receptors farnesoid X receptor (FXR) [19], liver X receptor
Whereas the definitive diagnosis of both MAFLD and (LXR) [20], pregnane X receptor (PXR) [21], and vitamin
NASH requires a liver biopsy, imagine techniques such as D receptor (VDR) [22] leading to hepatic inflammation by
magnetic resonance imaging (MRI) (MRI proton density different downstream effects. Hepatic stellate cells are acti-
fat fraction [MRI-PDFF] or magnetic resonance spectros- vated by these signals may trigger a fibrogenic response with
copy), computed tomography (CT), ultrasound (US) with extracellular matrix production [23].
controlled attenuation parameter (CAP), and/or elastogra- Diet with excess carbohydrates and saturated fat lead to
phy may provide a valuable assessment of fat deposition an energy metabolism imbalance with lipid deposition in
and significant fibrosis [6]. Although no specific treatments skeletal muscle. Subsequent muscle insulin resistance due
other than the control of the associated metabolic disorders to increased intramyocellular lipid content impedes the stor-
is available, follow-up to control comorbidities is recom- age of ingested glucose as muscle glycogen [24]. Glucose is
mended to detect disease progression. then rerouted to the liver where insulin resistance stimulates
sterol regulatory element–binding protein 1c (SREBP1c)
Genetics and pathogenesis [25] which increases the expression of hepatic enzymes
that regulate de novo lipogenesis with higher VLDL produc-
Most individuals with MAFLD have no symptoms, and the tion and hypertriglyceridemia. Other transcription factors
disease may remain silent until it has progressed to cirrho- such as carbohydrate-responsive element–binding protein
sis [8]. Recent data suggest that the transition from NAFL (ChREBP) [26], peroxisome proliferator–activated recep-
to NASH is quite dynamic whereas fibrosis development is tor gamma coactivator 1-beta (PPARg coactivator 1-b) [27],
significantly slower in NAFLD than in NASH, needing even and LXR [28] also foster liver lipogenesis.
up to 14 years [9]. Up to 20% of patients with NASH are Although visceral adipose tissue has been related to the
considered as “rapid progressors” where, although predic- pathogenesis of NASH, visceral adipose tissue may just be
tors are largely unknown, genetic susceptibility might play an additional site for lipid accumulation when subcutane-
a role [10]. The relevance of the genetic determinants is ous adipose tissue capacity is surpassed [29]. Circulating
just beginning to be elucidated [11], but they may involve triglyceride-enriched lipoproteins are cleared by peripheral
intrahepatic lipolysis, triglyceride export, hepatic mito- lipoprotein lipase (Lpl) [30]. However, an increase in endog-
chondrial oxidation, or glucokinase activity. For instance, enous Lpl inhibitors, such as apolipoprotein C3 (ApoC3)

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Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances… 871

[31], angiopoietin-like proteins 3/8 (ANGPTL3/8) complex, In the last 10 years, more than 20 molecules have been
and ANGPTL4 [32], impedes clearance of these circulating tested for the treatment of NASH. Most drugs were dis-
triglyceride-enriched lipoproteins and therefore, induces an carded after unsuccessful clinical trials, others are still in
increased hepatic triglyceride uptake. Increases in endog- early stage of clinical development (phase 1 and 2 clinical
enous Lpl inhibitors have been described in NASH patients. trials) and a few have reached phase 3 trials. So far, drugs
All in all, NASH is a heterogeneous disease with a com- at most advanced clinical development include antidiabetic
plex pathophysiology that makes finding a single effective drugs, FXR agonists, PPAR agonists, and thyroid hormone
treatment a major challenge. receptor (THR) agonists (Fig. 1). Table 1 includes a synthe-
sis of the clinical trials (phase II/III) in treatment of NASH.

Drug therapy in NASH Antidiabetic drugs

It is well-known that the first approach to treat NAFLD As insulin resistance and type 2 diabetes mellitus are closely
patients is the nutritional intervention with a change in life- associated with NASH, the efficacy of several antidiabetic
styles. However, the complexity of NASH pathophysiology agents has been studied in NASH. Pioglitazone showed his-
and the interplay of multiple genetic and environmental fac- tological benefits (improved NAFLD activity score, also
tors in disease progression explains why the pharmacother- called NAS or improvement in single histological com-
apy of this clinical condition includes a variety of molecules ponents of NASH) in three randomized trials in diabetic
with different biological targets, from drugs used to treat and prediabetic patients with NASH. However, the effect
of the diseases that contribute to NASH development and on liver fibrosis was not significant, although worsening of
progression (i.e., antidiabetic agents) to drugs targeting liver liver fibrosis was not observed [33–35].
inflammation and fibrosis. Its long natural history and wide Newer antidiabetic agents including SGLT1/2 (sodium-
spectrum of severity, from mild inflammation to end-stage glucose co- transporter-1/2) inhibitors and GLP-1R (gluca-
cirrhosis, are challenges in the evaluation of pharmacologi- gon-like peptide 1 receptor) agonists are being tested in
cal interventions and requires specific interventions for each NASH. Dapagliflozin and semaglutide have reached late-
disease stage. stage clinical development.

Fig. 1  Main drugs and targets in NASH treatment

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 Table 1  Main clinical trials in treatment of NASH/NAFLD (phase II/III)
872

Molecule and main trial Mechanism of action Primary objective Patients Grade of fibrosis Main results Most frequent adverse events
recruited

13
(n)

New anti diabetic agents

Dapaglifozin Inhibitor of SGLT2 Improvement in scored liver 100 NA Recruiting
DEAN study histology over 12 months
(NCT03723252) phase 3
Semaglutide Agonist GLP1 NASH resolution without 320 2- 3 NASH resolution Nausea, diarrhea, abdominal
(NCT02970942) phase 2 worsening of fibrosis No fibrosis improvement discomfort, reaction site injec-
tions
Semaglutide Agonist GLP1 NASH resolution without 1200 2–3 Recruiting
ESSENCE study worsening of fibrosis
(NCT04822181) phase 3 Improvement of fibrosis with-
out worsening NASH
Liraglutide Agonist GLP1 Histological resolution of 26 NA NASH resolution with worsen- Nausea, diarrhea, abdominal
LEAN trial NASH ing of fibrosis discomfort, reaction site injec-
(NCT01237119) phase 2 tions
PPAR modulators
Pioglitazone PPARγ agonist Improvement in scored liver 166 1–3 Recruiting
AIM 2 trial histology over 72 weeks
(NCT04501406) phase 2
Pioglitazone/vitamin E PPARγ agonist Improvement in scored liver 247 NA Vitamin E vs. placebo:
PIVENS trial histology over 96 weeks improvement Pioglitazone vs.
(NCT00063622) phase 3 placebo: no improvement
Saroglitazar Dual PPARα and PPARγ Reduce ALT from baseline 104 0–3 Improvement of NASH by Diarrhea and cough
EVIDENCES II study agonist liver biopsy after 52 weeks of
(NCT03061721) phase 3 treatment
Reduction of ALT from
baseline
Lanifibranor Pan-PPAR agonist Histological resolution of 247 0–3 Improvement of NASH and Nausea, diarrhea, peripheral
NATIVE study NASH fibrosis by liver biopsy edema, anemia, and weight
(NCT03008070) phase 2 gain
Elafibranor Dual PPARα and PPARδ NASH resolution without 2157 1–3 No improvement in NASH
RESOLVE-IT study agonist worsening of fibrosis
NCT02704403) phase 3
Pemafibrate PPARα agonist Percentage change in liver fat 118 No differences in liver fat con- Mild-or-moderate adverse events
(NCT03350165) phase 2 content measured by MRI tent but there was a reduction
from baseline to week 24 in stiffness measured by MRI
FXF agonist
Cenicriviroc CCR2/CCR5 agonist Improvement in liver fibrosis 2000 2–3 Ended trial by interym analisys Well tolerate in general way,
AURORA trial by ≥ 1 stage and no worsen- and lack of efficacy but safety was no reported in
(NCT03028740) phase 3 ing of steatohepatitis on liver Aurora trial
histology
P. Sangro et al.
 Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances… 873

Dapagliflozin is an oral SGLT2 inhibitor which impedes

Most frequent adverse events glucose reabsorption in the proximal tubule leading to gluco-
suria and plasma glucose reduction. Between 2018 and 2021,
many studies regarding the use of dapagliflozin in NASH
patients were published. A meta-analysis of 7 trials showed
that treatment with 10 mg dose dapagliflozin compared to

Well tolerated
the placebo or control group in patients with NASH (image-
based diagnosis) significantly lowered ALT (weighted mean
difference (WMD): − 6.62U/L; 95%CI: − 12.66, − 0.58;
p = 0.03) and AST levels (WMD: − 4.20U/L; 95%CI: − 7.92,-
worsening of NASH on liver 0.47; p = 0.03). Gamma-glutamyl transferase (GGT) levels
MRS. Improvement in liver

Improvement in liver fat con-

tent and improve in fibrosis
fibrosis by ≥ 1 stage and no

were non-significantly decreased whereas homeostatic

No changes in liver fat by
Trial fails in this primary

model assessment of insulin resistance (HOMA-IR) was

significantly affected (WMD: − 0.88; 95%CI: − 1.43,-0.33;
p = 0.002). Although levels of total cholesterol increased
Patients Grade of fibrosis Main results

under dapagliflozin treatment, safety profile between

histology
objective

groups had no significant difference [36]. The DEAN study

stage

(NCT03723252) is a phase 3 trial which compares dapagli-

flozin vs. placebo among patients with histologically con-
firmed NASH with the primary endpoint of improvement in
scored liver histology at 12 months. Other endpoints include
resolution of NASH, changes in fibrosis score and changes
0–3

1–3

in metabolic features such as body weight, hemoglobin A1

(Hb1Ac) or insulin resistance.
recruited

Other SGLT1/2 inhibitors are in earlier phases of clini-

cal testing in NASH. The ELIVATE study (NCT04065841)
247

123
(n)

is assessing if licogliflozin alone or in combination with

tropifexor, an agonist of the bile acid receptor FXR,
Hepatic fat fraction measured

Hepatic fat fraction measured

improves fibrosis and/or NAS score in patients with NASH

and fibrosis stage 2 or 3. A phase 2a study to evaluate the
safety and tolerability of MET409 (a synthetic FXR agonist)
Primary objective

alone or in combination with empagliflozin in patients with

type 2 diabetes mellitus and NASH has finalized recruitment
by MRI

by MRI

and the results will be reported soon.

Semaglutide is a GLP-1R agonist which enhances insulin
secretion to regulate blood glucose level. This GLP-1R ago-
nist was first assessed in a 72-week phase 2 clinical trial [37]
pyruvate carrier and acyl-

in patients with biopsy-confirmed NASH and liver fibrosis

Partial inhibitor of hepatic
stearoyl-CoA desaturase

Inhibitor of mitochondrial

stages 1, 2, or 3. Patients were randomly assigned to receive

Mechanism of action

CoA synthetase 4

semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78

Inhibitor of ASK1

patients), or 0.4 mg (82 patients) or placebo (80 patients).

Primary outcome was NASH resolution without worsening
of fibrosis and only patients with stage 2 or 3 fibrosis levels
were assessed in this cohort. This outcome was achieved
in 40% of patients in the 0.1-mg group, 36% in the 0.2-
mg group, 59% in the 0.4-mg group, and 17% in the pla-
Other metabolic treatments

cebo group (p < 0.001 for semaglutide 0.4 mg vs. placebo).

(NCT02279524) phase 2

(NCT04321343) phase 2
Molecule and main trial

However, no significant differences were observed between

Table 1  (continued)

Stellar 3–4, (PMID:

32,147,362) (fail)

the different doses used and the percentage of patients with

an improvement in fibrosis staging (43% with 0.4 mg vs.
ARREST study
Selonsertib

33% with placebo, p = 0.48). Gastrointestinal and gallblad-

Aramchol

PXL065

der disorders occurred in a higher percentage of patients

in the semaglutide groups. Increases in amylase and lipase

13
874 P. Sangro et al.

from baseline were also observed in the treated groups placebo in histological resolution of NASH (49% and 39%,
without any acute pancreatitis episode. A phase 3 clinical respectively, vs. 22%), histological improvement of fibrosis
trial (ESSENCE, NCT04822181) is recruiting non-cirrhotic (48% and 34%, respectively, vs. 29%), or both (35% and
NASH patients to evaluate the potential resolution of steato- 25%, respectively, vs. 9%) were observed [43]. Nausea, diar-
hepatitis and the improvement in fibrosis with this GLP-1R rhea, peripheral edema, anemia, and weight gain occurred
agonist. more frequently with lanifibranor than with placebo.
The LEAN trial [38], a phase 2 trial evaluating the effect The PPARα agonist pemafibrate has been tested in
of liraglutide (1.8 mg daily) compared to placebo in patients NASH patients (MRI diagnosis with ALT elevation) [44].
with biopsy-confirmed NASH, showed histological resolu- The primary endpoint of percentage change in liver fat
tion of NASH (39% with liraglutide vs. 9% with placebo, content measured by MRI at week 24 was not met (− 5.3%
p = 0.019). Fibrosis progression was observed in 36% of vs − 4.2%; treatment difference − 1.0%, p = 0.85). However,
patients receiving placebo vs in 9% of liraglutide-treated liver stiffness measured by MRI decreased at week 48 (treat-
patients (p = 0.04). Adverse events reported were mainly ment difference − 5.7%, p = 0.036), and was maintained at
gastrointestinal disorders or administration site reactions. week 72 (treatment difference − 6.2%, p = 0.024).
Others GLP1R such as cotadutide (NCT04019561), tirze-
patide (NCT04166773), or efinopegdutide (NCT04944992) FXR agonists
have been tested or are still being tested in phase 2 trials and
the results have not been published yet. FXR modulation may have multiple implications in the treat-
ment of NASH since, besides bile acid (BA) synthesis, this
PPAR modulators receptor is involved in glucose and lipid metabolism, and in
the regulation of inflammation [45]. FXR activation down-
The peroxisome proliferator-activator receptor (PPAR) regulates bile acid synthesis through the upregulation of
family is formed by PPARα, PPARγ, and PPARδ which fibroblast growth factor (FGF)-19 expression and by reduc-
are mainly located in liver, brown adipose tissue, and mac- ing the expression of CYP7A1, the rate-limiting enzyme of
rophage. They activate fatty acid oxidation, lower synthesis the BA synthesis. This results in a protective effect against
of triglycerides, and increase insulin sensitivity. Saroglitazar the toxic accumulation of BAs through increased conjuga-
is a dual PPARα and PPARγ agonist, that was first approved tion in the liver and secretion into the bile canaliculi. FXR
in India for the treatment of type 2 diabetes mellitus patients activation improves glucose tolerance by reducing hepatic
with hypertriglyceridemia [39]. Since 2020, it is widely used gluconeogenesis and increasing glycogen synthesis [46].
as treatment for NASH patients in India. Among patients Additionally, FXR activation reduces fat accumulation in
with NAFLD (stages 0–3) diagnosed by imaging (ultra- the liver by targeting SHP expression and CYP7A1 activ-
sound, CT scan, or MRI) or liver biopsy showing NASH or ity [47]. Obeticholic acid (OCA) is a semi-synthetic bile
simple steatosis, and alanine aminotransferase (ALT) > 1.5 acid analog of chenodesoxicholic acid with a potent ago-
upper limit of normal recruited into a phase 3 trial (EVI- nist activity on the FXR in the liver and in the intestine.
DENCES II), saroglitazar reduced ALT levels after 16 weeks OCA, as the other members of FXR agonists family, may
of therapy [40]. Patients receiving saroglitazar 4 mg reduced exert multiple therapeutic effects on NASH by improving
the most their levels of ALT (− 45.8% vs. 3.4%, p < 0.001). hepatic lipid and glucose metabolism and through its anti-
Histological improvement of NASH after 16 weeks of treat- inflammatory and anti-fibrotic activity. OCA lowers plasma
ment was observed with 4 mg of saroglitazar (reduction in triglycerides by downregulating the expression of SREBP1c
liver fat content − 19.7% vs. 4.1% with placebo (p = 0.004)). expression (48) and increases hepatic fatty acid oxidation
Safety and tolerability of saroglitazar were further assessed through upregulation of pyruvate dehydrogenase kinase 4
in a phase 2 study (EVIDENCES IV), and the most frequent (PDK4) and modulating glucose-dependent lipogenic genes
adverse effects were diarrhea and cough [41]. [49]. It has been shown that OCA reduces insulin resist-
After a successful phase 2 b trial, elafibranor, a dual ance and improves glucose homeostasis in diabetic patients
PPAR-alpha/delta agonist, was tested in a phase 3 clinical with NASH [50]. OCA may also contribute to reduce portal
trial in patients with non-cirrhotic NASH. In this trial, elafi- pressure by increasing nitric oxide synthases (iNOS) and
branor did not meet histological endpoints (NASH resolution decreasing inflammation mediators.
without worsening of fibrosis) nor the key secondary end- After a phase 2b clinical trial in patients with biopsy-
point (fibrosis improvement at least one stage) [42]. proven NASH without cirrhosis (FLINT trial) in which OCA
Lanifibranor, the only pan-PPAR agonist, was assessed displayed a beneficial impact on fibrosis without resolution
in non-cirrhotic biopsy-confirmed highly active NASH of advanced fibrosis and at least of 2 points improvement
(stages 0–3) patients in a phase 2b trial (NATIVE study) in NASH compared to placebo [51], this drug is now being
were 1200 mg showed better results than 800 mg dose or tested in a large phase 3 randomized, placebo-controlled trial

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Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances… 875

(REGENERATE trial, NCT2548351) to evaluate the long- inflammation and fibrosis measured by using a non-invasive
term effects on NASH and fibrosis in patients with stage 1–3 composite marker assessed by MRI (cT1) and MRI-PDFF
fibrosis. The results of an interim analysis showed a signifi- [57].
cant improvement of fibrosis in approximately 20% of patients
treated with OCA vs. 12% of placebo [52]. The NASH resolu-
tion endpoint was not met in this preliminary analysis. The FGF analogs
most significant side effect was a dose-dependent pruritus,
that in some cases (< 10%) required treatment discontinua- FGF19 and FGF21 are members of FGF superfamily that
tion. Increased cholesterol levels were frequently observed, exert similar but not identical beneficial effects on lipid
and statins were newly prescribed in almost 50% of patients and glucose metabolism. Indeed, the administration of
receiving OCA [52]. both FGF19 and FGF21 in animal models improve insulin
At the same time, the antifibrogenic effect of OCA sensitivity, improve body weight and fat mass, lipid levels,
is being tested in a phase 3 trial including patients with and liver steatosis. This latter effect probably depends on
compensated cirrhosis due to NASH (REVERSE trial, the inhibition of SREBP1 and reduced expression of genes
NCT03439254). involved in triglyceride synthesis [58].
MET642 and MET 409 are other structurally optimized In the last years, different FGF21 analogs and one FGF19
synthetic FXR agonists. Preliminary reports suggest that analog have been tested in phase 1 and 2 trials for the treat-
these compounds produce less pruritus than OCA. MET642 ment of NASH.
is now being tested in a phase 2 clinical trial in patients with In a phase 2b trial, the FGF19 analog aldafermin failed
NASH (NCT0477396). After the results of a phase 1b trial to improve liver fibrosis among patients with NASH-related
in which MET409 showed its ability to reduce the liver fat stage 2 or 3 fibrosis. Other FGF21 analogs are pegbelfermin
content in monotherapy, this drug is now being tested in a and efruxifermin. In a phase 2 trial in patients with stage
phase 2b trial in combination with empagliflozin. 1–3 liver fibrosis, efruxifermin reduced liver fat content,
Tropifexor, another highly potent non-bile acid FXR improved liver function tests, and fibrosis and inflammation
agonist, is being tested in a phase 2 clinical trial (FLIGHT markers (including NAS score). Fibrosis stage improvement
FXR, NCT02855164) in patients with stage 1–3 fibrosis of at least 1 point was observed in almost half of the patients
due to NASH. In a preliminary analysis, treatment with and NASH resolution in almost one third. Safety profile was
tropifexor lead to a significant reduction of hepatic fat, liver favorable [59].
transaminases, and body weight compared to placebo with
a favorable safety profile. Complete results are expected to
be released in the next few months [53]. THR beta agonists
Cilofexor is another nonsteroidal FXR agonist that
showed efficacy in decreasing liver steatosis a phase 2 THR-β is involved in the regulation of lipid metabolism,
trial [54]. The preliminary results of a phase 2 trial testing plays a role in insulin sensitivity, and promotes liver
cilofexor in combination with firsocostat (an acetyl-CoA car- regeneration and reduces hepatocyte apoptosis in the liver.
boxylase inhibitor) and semaglutide suggest a synergistic In a phase 2 trial in patients with NASH and fibrosis, the
activity of this combination in improving liver steatosis and THR-β agonist resmetirom decreased liver fat content and
liver biochemistry [55]. improved lipid metabolism parameters and liver function
EDP305 is another FXR agonist. A phase 2 randomized, tests, with a positive impact on lipid profile and fibrosis
double-blind, placebo-controlled, dose-ranging trial markers, with no significant effect on body weight [60]. A
(ARGON-1) has shown that when administered to non-cir- phase 3 study on patients with non-invasive diagnosis of
rhotic biopsy-proven NASH patients, a 12-week course of NAFLD showed that 100 mg of resmetiron administered
EDP305 reduced liver fat content and decreased ALT [56]. daily for 52 weeks improved liver fat content in approxi-
The most frequent adverse event was pruritus and changes mately 50% of treated patients vs 8% of placebo-treated
in lipid parameters were milder than with first-in-clasee patients; liver fibrosis in approximately 20% of treated
FXR agonists. ARGON-2 is a phase 2b study testing the patients vs. 10% of placebo-treated patients (both meas-
efficacy of EDP305 in NASH patients with stage 2–3 fibrosis ured by a non-invasive test). Lipid metabolism param-
(NCT04378010). eters, liver enzymes, and inflammatory biomarkers also
Finally, TERN-101 is a nonsteroidal FXR agonist with improved compared to placebo [61]. There were no major
enhanced liver distribution. In a preliminary analysis of a safety concerns. Main adverse events were gastrointestinal
phase 2 trial (LIFT study) in patients with stage 1–3 liver (diarrhea, nausea). A phase 3 study in NASH patients with
fibrosis, a 12-week course of TERN-101 rapidly decreased fibrosis is still ongoing and data will be available soon
ALT and GGT and seemed to have positive effect on (MAESTRO-NASH, NCT03900429).

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876 P. Sangro et al.

A liver-directed THR-β agonist, VK2809, improved in patients with stage 3 fibrosis; and STELLAR-4, in
liver fat content compared to placebo among patients with patients with compensated cirrhosis) [66].
NAFLD treated with two different doses in a preliminary
analysis of a phase 2 trial [62]. No serious adverse events Other metabolic treatments
were reported.
Molecules involved in other metabolic pathways are at dif-
ferent stage of clinical development for the treatment of
Anti‑fibrotic and anti‑inflammatory agents NASH.
Stearoyl-coenzyme A desaturase-1 (SCD-1) is consid-
Currently, many agents with anti-fibrotic and anti-inflam- ered a mediator of liver steatosis and fibrosis because of its
matory effects are being tested in NASH. Most of them are role in fatty acid biosynthesis [67] [68]. Aramchol is an oral
still in early stage of clinical development: in phase 1 (as SCD1 modulator which showed an ability to reduce liver
for example GB1211 targeting galectin 3, DFV890 target- fat and improve NASH and fibrosis with favorable tolerance
ing NLPR-3, or nimacimab targeting CB1) and phase 2 (as among patients with overweight or obesity and prediabetes
for example tipelukast, a leucotrien, or nitazoxanide, an in a phase 2b trial (ARREST) [69]. An ongoing phase 3 trial
antiparasitic agent). The description of all of them exceeds (ARMOR study, NCT04104321) in patients with advanced
the objective of this review. fibrosis and NASH aims to evaluate the efficacy of aramchol
The available information from molecules in later vs. placebo on NASH resolution, fibrosis improvement, and
stages of clinical development is summarized below. clinical outcomes related with NASH progression.
Cenicriviroc (CVC) is an orally administered, small Icosabutate is a synthetic omega 3 fatty acid (a structur-
molecule antagonist that blocks chemokine 2 and 5 recep- ally engineered eicosapentaenoic acid that resist oxidation
tors, both with well-known roles in liver inflammation and does not accumulate in hepatocytes) that could confer
and fibrosis. In a phase 2b trial (CENTAUR), the primary beneficial effects on hepatic oxidative stress, inflammation,
objective of histological improvement in NASH was not and fibrosis. A phase 2b study is evaluating the efficacy of
met although CVC improved measurable liver fibrosis different doses of icosabutate on the resolution of NASH
without worsening NASH [59]. A phase 3 trial (AURORA, without worsening of fibrosis. The primary endpoint is
NCT03028740) was prematurely stopped when an interim to evaluate the percentage of patients with resolution of
analysis casted doubts on the efficacy of the drug. Prelimi- NASH defined as disappearance of ballooning with lobular
nary results of a phase 2b trial (TANDEM, NCT03517540) inflammation without worsening in fibrosis (ICONA study,
showed that the combination of tropifexor with CVC was NCT04052516).
safe and able to reduce body weight and ALT in patients MSDC-0602 K is a thiazolidine-dione designed to
with biopsy-proven NASH with fibrosis. However, the modulate the mitochondrial pyruvate carrier (MPC), a pro-
combination was not superior to either drug in monother- tein complex that regulates the entry of pyruvate into the
apy in terms of histological endpoints [63]. mitochondria. A phase 2b placebo-controlled randomized
Belapectin is a complex carbohydrate that targets trial (EMMINENCE) failed to show improved histological
galectin-3, a B-galactoside-binding lectin that plays a outcomes (≥ 2-point NAS improvement without worsening
role in inflammatory response and fibrosis [64]. A phase fibrosis, NASH resolution, and fibrosis reduction) among
2b clinical trial (NASH-CX, NCT02462967) showed that patients with biopsy-proven NASH and stage 1–3 fibrosis
belapectin has not any significant effect on inflammation [70]. A dose-dependent improvement in the glycemic control
and fibrosis compared to placebo. However, it produced and liver enzymes were nevertheless observed.
a significant decrease of the hepatic venous pressure gra- A novel, deuterium-stabilized R-pioglitazone, PXL065,
dient in patients with NASH-related cirrhosis without that lacks PPAR-gamma activity but exerts its non-genomic
esophageal varices [65]. A phase 2b/3 trial (NAVIGATE, target activities (mitochondrial pyruvate carrier and acyl-
NCT04365868) is assessing the proportion of NASH CoA synthetase 4 inhibition) has been tested in a phase 2
patients with compensated cirrhosis who develop new trial in non-cirrhotic patients with NASH (NCT04321343).
esophageal varices after an 18-month course of belapectin According to the preliminary results reported at AASLD 2022
compared to placebo, as well as the incidence of long-term meeting, this drug can reduce the liver fat content in 40% of
clinically significant cirrhosis-related events. patients and improve at least 1 fibrosis stage in 30–50% of
Selonsertib is an oral inhibitor of the apoptosis sig- treated patients. In this trial, up to 30% of patients showed
nal–regulating kinase-1 (ASK1). Although well tolerated, NASH resolution after 36 weeks of treatment with a good
it failed to show improvement in fibrosis without worsen- safety profile since it lacks the PPAR-gamma side effects of
ing of NASH in two different phase 3 trials (STELLAR-3, glitazones [71]. The phase 3 trial has not started yet.

13
Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances… 877

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