REVIEW

Pharmacological Treatment for Non-alcoholic FattyLiver Disease

Sven Francque . Luisa Vonghia

Received: July 4, 2018 / Published online: March 19, 2019� The Author(s) 2019

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) hasbecome the most frequently encounteredchronic liver disease. NAFLD is associated withincreased liver-related morbidity and mortality,but also contributes to cardiovascular disease,diabetes and non-liver-related malignancy.Non-alcoholic steatohepatitis (NASH) is con-sidered the more severe subtype of NAFLD thatdrives most of these adverse outcomes. Lifestylemodification and associated weight loss canimprove NASH but are not always sufficient andsustained results are difficult to obtain. There ishence an urgent need for pharmacologicaltreatment. In this review we discuss some of theconcepts and challenges in the development ofpharmacological treatment. We also brieflysummarise what can be achieved with some ofthe drugs that are currently available for otherindications but have demonstrated benefit in

the treatment of NASH. Finally we present anoverview of some of the main drugs or types ofdrugs, mainly based on their mode of action,that are now being developed specifically totreat NASH and that might soon result in theavailability of drugs licensed for NASH.

Keywords: Cardiovascular disease; Clinicaltrials; Diabetes; Endpoints; Hepatology; Non-alcoholic steatohepatitis; Pharmacologicaltreatment

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) isdefined as the presence of vesicles of fat (mainlytriglycerides) in the hepatocytes in the absenceof classic causes of steatosis, with alcohol beingone of the most frequent of these causes [1]. Thelatter explains the name that was given to thisdisease, but other causes, such as the use ofsteatogenic drugs or viral hepatitis (steatosis hasparticularly been associated with genotype 3),also need to be excluded to make a diagnosis ofNAFLD. This type of steatosis also needs to bedistinguished from microvesicular steatosis thatis seen in acute fatty liver of pregnancy or inReye’s syndrome, where fat accumulation ismostly micellar and in an acute setting. NAFLDis closely related to overweight, disturbances ofglucose homeostasis and metabolic syndrome

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.7667744.

S. Francque (&) � L. VonghiaDepartment of Gastroenterology and Hepatology,Antwerp University Hospital, Antwerp, Belgiume-mail: sven.francque@uza.be

S. Francque � L. VonghiaLaboratory of Experimental Medicine andPaediatrics, University of Antwerp, Antwerp,Belgium

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https://doi.org/10.1007/s12325-019-00898-6

(although it can also be present in patients thatdo not exhibit features of metabolic syndrome,often referred to as ‘‘lean NASH’’) [2, 3]. Thecurrent definition tends to reduce NAFLD to adiagnosis of exclusion, but it is important torealise that NAFLD can co-exist with otherchronic liver diseases, which often results insynergistic effects in terms of disease progres-sion. An overweight patient with diabetes whoalso regularly drinks alcohol and presents withsteatosis should not simply receive the diagno-sis of alcoholic liver disease, but the potentialrole of both alcohol and the metabolic factorscausing NAFLD should be taken into account.When it comes to clinical trials and pharmaco-logical therapy for NAFLD, however, the exclu-sion of other causes of steatosis before puttingforward the diagnosis of NAFLD remains animportant issue [4].

NAFLD encompasses a whole spectrum ofliver disease. Steatosis can be the only lesiondefining non-alcoholic fatty liver (NAFL).Steatosis can, however, be accompanied bychronic low-grade inflammation and features ofhepatocellular damage [1]. When lobularinflammation and ballooning of hepatocytes(rounding and enlargement of hepatocytes, notbecause of fat accumulation but because ofdegeneration of the cytoskeleton that isresponsible for the classic rectangular shape ofhepatocytes) are both present, the diagnosis ofnon-alcoholic steatohepatitis (NASH) can beestablished [1, 5–7]. Various degrees of liverfibrosis, up to cirrhosis, can be present (butfibrosis is not part of the definition of NASH).Fibrosis can be present without the presence ofsteatohepatitis at the biopsy, an entity calledsteatofibrosis [8]. The exact clinical significanceof this entity remains to be determined. Fur-thermore, patients may exhibit histologicallesions besides steatosis, but without meetingthe formal criteria for the diagnosis of NASH.These borderline cases potentially have a dif-ferent outcome compared to those with steato-sis as the only lesion, but are currently classifiedwithin the NAFL group. NAFLD-related cirrhosiscan lead to the classic complications of cirrho-sis, including the development of a hepatocel-lular carcinoma (HCC). HCC can also developon the background of a non-cirrhotic and even

non-fibrotic NAFLD, but the exact magnitude ofthis risk is currently unknown.

It is clear from these definitions (which is ofgreat relevance when it comes to pharmaco-logical treatment of NAFLD) that histology andhence the liver biopsy are the cornerstone ofour current understanding of the disease.

In the present review, we will address severalquestions relevant to the pharmacologicaltreatment of NASH and give a short overview ofwhat is currently available and what is in thepipeline for the near future.

METHODOLOGY

A literature search using the PubMed and Webof Science database was performed. Articleswere ranked according to their relevance. First,we performed a MeSH search using the follow-ing MeSH terms: ‘‘NonAlcoholic Steatohepati-tis’’[MeSH] OR ‘‘Non-alcoholic Fatty LiverDisease’’[MeSH]) AND ‘‘Therapy’’[MeSH]; ‘‘Non-alcoholic Fatty Liver Disease’’[MeSH] AND‘‘Pathophysiology’’[Subheading] AND ‘‘Drug’’;‘‘Pharmacological therapy’’[MeSH] AND ‘‘Non-alcoholic Fatty Liver Disease’’[MeSH]. Thereafterthe abstracts were screened. Books of abstractsfrom annual meetings of the European Associ-ation for the Study of the Liver (EASL) and theAmerican Association for the Study of LiverDiseases were also screened for the years2015–2018 (NAFLD sections). Finally, theauthors used a personal archive of papers.Clinical trials were further identified by con-sulting ClinicalTrials.gov (latest search on 3December 2018).

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

WHAT ARE THE CONSEQUENCESOF NAFLD THAT COULDPOTENTIALLY BE PREVENTED?

As outlined before, NAFLD can be associatedwith progressive fibrosis and hence result inliver cirrhosis with decompensation and/or the

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development of HCC. The natural history ofNAFLD is still largely unknown. Estimates onNAFLD prevalence, mainly based on non-inva-sive tests such as liver enzymes or ultrasound,tend to show a 25–30% prevalence in the Wes-tern adult population, with higher prevalencein populations with risk factors such as obesityor diabetes [9].

As a biopsy is required for accurate diagnosisof NASH, data on large populations using non-invasive tools cannot accurately distinguishbetween NASH and NAFL, and series of biopsy-proven cases are smaller and tend to be enri-ched with more severe cases by obvious selec-tion bias. This hampers the quality of the dataon prevalence of NAFLD and its subtypes andon their natural history.

A basic concept, looking at NAFLD from anexclusively liver perspective, is that isolatedsteatosis without any sign of inflammation orhepatocellular damage is considered harmlessand probably needs to be considered as anadaptive mechanism to a calorie overload thatis insufficiently buffered by the adipose tissue.When there is inflammation and hepatocellulardamage, the activation of several pathwayspotentially leads to extracellular matrix depo-sition and fibrogenesis. These events will becounterbalanced by fibrinolytic and repairmechanisms, but when there is an imbalance,progressive fibrosis can develop [10]. HenceNASH is considered the more severe form of thedisease, with a risk of progression towardsadvanced fibrosis and cirrhosis. To complete thepicture, the occurrence of HCC outside thesetting of cirrhosis, as mentioned before, shouldalso be taken into account, but the magnitudeof this problem is unknown and specific riskfactors are ill defined.

Interestingly, the dogma that isolatedsteatosis is (almost) harmless and NASH is theculprit has recently been challenged by pairedbiopsy studies showing that patients with iso-lated steatosis also exhibit progressive fibrosis[11]. Furthermore, recent data also identifiedthe degree of fibrosis as the most importantpredictor of not only liver-related but alsooverall mortality, regardless of the presence ofNASH, overruling previous data showing thatNASH patients had a worse outcome compared

to patients with isolated steatosis [12]. Thefibrosis progression rate in NAFL is, however,only half that compared to NASH. Of note, iflooking into the details of the data, most of thepatients in the paired biopsy cohorts who pro-gressed had some degree of inflammation orballooning and/or portal inflammation atbaseline and almost all had some degree ofNASH on the follow-up biopsy [13]. Further-more, several reports show a very significantcorrelation between disease activity and degreeof fibrosis.

Several factors might explain some of thesefindings. First, the dichotomy of NAFL/NASHdoes not capture the borderline cases that havein addition to steatosis some abnormalities (e.g.some ballooning or little lobular inflammationor portal inflammation), not enough to qualifyfor the diagnosis of NASH according to thecurrent definition, but also not qualifying forthe concept of isolated steatosis. Second, thehistological criteria for NASH diagnosis poten-tially do not capture subtle changes in necro-inflammatory cascades that need more granularand sophisticated techniques to be picked upand hence currently remain unrecognised.Third, in a liver biopsy, which is just a snapshot(to some extent comparable to a blood glucoselevel in a diabetic patient), we tend to look atactivity and fibrosis in the same way. Theactivity component of the disease is, however,probably highly dynamic (influenced by diet,exercise, small fluctuations in weight). By con-trast, the fibrosis component (although also notstatic) probably reflects the activity of the dis-ease over a longer period preceding the biopsy,just as the HbA1c reflects glycaemic controlover a longer period. Consequently, activity canshow fluctuations between certain levels,whereas fibrosis, by the way we assess anddefine it, can continue to increase along abroader spectrum. The time point at which thebiopsy is taken can hence show quite differentpictures in terms of activity whereas the fibrosisshows a more stable picture that is potentiallyprogressive over time [14].

The fluctuating nature of NASH and itsdichotomous character as a parameter (NASHvs. no-NASH) compared to the more stable andpotentially progressive nature of fibrosis along a

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broader scale (0–4) might explain why statisti-cally fibrosis comes out as the most importantpredictor of outcome, whereas the snapshotassessment of disease activity does not. Fromthere to the conclusion that fibrosis and notdisease activity is what we have to look for andwhat we have to treat seems, at least in ouropinion, erroneous. We should consider thepossibility, if we assume that disease activity isthe driving force of adverse outcomes, that thecurrent definitions of disease activity and/or thetools to assess it are largely imperfect.

Besides the liver-centred approach, evidenceis accumulating that NAFLD, beyond the sharedrisk factors, independently contributes to thedevelopment of cardiovascular disease (CVD),chronic kidney disease, diabetes (if not presentupfront) and non-liver related or extrahepaticmalignancy [15–18]. CVD and non-liver malig-nancies constitute the most frequent causes ofdeath in patients with NAFLD but the incre-mental risk attributable to NAFLD, on top of theclassic risk factors, is difficult to decipher.Although fibrosis comes out as the mostimportant predictor of long-term liver and non-liver-related outcomes, NASH patients seem tobe more at risk than patients with NAFL [15].Importantly, the impaired prognosis is notrestricted to patients with cirrhosis or advanced(i.e. fibrosis stage 3 on a 0–4 scale, F3) fibrosis,but clearly starts to decrease from stage F2onwards (so-called significant fibrosis) (thefibrosis grades are based on the NASH CRN andFLIP/SAF system ranging from 0 to 4 and not tobe confused with the Metavir scoring system forviral hepatitis, which also ranges from 0 to 4 butwith different definitions for the stages, as thefibrosis pattern differs) [12].

This all leads to the current concept thatfibrosis is the most important predictor of bothliver- and non-liver-related adverse outcomeswith NASH as the driving force of these out-comes (and hence fibrosis as a marker or read-out of long-standing active disease with animbalance between damaging and repairmechanisms). This implies that, althoughregression of fat might be an endpoint in earlydevelopment of drugs, the target of pharmaco-logical treatment is NASH and/or fibrosis [19].Although patients with NAFLD suffer from

fatigue and impaired quality of life [20], with todate a paucity of data on the exact relation todisease severity, this is currently not consideredan indication or target for pharmacologicaltreatment. Data on the last aspects are, how-ever, captured in most of the clinical trials,which might allow for a better understanding ofthese aspects and for a change in the conceptsin the future.

A final consideration is that this approach isalso based on the assumption that if we improveNASH and/or fibrosis we will positively influ-ence the long-term outcomes of the disease.Although plausible, this has to date not beenproven. It is well known that, although diabetescontrol lowers the risk of diabetes-related com-plications, even well-controlled patients maydevelop significant consequences of their dis-ease. Some studies on the impact of glycaemiccontrol on long-term outcome failed to show areduction in CV mortality despite good gly-caemic control. This has been attributed to theso-called metabolic memory, denoting the per-sistence of endothelial dysfunction despite cor-rection of glycaemia [21]. Only patients withshort duration of diabetes mellitus, low baselineHbA1c and no history of a CVD event benefitted(in terms of improved survival) from good gly-caemic control, suggesting that early interven-tion is needed to improve survival and oncevascular damage is well established, improvedmetabolic control hardly impacts on long-termsurvival. For all these reasons, histologicalimprovement in NAFLD lesions is, until furtherdata become available, not a validated (only a‘‘reasonably likely’’) surrogate for clinicallymeaningful benefit.

ANTI-NASH VS. ANTI-FIBROSIS: THE(NON-)DEBATE

As outlined previously, progressive fibrosis ismainly responsible for the liver-related conse-quences of the disease in terms of cirrhosis andits complications. Furthermore, fibrosis hasbeen identified as the most important predictorof overall and liver-related mortality (with adecline in prognosis from F2 onwards) [12]. Thishas led to the concept of an anti-fibrotic

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strategy to treat NAFLD in an attempt to pre-vent these fibrosis-related outcomes.

Fibrosis is, however, not a stand-alone pro-cess, but the result of the activation of severalcomplex pathways, including pathways thatcounteract the damage and try to repair thetissue [10, 14]. Hence, NASH is what drives thedisease. In this context, we use NASH not in thesense of its strict histological definition but asthe entity that denotes the activation ofinflammatory cascades and hepatocyte suffer-ing in relation to the (mainly metabolic) factorsthat also lead to steatosis. Steatosis is not per sedriving the inflammation by lipotoxicity orother mechanisms but can also be an associated,concomitant feature without a strict causal role,hence a marker of metabolic overload orimpairment. Locally NASH can result in pro-gressive fibrosis if damage and repair are notbalanced; and extra-hepatically it potentiallycontributes to several deleterious processes(endothelial dysfunction and others) via com-plex mechanisms, including the release ofnumerous mediators by the chronicallyinflamed and metabolically deranged liver [22].

Besides the aforementioned arguments, therole of NASH is further substantiated by theanalysis of clinical trial data showing thatpatients that experience an improvement inNASH are also those that have an improvementin fibrosis, whereas those whose NASH worsensare also more prone to fibrosis progression [23].Although selonsertib showed fibrosis regressionwithout an impact on NASH, at first sightchallenging the role of NASH because of thisapparent disconnect, improvement in NAFLDActivity Score (NAS) was amongst the strongestpredictors of fibrosis improvement [24].

Hence fibrosis progression is closely linked toNASH and, especially when it comes to theimpact on overall mortality, is probably to beconsidered a marker of long-standing diseaseactivity and damage–repair imbalance ratherthan it being the fibrosis per se that drives theadverse outcomes.

The pathophysiology of NAFLD/NASH iscomplex and incompletely understood. It isbeyond the scope of this review and we refer thereader to excellent extensive reviews for furtherreading [10, 25, 26]. It is, however, important to

emphasise its extremely complex nature. Incontrast to alcohol or viral hepatitis, there is noclearly identifiable external agent (besides per-haps calorie overload and some specifics in foodcomposition) that causes the disease. It is on thecontrary an intrinsic disease, driven mainly bymetabolic derangements and with a very com-plex and multidirectional interplay betweenseveral other body sites, such as the (severaltypes of) adipose tissue, the gut, the gutmicrobiome or the CV system (Fig. 1). If wefocus on the liver, numerous pathways areinvolved in the several liver cell types (hepato-cytes, stellate cells, Kupffer cells, infiltratingmonocytes/macrophages and other inflamma-tory cell types, endothelial cells etc.) (Fig. 1).Not only does this imply that potential thera-peutic targets are numerous, it also implies that,up to a certain level, the separation of inflam-mation-related pathways and fibrosis-relatedpathways is artificial. Many drugs that targetmetabolic pathways or inflammatory pathways(hence anti-NASH drugs) not only indirectly (byreducing mediators or mechanisms that pro-mote fibrogenesis downstream) but in manycases also directly interfere with fibrogenesis.The direct role of nuclear receptors like peroxi-some proliferator-activated receptor (PPAR) orfarnesoid receptor X (FXR) in fibrogenesisillustrate this complexity [27, 28].

It is obvious that the more downstream inthe process of fibrogenesis a drug interferes, themore purely anti-fibrotic its strategy will be.Simtuzumab, a lysyl oxidase homolog 2 (LOX-L2) antibody interfering with collagen cross-linking, is an example of this approach. It,however, failed to show clinical efficacy[24, 29]. The reasons for this failure can beseveral, including insufficient suppression ofLOX-L2, but a plausible one is that a pure anti-fibrotic strategy (which means with a target veryclose to the final steps of fibrosis) is far toodownstream to be efficient if the upstreamdriving force is left untouched. Interestingly,cenicriviroc, a C–C motif chemokine receptor(CCR) 2 and 5 dual antagonist mainly influ-encing macrophage recruitment and activationand hence having an anti-inflammatory profile,appeared to have anti-fibrotic properties despitethe absence of a clear effect on steatohepatitis

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Fig. 1 Current therapeutic targets in the complex patho-physiology of NASH. NASH is the result of a complexinterplay of metabolic, inflammatory and fibrogenic pro-cesses. Within the liver, hepatocytes and several of itsintracellular organelles, most notably mitochondria, playan important role, alongside the stellate cells and severalresident and infiltrating immune cells of different popu-lations. NASH furthermore results from and impacts onan important crosstalk between the liver, the adipose tissue,the gut (including the gut microbiome) and the muscle.The cardiovascular system is even so implicated (notdepicted, see ref. [22]). Numerous mediators are involved.Drugs that have been tested in NASH or that are underdevelopment have differential targets inside and outsidethe liver to ultimately result in an improvement of the

steatohepatitis and/or fibrosis. DNL de novo lipogenesis,FAS fatty acid synthase, FGF19 fibroblast growth factor 1,FGF21 fibroblast growth factor 21, GLP-1 glucagon-likepeptide 1, IFN interferon gamma, IL1-b interleukin 1beta, IL-6 interleukin 6, IL-17 interleukin 17, LD lipiddroplets, LPS lipopolysaccharide, MCP-1 monocytechemoattractant protein 1, NEFA non-esterified fattyacids, NKT cell natural killer T cell, OCA obeticholic acid,ROS reactive oxygen species, Th17 T helper 17 cell, TGFbtumour growth factor beta, TNF tumour necrosis factoralpha, VLDL very low density lipoproteins. Reproducedwith permission from the Annual Review of Physiology,Volume 78 � 2016 by Annual Reviews, http://www.annualreviews.org [10] (courtesy of J. Haas)

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(albeit with a reduction in systemic inflamma-tory markers). This again illustrates the complexentanglement of inflammation and fibrosis andthe difficulties with the ‘‘anti-NASH’’ or ‘‘anti-fibrosis’’ concept [30]. Finally, although haltingfibrosis progression or reversing fibrosis willmost likely reduce the liver-related outcomesand are hence potentially beneficial in a purelyliver-centred view, their impact on the pre-sumed systemic consequences of the disease(which are substantially larger in terms ofevents to prevent) might be limited if theyhave little or no impact on NASH. This mightreduce their target population to those witha high risk of evolving towards cirrhosis orwith already established cirrhosis to preventdecompensation.

In conclusion, many targets for pharmaco-logical treatment potentially have an effect onboth necro-inflammatory and also directly orindirectly on fibrogenic mechanisms, makingthe concepts of anti-fibrotic or anti-inflamma-tory or anti-metabolic drugs somewhat artificialand irrelevant in many cases. A more purelyanti-fibrotic approach implies targeting down-stream mechanisms and might be difficult if thedriving force of NASH persists and might, ifefficient, have a more restricted target popula-tion who could potentially benefit.

COMPLEXITYOF THE PATHOPHYSIOLOGY:CONSEQUENCES

As numerous and sometimes closely entangledpathways are involved, the fact that a certainstep in a particular pathway has been shown toimpact on disease pathophysiology does notnecessarily mean that targeting this step willresult in benefit. First, several escape routes areusually present to circumvent a specific block-ade or stimulation, neutralising the effect. Thestep that is targeted should be crucial enough orrate-limiting and the agonism or antagonismpowerful enough to have a net impact. Second,although a specific step might be altered andhave an impact on disease occurrence, thismight not be enough to cause disease regres-sion; so, an impact on a combination of several

pathways might be required to induce cure.Consequently, targeting only one of thesepathways might be insufficient to restore thetissue. Furthermore, the mechanism or thecombination of mechanisms that explain theoccurrence and severity of the disease are pre-sumably not identical in all patients. We knowthat the patient population is heterogeneous,probably reflecting this potential heterogeneityin underlying pathophysiological mechanisms.Whether this is a continuous spectrum orwhether different subtypes exist is currentlyunknown, and we currently do not have toolsto identify and classify patients on thesegrounds [31]. Nevertheless, these factors mightexplain the non-responders in the trials con-ducted so far. They also provide the rationale forcombined treatments. Furthermore, theystrengthen the need to develop tools to identifythe mechanisms at play in a given patient, sothat response or non-response can be predictedand a patient-tailored or personalised treatmentcan be proposed [32]. For the time being, how-ever, no tools exist to guide pharmacologicaltreatment in this respect.

WHICH PATIENTS QUALIFYFOR PHARMACOLOGICALTREATMENT?

Lifestyle modification, if it results in sustainedweight loss, can improve the histological lesionsof NASH [33]. Sufficient and sustained weightloss is, however, not obtainable in all patientsfor several reasons, including importantosteoarticular problems limiting the possibilityto increase the level of physical activity (whichis, in conjunction with caloric restriction, cru-cial to achieve and maintain a substantialreduction in fat mass). Furthermore, even dia-betic patients who are well treated for a longtime with optimal metabolic control still mayexhibit features of NASH. Genetic factors mightinfluence not only the risk of having NASH andprogressive fibrosis but also the responsivenessto weight loss and lifestyle modifications [34].This might help explain why even lifestylemodification, if successful, does not alwaysresult in the desired endpoints. Hence for many

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patients, pharmacological treatment will berequired.

Indications and goals for pharmacologicaltreatment can be debated. As outlined before,fibrosis is the best predictor of prognosis, with aclear decline from F2 onwards, and NASH is tobe considered the driving force of the disease.Hence, in our current understanding, pharma-cological therapy should be restricted topatients who have NASH and some degree offibrosis. Generally, a steatohepatitis with a NASof 4 of higher (there is currently no equivalentdefinition based on the Steatosis ActivityFibrosis (SAF) scoring system, but A C 3 couldbe proposed) with a fibrosis of F2 onwards isconsidered an indication for pharmacologicaltreatment [4, 19]. F1 patients with a NAS of atleast 5 and/or severe (mostly metabolic) co-morbidities (persistently elevated ALT, diabetes,metabolic syndrome) should, however, also beconsidered as they have a high risk of fibrosisprogression. As a biopsy is still needed to accu-rately diagnose these different aspects of thedisease, a liver biopsy is currently consideredmandatory before initiating a pharmacologicaltherapy specifically for NASH [6, 7, 35]. Excep-tions can be made for some of the early phaseproof-of-concept clinical trials that try to pickup a signal of efficacy of a drug based on non-invasive parameters, but in general a pharma-cological treatment for NAFLD should not bestarted without a liver biopsy showing theaforementioned criteria. As non-invasive bio-marker research progresses, this principle islikely to change in the near future.

WHAT ARE THE GOALSOF THERAPY?

In terms of the goals to achieve, several possi-bilities can be considered. Most of the defini-tions of endpoints in clinical trials, which canserve as a basis for routine clinical practice,focus on the resolution of NASH (which isdefined as the specific prerequisite of a completedisappearance of ballooning) and/or regressionof fibrosis, but stable disease and hence haltingprogression might also be a valuable target [36].The goals mentioned are currently the outcome

measures approved by the regulatory authoritiesas acceptable surrogate markers that ‘‘reason-ably likely’’ predict clinically meaningful benefitin the long run and that can serve as the basisfor conditional approval of drugs in phase 3.Besides these endpoints, reduction in activity ofthe steatohepatitis or other criteria of improve-ment might also be considered beneficial, aswell as stabilising the disease and halting dis-ease progression.

Furthermore, the impact of drugs on thecardiometabolic co-morbidities is also animportant aspect, both in terms of safety andefficacy. As CVD is the most important cause ofdeath in these patients who already frequentlyaccumulate several CV risk factors, these drugs,which probably need to be taken for a longtime, need to be safe from a CV point of view.Impacts on lipid profile, glycaemic control,body weight, blood pressure, renal function andother related parameters need to be carefullyassessed and negative effects might hamperlong-term applicability if a certain potentiallynegative side effect cannot be properly man-aged. On the other hand, a drug that not onlyimproves NASH and/or fibrosis but also reducesbody weight, improves lipid profile, improvesglycaemic control or results in any other car-diometabolic improvement might represent asubstantial additional benefit that influences itsposition within the future therapeuticlandscape.

CURRENTLY AVAILABLEPHARMACOLOGICAL TREATMENTOPTIONS

Several drugs that are not specifically licensedfor the treatment of NASH but with a potentialbenefit based on their mode of action have beentested.

Ursodeoxycholic acid (UDCA), a bile acidthat has hepatoprotective effects and showedbenefit in cholestatic disease, improved livertests and some histological features, mainlyinflammation, but failed to show histologicalbenefit in two long-term trials [37] and hence isnot recommended.

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Drugs that impact on insulin sensitivity andglycaemic control have for obvious reasonsattracted some attention as they are of potentialbenefit in NASH.

Metformin improves insulin resistance, a keypathophysiological mechanism in NASH, butfailed to show histological benefit [37]; hence,despite data suggesting that metforminimproves the risk of cancer (including HCC)[38], it should not be used with the intent totreat NASH but only if there is an approvedindication.

Dipeptidyl peptidase 4 (DPP4) rapidlydegrades incretins like glucagon-like peptide(GLP)-1, which plays an important role in gly-caemic control, and hence DPP4 inhibitors,which are used in the treatment of diabetes,have also been tested. A recently publishedsmall trial with sitagliptin was negative butfurther studies are awaited [39].

Sodium/glucose co-transporter 2 (SGLT2)inhibitors or gliflozins that inhibit glucosereabsorption from the urinary ultrafiltrateeffectively improve glycaemic control andhence are licensed for the treatment of diabetes.Preclinical data suggest benefit in NASH. Asmall trial of 50 patients with type 2 diabetesrandomised to empagliflozin vs. placebo on topof their treatment showed significant reductionin liver fat content and liver enzymes, but noresults of randomised controlled trials (RCTs)including histological endpoints have beenpublished so far, so their clinical utility in NASHhas not yet been established [40].

GLP-1 analogues or incretin mimeticsimprove glycaemic control and reduce weight.They have been approved for the treatment oftype 2 diabetes and several molecules for thatindication are available on the market. In 2015liraglutide in a dose up to 3 mg QD was alsoapproved for the treatment of obesity [41].Liraglutide, used on top of a hypocaloric dietand increased physical activity, has been shownto reduce body weight by more than 5% in 63%of treated individuals after 1 year [42]. Liraglu-tide (at a dose of 1.8 mg QD) has been reportedto beneficially affect liver histology in a smallRCT with 23 patients in each arm [43]. Theinduced weight loss is likely one of the maindrivers of the histological benefit, although

other hormonal effects also might contribute tothe overall effect on liver histology. Side effectsinclude nausea and diarrhoea. Until furtherdata become available (several other GLP-1analogues are currently being studied, includingsemaglutide), its use should be restricted to theapproved indications, with the only extensionbeing that we propose to add NASH to this listof co-morbidities of obesity that justify phar-macological treatment of obesity.

Thiazolidinediones or glitazones are agonistsof PPAR, a nuclear receptor that has a key role inglucose and lipid homeostasis, but also impactson inflammation and fibrogenesis [27]. PPAR isexpressed in adipose tissue and to a certainextent in other cell types, including non-acti-vated stellate cells (PPAR expression decreasesupon activation), whereas it is poorly expressedin hepatocytes. Glitazones have been approvedfor the treatment of diabetes but were alsoshown to be effective in improving histologicallesions of NASH in several trials [37, 44, 45]. Theimprovement in liver histology is probably dri-ven by both extrahepatic effects that subse-quently benefit the liver (especiallyimprovement in adipose tissue dysfunction)and by direct intrahepatic effects. The safetyprofile is not alike for all molecules and someharbour safety concerns. There is some weightgain, but with a shift from visceral to subcuta-neous adipose tissue, implying that the weightgain is not deleterious from a medical point ofview. Pioglitazone clearly improved CV out-comes in diabetic patients and has a morefavourable safety profile [46], but is neverthelessnot frequently used. There are some concernsregarding the possibility of eliciting heart fail-ure in predisposed individuals, although, asmentioned, an overall significant CV benefithas been recently demonstrated [46, 47].

Also for lipid-lowering drugs there was agood rationale to explore their potential utilityin the treatment of NASH. Fibrates, which areagonists of the PPAR isoform that is mainlyexpressed in hepatocytes, were only tested insmall trials, showing no benefit, but probablymerit further study [37]. Ezetimibe, a choles-terol uptake inhibitor, showed no effect onimaging-assessed liver fat content [48]. The

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same holds true for the bile acid sequestrantcolesevelam [49].

Although statins might have pleiotropicbeneficial effects, they have not been testedproperly [37]. A few small open-label studiessuggested some histological improvement[50, 51]. They have also been shown to reducethe risk of HCC and to reduce the progressiontowards cirrhosis and decompensation of cir-rhosis [38, 52]. In preclinical models theyshowed a beneficial impact on fibrogenesis andangiogenesis and specifically impacted oninsulin resistance, endothelial function andportal pressure in an animal model of steatosis[53, 54]. Given the role of endothelial dysfunc-tion and increased intrahepatic resistance in theearly development of NASH, these findings holdpromise for statins as adjuvant drugs in NASHtreatment [55]. The potential for hepatic toxic-ity has withheld physicians from the use ofstatins in NAFLD patients with elevatedtransaminases, but recent studies have shownthat there is no increased risk of drug-inducedliver injury with statins in NAFLD patients[56, 57], so they should be used if there is anindication in the context of dyslipidaemiatreatment.

As highlighted above, these hypolipidaemicdrugs should be used to appropriately treatdyslipidaemias according to their properguidelines, but should not be prescribed for thesole indication of treating NAFLD until moredata become available. Omega-3 fatty acidsshowed some promise in initial trials, but morerecent trials did not show a clear benefit.Although probably not of harm, they shouldcurrently not be prescribed as a NASH treatment[6, 7, 35].

Vitamin E has also shown beneficial effectson liver histology in non-diabetic and non-cir-rhotic NASH patients, so its use can be recom-mended in this patient category [58]. Vitamin Eis hence not to be recommended in patients inwhom NASH was not histologically docu-mented and in diabetic or cirrhotic patients.Although a recent large meta-analysis did notconfirm earlier safety issues [59], the potentialfor increased prostate cancer in men is anunresolved issue of concern. The dose that

proved efficacy in the PIVENS trial is 800 IU/day[58].

For glitazones, vitamin E and liraglutide,evidence on efficacy has been demonstrated byhistology. There is, however, no clear guidanceon how to assess efficacy of treatment in routineclinical practice. Improvement in liver enzymeshas been shown to be in line with histologicalimprovement in several trials [23, 60], regard-less of baseline values, but there are no clearrules on how to interpret liver enzyme changesin individual patients. In a subanalysis of theFLINT trial (vide infra) a reduction in ALT of17 U/L was an independent predictor of histo-logical response (defined as a reduction in NASof 2 points), but this needs further validation.

There is hence currently no pharmacologicaltreatment that has NASH on its label. There is,however, a large pipeline of drugs that are beingtested, some of them already in phase 3. Thefirst to come on the market, if the registrationtrials are positive, will presumably do so by2020.

Meanwhile, patients with significant diseaseeligible for pharmacological treatment asdefined above can be offered treatment in thecontext of a clinical trial. Given the potentialbenefit for the patients, the possibility of par-ticipating in a clinical trial should systemati-cally be considered and offered to the patient,reinforcing also the recommendation to screenand adequately diagnose patients at risk.

DRUGS IN DEVELOPMENT

Numerous drugs are currently being tested forthe treatment of NASH. The development iscomplex, as different endpoints can be definedand a variety of targets proposed. When itcomes, however, to drug licensing, drugs haveto show a proven clinically meaningful benefit.What is currently accepted by the regulatoryauthorities is that efficacy must be proven onclinical endpoints that are mainly restricted tothe concept of NASH as a liver disease: devel-opment of cirrhosis or cirrhosis-related compli-cations (although all-cause mortality is alsoincluded) [61]. As these phase 3–4 trials will takea long time, drugs can be granted conditional

Adv Ther (2019) 36:1052–1074 1061

approval based on histological benefit, which isconsidered a reasonably likely surrogate for laterclinical outcomes, and which has been definedas resolution of NASH without worsening offibrosis or improvement in at least one stage offibrosis without worsening of NASH [61]. Thelast two endpoints are in line with the afore-mentioned dichotomous concept, tending todiscern two approaches: an anti-NASHapproach or an anti-fibrotic approach. As NASHdrives fibrosis, this dichotomy is in our opinionrather artificial and not very useful, althoughsome drugs might preferentially fall into one orother category.

A consequence of these regulatory consider-ations is that phase 3 trials rely on serial biop-sies. Also phase 2 trials that should provide datato justify progression to a phase 3 trial need ahistological proof of efficacy. Earlier phase 2trials can use other endpoints and other efficacyassessments besides biopsy. In the subsequentparagraphs we will briefly discuss most of theclasses of drugs currently under investigation.As a multitude of mechanisms are potentiallyinvolved and targeted by a long list of com-pounds in early development, an extensivereview of all potential targets is beyond thescope of this article. The most important path-ways are depicted in Fig. 1. An overview of themolecules currently in phase 2 (without or withhistological endpoints) and phase 3 trials isgiven in Tables 1, 2, 3 and 4.

PPAR Agonists

Three isoforms of PPAR exist [27]. PPAR ismainly expressed in hepatocytes but also inmany other cell types, including muscle cells.PPAR agonists like fibrates have not beenextensively studied, but the small studies per-formed failed to show a histological benefit [37].We demonstrated previously that PPAR expres-sion is inversely correlated to the severity ofNASH and that NASH improvement is associ-ated with increased PPAR expression, givingrationale to a PPAR-targeted treatment despitethe negative data with fibrates [62]. Elafibranoris a hepatotropic dual PPAR agonist, hence tar-geting not only PPAR but also PPAR that is

expressed in stellate cells and several other celltypes. In a large phase 2b trial including 276patients (GOLDEN), elafibranor was able toinduce resolution of NASH without worseningof fibrosis in significantly more patients com-pared to placebo if baseline NASH was suffi-ciently severe [23]. Fibrosis regression was alsonoted in those that responded to treatment,highlighting again the link between NASH andfibrosis. The drug had a very good safety profileand also improved serum lipids and glycaemiccontrol, reducing the calculated overall CV risk.Elafibranor is now in phase 3 and the first partof the cohort needed for the interim analysishas been fully recruited.

Several other PPAR drugs are in develop-ment, including lanifibranor (a pan-PPAR ago-nist potentially combining positive effects ofthe glitazones with PPAR agonism and currentlyin phase 2b) [63] as well as saroglitazar (a PPARdual agonist) and seladelpar (a PPAR agonist).

FXR Agonist

FXR plays in important role in bile acid meta-bolism but also impacts on several metabolic,inflammatory and fibrogenic pathways. FXR ispresent in the liver and the intestine, with somedifferences in effect according to the site [28].

Bile acids are the natural ligands of FXR.UDCA has no FXR agonistic effect, but the bileacid obeticholic acid (OCA) is a potent FXRagonist and resulted in a significant responsecompared to placebo as defined by a 2-pointreduction in NAS in the FLINT trial in 110treated vs. 109 placebo patients eligible forpaired biospies (there was also a beneficial effecton fibrosis, a secondary endpoint) [64]. Therewas a trend for resolution of NASH, which wasanother secondary endpoint. Because of thesignificant benefit in terms of the primaryendpoint, the study was stopped prematurelyand the drug went on to phase 3. Pruritus is aknown side effect of OCA, which is currentlyalready licensed for the treatment of primarybiliary cholangitis. Furthermore, OCA decreasedHDL cholesterol levels and did not improveglycaemic control. The first part of the cohortneeded for the interim analysis was fully

1062 Adv Ther (2019) 36:1052–1074

recruited by the end of 2017. Recently positiveresults on liver fibrosis have been reportedresulting from the interim analysis that shouldbe the basis of registrational approval in a pressrelease, but the full data have not been pre-sented so far.

Several other bile acid FXR agonists are beinginvestigated, nor-UDCA being the most

advanced (currently in phase 2) and promising.Furthermore, several non-bile acid FXR agonistare being developed. According to their differ-ential effects on intestinal or hepatic FXR andother pharmacokinetic and pharmacodynamicproperties, the net effects on the liver as well ason the metabolic parameters and their safetyand side effect profile should be waited for

Table 1 Phase 2 placebo-controlled trials with histology as a primary endpoint (Source: clinicaltrials.gov)

Drug Mode of action Mode ofadministration

Primary endpoint Treatmentperiod toprimaryendpoint

Remarks

Semaglutide GLP-1 Receptor

agonist

SC NASH resolution without

worsening of fibrosis

72 w

Lanifibranor

(IVA337)

PanPPAR PO C 2 points decrease from

baseline in activity score

(SAF)

24 w

MSDC

0602K

PPARc-

independent

(?) regulator of

mitochondrial

pyruvate entry

PO C 2 points decrease in

NAS without worsening

of fibrosis

12 w

Emricasan Pan-caspase

inhibitor

PO C 1 stage improvement in

fibrosis without

worsening of

steatohepatitis

72 w Also in phase 2 with

composite clinical

endpoint without

histology and trial in

cirrhotic patients with

effect on HVPG as

outcome measure

BMS-

986036

Pegylated FGF21

analogue

SC C 1 stage improvement in

fibrosis without

worsening of

steatohepatitis or

NASH improvement

without worsening of

fibrosis

24 w

SAR 425899 Dual GLP-1

receptor/

GCGR agonist

SC Resolution of NASH 52 w

FGF fibroblast growth factor, GCGR glucagon receptor, GLP-1 glucagon-like peptide, HVPG hepatic venous pressuregradient, NAS NAFLD activity score, NASH non-alcoholic steatohepatitis, PO per os, PPAR peroxisome proliferator-activated receptor, SAF steatosis-activity-fibrosis scoring system, SC subcutaneous

Adv Ther (2019) 36:1052–1074 1063

Table 2 Placebo-controlled trials with non-invasive primary endpoint (Source: clinicaltrials.gov)

Drug Mode of action Mode ofadministration

Primaryendpoint

Treatmentperiod toprimaryendpoint

Remarks

Aparenone

(MT-3995)

Non-steroidal

mineralocorticoid

receptor antagonist

PO ALT change 24 w

Tropifexor

(LNJ452)

Non-steroidal FXR

agonist

PO Change in

transaminase

levels

Change in liver

fat (MRI)

12 w

Seladelpar

(MBX-8025)

Selective PPARd

agonist

PO Relative change

in MRI-PDFF

12 w Study continues for 52

weeks including histology

as secondary outcome

measure

Namodenoson

(CF102)

A3 adenosin receptor

inhibitor

PO Mean % change

in ALT levels

12 w

LIK 066 Dual SGLT1/2

inhibitor

PO Change from

baseline ALT

12 w

BI 1467335 AOC3 (VAP1)

inhibitor

PO AOC3 activity

relative to

baseline

12 w ALT change from baseline

as a secondary outcome

measure

Foralumab Oral anti-CD3

antibody

PO Safety 30 d Change in ALT as a

secondary outcome

measure

SNP-610 Enzyme modulator at

several steps of TG

metabolism and lipid

peroxidation

(CYP2E1 pathways)

PO Absolute change

from baseline

in serum ALT

12 w

Emricasan Pan-caspase inhibitor PO Event-free

survival based

on composite

clinical

endpoint

48–120 w In patients with

decompensated cirrhosis.

Compound also phase 2

with histological endpoint

Emricasan Pan-caspase inhibitor PO Mean change in

HVPG

28 d In cirrhotic patients

1064 Adv Ther (2019) 36:1052–1074

Table 2 continued

Drug Mode of action Mode ofadministration

Primaryendpoint

Treatmentperiod toprimaryendpoint

Remarks

Saroglitazar Dual PPARac agonist PO % change in

ALT levels

16 w Also trial of 24 w in women

with PCOS and with

changes in liver fat by

MRI-PDFF as primary

outcome

Pemafibrate PPARa agonist PO % change in

liver fat

measured by

MRI-PDFF

24 w

HTD1801 Lipid modulator

(2 moities)

PO % change in

liver fat

content

measured by

MRI

18 w

PF-5521304 ACC inhibitor PO % change in

liver fat

content

measured by

MRI PDFF

16 w

SGM-1019 Small molecule

modulator of

inflammasome

activity

PO Safety 12 w Monitoring of ALT as

secondary outcome

measure

EDP-305 Non-steroidal FXR

agonist

PO Change in ALT 12 w

Tesamorelin Growth hormone

releasing hormone

analogue

SC Liver fat content

by MR

spectroscopy

12 months

MGL-3196 TRHb agonist PO Change from

baseline in

hepatic fat

fraction

measured by

MRI-PDFF

12 w Study continues for a total

of 36 weeks with histology

as secondary outcome

measures; study has been

completed and results

presented (EASL 2018,

AASLD 2018). Will enter

Phase 3

Adv Ther (2019) 36:1052–1074 1065

before any claims can be made. Meanwhile thenon-bile acid FXR agonist tropifexor hasentered a phase 2 trial in combination withcenicriviroc (vide infra).

Cenicriviroc

Cenicriviroc is a CCR2 and CCR5 dual antago-nist. CCR2 and CCR5 play an important role inmacrophage recruitment and polarisation andhave been implicated in NASH pathogenesis. Alarge 2-year phase 2 trial (CENTAUR) including289 patients has recently been completed andreported [30]. Year 1 analysis demonstrated asignificant decrease in systemic inflammation,but this did not translate into a clear effect onNASH. By contrast, there was a significant ben-efit of cenicriviroc over placebo in terms ofregression of fibrosis. Therefore, the drug is nowin phase 3 with reduction in fibrosis as the pri-mary endpoint.

Selonsertib

Selonsertib is an apoptosis signal-regulatingkinase 1 (ASK1, involved in response to variousstresses) inhibitor that was tested in a 6-monthtrial in combination with or without sim-tuzumab in an anti-fibrotic strategy in 72patients [24]. When the other simtuzumab trialsturned out negative, simtuzumab was consid-ered as placebo and the patients in the differentarms were regrouped. In this new setting,selonsertib was superior to placebo in terms offibrosis regression, without an effect on steato-hepatitis or on the metabolic features. Twophase 3 trials have been initiated, one for F3patients and one for cirrhotic patients, with aninterim analysis planned after one year oftreatment. The trial in cirrhotic patients did notmeet its primary endpoint and was stopped,whilst the trial in F3 patients is currentlyongoing.

Besides the four molecules currently in phase3, several other molecules are under investiga-tion. Some have already been mentioned.

Table 2 continued

Drug Mode of action Mode ofadministration

Primaryendpoint

Treatmentperiod toprimaryendpoint

Remarks

DS102 Anti-inflammatory and

anti-fibrotic lipid

PO Change in

serum ALT

12 w

ISIS703802 ANGPTL3 protein

inhibitor

SC % change in

fasting TG

6 months Changes in liver fat

measured by MRI PDFF

in secondary outcome

measures

AZD4076 GalNAc-conjugated

anti-miRNA-103/

107 oligonucleotide

SC Reduction in

liver fat

content

measured by

MRI

54 days

ACC acetyl-CoA carboxylase, ALT alanine aminotransferase, ANGPTL3 angiopoietin 3, AOC3 amine oxidase copper-containing 3, CYP cytochroom P, FXR farnesoid receptor X, GalNAc N-acetylgalactosaminyl, miRNA microRNA, HVPGhepatic venous pressure gradient, MRI-PDFF magnetic resonance imaging proton density fat fraction, PO per os, PPARperoxisome proliferator-activated receptor, PCOS polycystic ovary syndrome, SGLT sodium glucose transporter, TGtriglycerides, THR thyroid hormone receptor, VAP1 vascular adhesion protein 1, W week

1066 Adv Ther (2019) 36:1052–1074

Aramchol is another compound for which thephase 2 ARREST study data in 247 patients haverecently been presented [65]. The full data set ishence still to be published. Aramchol is a bileacid–fatty acid conjugate acting as a stearyl-CoAdesaturase 1 (the rate-limiting enzyme in thesynthesis of unconjugated fatty acids) inhibitorand showed some efficacy in mice [66]. The

primary endpoint of the trial was reduction inthe amount of liver fat (with overall no signifi-cant reduction in liver fat, but a significantlygreater percentage of patients with 5% reduc-tion of liver fat according to magnetic reso-nance (MR) spectroscopy was observed in thehigh dose aramchol arm). Also, on secondaryendpoints, especially resolution of NASH, a

Table 3 Phase 2 randomised combination trials (not all placebo-controlled) (Source: clinicaltrials.gov)

Drug Mode ofaction

Mode ofadministration

Primary endpoint Treatmentperiod toprimaryendpoint

Remarks

Selonsertib ASK-1

inhibitor

PO C1 stage improvement in

fibrosis without

worsening of NASH

48 w Placebo-controlled;

multiple combination

armsGS-0976 ACC

inhibitor

GS-9674 Non-

steroidal

FXR

agonist

Selonsertib ASK-1

inhibitor

PO Safety 12–24 w

according to

the different

arms

No placebo-arm

GS-0976 ACC

inhibitor

GS-9674 Non-

steroidal

FXR

agonist

Fenofibrate PPARa

agonist

Tropifexor

(LNJ452)

Non-

steroidal

FXR

agonist

PO Safety 48 w No placebo-arm;

histology as secondary

outcome measures

Cenicriviroc CCR2-

CCR5

dual

antagonist

ACC acetyl-CoA carboxylase, ASK-1 apoptosis signal-regulating kinase 1, CCR C-C motif chemokine receptor, FXRfarnesoid recpeptor X, NASH non-alcoholic steatoHepatitis, PO per os, PPAR peroxisome proliferator-activated receptor

Adv Ther (2019) 36:1052–1074 1067

significant effect of aramchol was noted. On thebasis of these results, the compound will enterphase 3. An Israeli study in 60 patients withNAFLD (only few had NASH) already previouslyshowed a reduction in liver fat content asmeasured by MR spectroscopy in the 300 mgdose [67]. Aramchol is an example of anapproach that initially is more oriented towardslipid accumulation in the liver (and subsequentcomposition of the bile) and hence a morepurely metabolic approach. Other attempts likeezetimibe have failed in that regard. Differentapproaches, like fatty acid synthase inhibitionand other targets of cholesterol and triglyceride

metabolism are tested in earlier phases of clini-cal development.

Fibroblast growth factor (FGF) 19 is releasedby the intestinal cells upon FXR stimulationand, after reaching the liver via the portal vein,exerts its actions on bile acid metabolism viathe FGF receptor 4/b-klotho complex and alsoimpacts on lipid and glucose metabolism. Viathe IL-6/STAT3 pathway, however, it also drivestumorigenesis [68]. NGM282, a recently engi-neered FGF19 analogue that lacks the effect onthe STAT3 pathway and hence most likely lacksthe tumorigenic effect of FGF19, demonstrateda significant reduction in liver fat content in aphase 2 study including 82 patients NASH [68].

Table 4 Phase 3 randomised placebo-controlled trials. Two more compounds have announced entering phase 3 (Aramcholand MGL-3196) (Source: clinicaltrials.gov)

Drug Mode ofaction

Mode ofadministration

Primary endpoint Treatmentperiod toprimaryendpoint

Remarks

Elafibranor

(GFT

505)

PPARad

dual

agonist

PO Resolution of NASH

without worsening of

fibrosis

72 w Study continues for composite

long-term outcome

(progression to cirrhosis, all-

cause mortality, liver-related

clinical outcomes)

Obeticholic

acid

Steroidal

FXR

agonist

PO 1 stage improvement in

fibrosis without worsening

of NASH or NASH

resolution without

worsening of fibrosis

18 m Study continues for long term

outcome (all-cause mortality

and liver-related clinical

outcomes)

Selonsertib ASK-1

inhibitor

PO C1 stage improvement of

fibrosis without worsening

of NASH

48 w Study continues for long term

outcome (Event free survival

at 240 w)

Cenicriviroc CCR2-

CCR5

dual

antagonist

PO C1 stage improvement of

fibrosis and no worsening

of NASH

12 m Study continues for long term

outcome (composite

endpoint of all-cause

mortality, histopathological

progression to cirrhosis or

liver-related outcomes)

ASK-1 apoptosis signaling kinase 1, CCR C-C motif chemokine receptor, FXR farnesoid receptor X, NASH non-alcoholicsteatohepatitis, PO per os, PPAR peroxisome proliferator-activated receptor, W week

1068 Adv Ther (2019) 36:1052–1074

Data from single-arm studies have also beenreleased recently and report histological benefit.This injectable drug appeared to have anacceptable safety profile and will be furtherstudied.

Thyroid hormones increase energy expendi-ture and have catabolic properties, acting viathe thyroid hormone receptor (THR), a nuclearreceptor with different isoforms. An intrahep-atic hypothyroidism has been shown to bepresent in NASH and potentially contributes toits pathophysiology [70]. This intrahepatichypothyroidism is potentially attributable toalterations in hepatic deiodinase expressionbecause of repair-related Hedgehog activation[70]. The THR agonist MGL-3196 has selectivityfor THR b1 receptor that is mainly expressed inthe liver and the kidney and therefore mostlikely lacks some potentially important sideeffects, amongst others on bone metabolism.MGL-3196 reduced liver fat significantly at12 weeks of treatment as assessed by MRI protondensity fat fraction (MR-PDFF), with concomi-tant beneficial effects on liver enzymes andmarkers [71]. The study of 107 patients went onfor a total of 36 weeks and results were recentlyprovided, showing a beneficial effect of thecompound over placebo in improving NASHseverity and NASH resolution [72], but the datastill need to be published before any firm con-clusion can be drawn. Based on the provideddata, this compound will also enter phase 3.

FGF21 is a so-called hepatokine, a peptidehormone produced by the liver (but also bymultiple other organs; circulating levels are,however, mainly determined by the hepaticproduction) that regulates sugar intake, glucosehomeostasis and energy expenditure. Interest-ingly, in view of the PPAR drugs in the pipeline,its expression in the liver is regulated by PPAR.Animal data suggest enhanced NASH and asso-ciated metabolic derangements upon FGF21deficiency and improvement upon administra-tion [73]. Human data are conflicting, withincreased FGF21 levels in NASH patients sug-gesting FGF21 resistance [74]. Recent data [75]demonstrated a beneficial effect on MR-PDFF-measured liver fat content of BMS986036, aninjectable pegylated analogue of human FGF21,along with a reduction in biomarkers of liver

injury and fibrosis in a placebo-controlled trialincluding 74 patients.

The Takeda G-protein-coupled membranebile acid receptor (TGR5) present on numerouscells, including intestinal epithelium, biliaryepithelium, adipocytes and stellate cells, is animportant mediator of the influence of bileacids on metabolism, including conversion offree thyroxine FT4 to the active thyroid hor-mone FT3 (again linking thyroid hormonefunction to NASH) [76]. Dual FXR-TGR5 ago-nists have been tested in preclinical models.Recently FXR-TGR5 crosstalk has been identi-fied and this might be implicated in the OCA-associated pruritus [77]. It is hence not clearwhat the role of TGR5 agonism in NASH treat-ment will be.

As with cenicriviroc, some drugs that mainlytarget inflammatory mechanisms are even tes-ted. BI 1467335, an oral small molecule inhi-bitor of amine oxidase copper-containing 3(AOC3), also called vascular adhesion protein 1(VAP-1), is currently in phase 2. AOC3 plays animportant role in the recruitment of variousinflammatory cell types to a site of inflamma-tion and was shown to play a role in NASHpathogenesis in preclinical models. Its solublevariant showed a correlation with NAFLDseverity [78]. Furthermore VAP-1 has beenimplicated in atherosclerosis and cardiovascularprognosis [79], reinforcing the link betweenNAFLD and CVD and the rationale for AOC3antagonists in NASH.

Inhibition of caspases to interfere withinflammatory and apoptotic processes isanother of the many pathways that are targeted.Emricasan, a pan-caspase inhibitor, showedefficacy in a preclinical animal model [80].Interestingly, it was reported to lower liverenzymes in chronic hepatitis C patients a dec-ade ago [81]. The compound is currently inphase 2.

Whilst we are still waiting for a phase 3 proofof efficacy of single drugs, several combinationsof drugs are being tested. As outlined before,disease pathophysiology is heterogenous andcomplex, offering a rationale for combiningdrugs with different modes of action that canhave additive or even synergistic effects. Besidestesting combinations of individual drugs (e.g.

Adv Ther (2019) 36:1052–1074 1069

tropifexor and cenicriviroc, Table 3), severalmolecules that combine different structures arebeing engineered and tested (e.g. a moleculethat combines a GLP-1 receptor agonist and aglucagon receptor agonist).

CONCLUSION

Pharmacological treatment for NASH focuses onpatients with some activity of the steatohep-atitis component combined with already somedegree of fibrosis. Definitions, concepts anddesigns are evolving, and a large number ofdrugs are currently being evaluated. As patho-physiology is complex, the patient populationheterogenous and diagnosis and therapy mon-itoring difficult, this area of drug developmentis particularly challenging. Some drugs cur-rently approved for other indications haveshown some efficacy and can be used, but newtreatments are eagerly awaited.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Sven Francque has a seniorclinical research mandate from the Fund forScientific Research (FWO) Flanders (1802154N)and has acted as an advisor and/or lecturer forRoche, Gilead, Abbvie, Bayer, BMS, MSD, Jans-sen, Actelion, Astellas, Genfit, Inventiva, andIntercept. Sven Francque is/was a partner in theEuropean Commission projects Hepadip (con-tract LSHM-CT-2005-018734) and Resolve(Contract FP7-305707) and the InnovativeMedicines Initiative 2 Joint Undertaking LIT-MUS consortium (Grant Agreement 777377).

Sven Francque is a member of the journal’seditorial board. Luisa Vonghia has acted as anadvisor for Inventiva, Abbvie and Bayer.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercialuse, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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