5 184

D P Sonne Targeting FXR in metabolic 184:5 R193–R205 Review disease

MECHANISMS IN ENDOCRINOLOGY FXR signalling: a novel target in metabolic

diseases Correspondence should be addressed to D P Sonne David P Sonne Email Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark david.peick.sonne@regionh. dk

Abstract

During the last decades, it has become clear that the gastrointestinal tract plays a pivotal role in the regulation of glucose homeostasis. More than 40 hormones originate from the gastrointestinal tract and several of these impact glucose metabolism and appetite regulation. An astonishing example of the gut’s integrative role in glucose metabolism originates from investigations into biology. From primary animal studies, it has become clear that bile acids should no longer be labelled as simple detergents necessary for lipid digestion and absorption but should also be recognised as metabolic regulators implicated in lipid, glucose and energy metabolism. The nuclear (FXR) is a part of an exquisite bile acid-sensing system that among other things ensures the optimal size of the bile acid pool. In addition, intestinal and hepatic FXR also impact the regulation of several metabolic processes such as glucose and lipid metabolism. Accordingly, natural and synthetic FXR agonists and certain FXR- regulated factors (i.e. fibroblast growth factor 19 (FGF19)) are increasingly being evaluated as treatments for metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease (and its inflammatory version, non-alcoholic steatohepatitis). Interestingly, decreased FXR activation also benefits glucose metabolism. This can be obtained by reducing bile acid absorption using bile acid sequestering agents (approved for the treatment of type 2 diabetes) or inhibitors of intestinal bile acid transporters,that is the apical sodium-dependent bile acid transporter (ASBT). This article discusses recent clinical trials that provide insights about the role of FXR-FGF19-targetted therapy for the European Journal of Endocrinology treatment of metabolic diseases.

European Journal of Endocrinology (2021) 184, R193–R205

Introduction

Today, bile acids are acknowledged as metabolic human perspective. It has been established that bile acids integrators and in recent years, several clinical and (patho) stimulate the secretion of the gut-derived glucagon-like physiological studies have explored this paradigm from a peptide 1 (GLP-1), an incretin hormone with profound

Invited Author’s profile David P Sonne, MD, PhD, is a clinical pharmacologist and Head of Zelo Phase 1 unit at Bispebjerg Hospital, University of Copenhagen, Denmark. Dr Sonne’s research interests encompass the regulatory peptides of the pancreas and gut and their importance in the regulation of the functions of the gastrointestinal tract and metabolism. With special interest in the role of bile acids in human metabolism, Dr Sonne’s research has had a particular emphasis on bile acid-induced secretion of gut hormones – particularly the incretin hormone glucagon-like peptide 1.

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-20-1410 European Journal of Endocrinology https://eje.bioscientifica.com which causesareduction in plasmaLDLcholesterol low-density lipoprotein(LDL) receptorexpression, increase inhepatic is accompanied by acompensatory circulation. Theresultingdepletionofthebileacid pool intestinal lumen, diverting them from the enterohepatic world ( been abusypursuitinmanyresearch groupsaroundthe subsequent implications for glucose metabolism has the modulationofbileacidreceptoractivationwith colesevelam forthetreatmentoftype2diabetes, and changesinluminallevelsofbileacids( gut barrierdamage and ensuingincreased permeability, liver disease, including an altered intestinal microbiota, features ofadisruptedgut–liveraxisaresharedbyfatty of mostformschronicliverdiseases( that thegut–liveraxisdisruptionleadstoprogression role ofFXRinlipidmetabolism).Thereisgrowingevidence (see Chávez–Talavera synthesis andglucoselipidmetabolismintheliver barrier function,andgutproductsregulatebileacid the liverregulatemicrobiotacompositionandintestinal the liveronother. Effectively, bileacidsproducedin gut anditsmicrobiotabileacidsontheonehand, axis; areciprocalinteractionthattakesplacebetweenthe signalling is centrally positioned in the so-called gut-liver version, non-alcoholicsteatohepatitis)( non-alcoholic fattyliverdisease(anditsinflammatory a therapeutictargetinpatientswithtype2diabetesand like actionsandthattheFXR-FGF-19axismayconstitute rodents have demonstrated that FGF19 displays insulin- the small heterodimer protein ( and theco-receptorbeta-Klotho,whichsynergisewith novo stimulation. FGF19 actions in the liver lead to reduced is secretedfromtheintestineuponpostprandialbileacid the hormonefibroblastgrowthfactor19(FGF19),which Several FXR-relatedeffectsaremediatedpartlythrough and possiblyviaalterations in bile acidmetabolism ( via FXR-derived actions on lipid and glucose metabolism, that FXRisalso implicated in metabolic control, possibly is repressed( liver, wherebyhepaticbileacidsynthesisfromcholesterol nuclear farnesoidXreceptor(FXR)intheintestineand secreting L cells ( is locatedonthebasolateralsideofintestinalGLP-1- receptor, Takeda Gproteinreceptor5(TGR5), which part, tobebileacid-inducedactivationoftheacid The mechanismbehindthisphenomenonisbelieved,in glucose-lowering and satiety-promoting capabilities ( Review Since theUSapprovalofbileacidsequestrant bileacidsynthesisviatheFGF-receptor4(FGFR4) 11 ). Bileacidsequestrantsbindbileacidsinthe 4 , 5 ). Inrecentyears,ithasbeenestablished 3 ). Moreover, bile acids activate the et al. ( 9 ) foradetailedreviewofthe 7 D PSonne ). Intriguing findings in 8 ). Indeed,FXR 10 10 ). Themain ). 1 , 6 2 de ). ). drugs targetingFXRinmetabolicdiseases. will bediscussedinthecontextofrecentclinicaltrials of FXRmaybenefitglycaemicregulationandmetabolism apparent paradox that both activation and deactivation for metabolicregulationwillbeoutlined,andthe bile acid-basedpharmacotherapy( cholangitis, and portal hypertension constitute targets for sclerosing cholangitis,primary biliary including primary fatty liverdiseaseareongoing,butalsootherdiseases targeting metabolicdiseasessuchastype2diabetesand a role ( increased TGR5-mediatedGLP-1releaseseemstoplay intraluminal trapping ofintestinal bile acids)alongside speculative; however, reducedFXR activation (dueto of ~0.5% ( properties (i.e. reduction inhaemoglobin A1c (HbA1c) concentrations. With regardtotheglucose-lowering ( acid synthesisandtheenzymatic activityofCYP7A1 its plasmaconcentrationhas beenshownto reflect bile 4-cholesten-3-one (C4),ispresent inbloodplasmaand product inthesynthesisof bileacids,7-alpha-hydroxy- the enterohepatic circulation ( colonic epitheliumandreturntotheliverforreuse in acids, whichsupportthepassiveabsorptionacross processes increasethehydrophobicityofbile acid andlithocholicacid.Thesemicrobiota-mediated bileacids,predominantly deoxycholicto secondary bile salthydrolasesand7 acid reaching thecolon are deconjugated by bacterial unabsorbed (~5%)cholicacidandchenodeoxycholic to theliverandrecycled(enterohepaticcirculation). The transporters andtransportedviatheportalcirculation (~95%) are absorbed in the terminal ileum by active absorption of fat.Mosttheconjugatedbileacids acids intothesmallintestinefacilitatingdigestionand ( and are excreted into bile and stored in thegallbladder acid, whichareconjugatedwithtaurineandglycine bileacidsarecholicacidandchenodeoxycholicprimary hydroxylase (cytochrome P450 7A1, CYP7A1). The acid synthesisfromcholesterolintheliveris7-alpha- The rate-limitingenzymeintheclassicalpathwayofbile enterohepatic circulation Bile acidmetabolismand disease Targeting FXRinmetabolic 17 16 , ). Postprandialgallbladdercontractiondeliversbile In the present paper, the role of FXR-FGF19 signalling 18 ). 13 , 14 12 ). Presently, several ‘bile acid programmes’ )), theunderlying mechanisms remain Downloaded fromBioscientifica.com at10/01/202103:48:50PM α -dehydroxylated bybacteria 16 15 ). An intermediary ). 184 :5 R194 via freeaccess European Journal of Endocrinology cells andmacrophages. TGR5 is most potently activated by brown adipose tissue, immune cells including dendritic TGR5 isalsofoundonsmoothmusclecells,neural including the GLP-1-producing enteroendocrine L cells. epithelial surfaceofthegallbladderandintestinalcells, ( finely regulatedtomaintainabeneficialmetabolicstate levels andhepaticfatcontent,twofunctionswhichare are central for metabolic homeostasis regulating glucose has becomeclearthatFXRandsmallheterodimerprotein inhibits the transcription of CYP7A1. In recent years, it to theinductionofsmallheterodimerprotein,which proliferation ( the abilitytoactivateFGFR4andinducehepatocyte through the inhibition of CYP7A1, but FGF19 also has FGFR4/beta-Klotho. FGF19inhibitsbileacidsynthesis FGF19, whichbindstothehepaticreceptorcomplex FXR stimulationleadstosynthesisandsecretionof or hepatocyteswhenbileacidsareabsorbed.Intestinal nuclear receptor, FXRisactivatedinilealenterocytes result ofintestinalandhepaticFXRactivation.Beinga acid transport proteins and synthesis of bile acids as a human bileacidmetabolismviadiverseeffectson .FXRisamajorregulatorof receptor forbileacidsandmostpotentlyactivatedby in theintestineandliver( bileacidreceptor,The primary FXR,ishighlyexpressed Bile acidreceptors–FXRandTGR5 5 Review , 16 The TGR5receptorislocatedoncholangiocytes,the , 20 ). 19 ). Hepatic FXR activation also leads D PSonne Fig. 1 ). Itisanatural

and glycaemicregulation,whichhasbeendemonstrated FXR agonismalsoexertsbeneficialeffectsonmetabolism circulation ofbileacids. Ithasturnedout,however, that disruption, launchedbyhamperingtheenterohepatic of FXR signalling represents an example of gut–liver axis patients withtype2diabetes.Suchindirectdeactivation FXR activationleadingtoimprovedglycaemiccontrolin As mentioned,bileacid-sequestratingtherapyreduces vs deactivation The ‘FXRconundrum’–activation intestinal motility( induce gallbladderrelaxationandrefillingtopromote activation tosuppresshepaticmacrophageactivation, animal models have reportedbileacid-mediated TGR5 inducing GLP-1-secretingactions( lithocholic acid,arelativelyunabundantbileacid.Besides demonstrated thatFXRactivationinLcellsinhibits deficiency increasedGLP-1plasmaconcentrations( induced hepaticgluconeogenesis( effectsofglucagononfasting- required forthestimulatory gluconeogenesis ( selective inhibitionofintestinalFXRattenuatedhepatic For example,arecentmousestudydemonstratedthatthe highlights theenormouscomplexityofFXRsignalling. The reasonforthisdiscrepancyisfarfromclearbut in bothanimalandclinicalstudies(seesubsequently). supporting animportantstudybyTrabelsi disease Targeting FXRinmetabolic 26 Takeda Gproteinreceptor5. GLP-1, glucagon-likepeptide1; TGR5, receptor 4;FXR,farnesoidXreceptor; factor 19;FGFR4,fibroblastgrowth factor hydroxylase; FGF19,fibroblast growth transporter; CYP7A1,cholesterol7-alpha- apical sodium-dependentbileacid classes underclinicalinvestigation.ASBT, the currentFXR/FGF19-targetingdrug enterohepatic circulationofbileacidsand A schematicrepresentationofthe Figure 1 11 ), butFXRhasalsobeenshowntobe , 24 Downloaded fromBioscientifica.com at10/01/202103:48:50PM , 25 ). https://eje.bioscientifica.com 27 21 184 ). Inaddition,FXR , :5 22 , t al. et 23 ), several , which R195 26 via freeaccess ), European Journal of Endocrinology https://eje.bioscientifica.com 2 diabetes(HbA1c~7.2%)were randomisedtotreatment 42 alcoholic steatohepatitis and obesity, respectively ( increased insulinsensitivity inpatientswithnon- ursodeoxycholic acid (~2000 mg oncedaily)demonstrated FXR antagonisticproperties( induction (mirroredbyelevatedC4),indicatingclear acid formationbyreducingFGF19,resultinginCYP7A1 demonstrated that ursodeoxycholic acid increased thebile study inpatientswithnon-alcoholicfattyliverdisease has beenknownforyears( and ursodeoxycholicacid-stimulatedbileacidsynthesis in patientswithnon-alcoholicfattyliverdisease( ( cholangitis andcholestaticdiseases biliary primary disorders including bile acid used for hepatobiliary might beobtainedwithursodeoxycholicacid,anatural deactivation inducedbybileacidsequesteringtherapy) the effectonglycaemicregulation(seesubsequently). two studieshaveprovidedconflictingresultsregarding reduction inmarkersofliverfibrosis( fatty liverdiseaseandtype2diabetestogetherwitha corrected insulin sensitivity in patients with non-alcoholic with obeticholicaciddemonstratedimprovedplacebo- inflammation ( alcoholic steatohepatitisincludingsteatosis,fibrosisand in improvingseveralpathologicalaspectsofnon- obeticholic acidwassuperiortoplacebo treatment with activation inhumans.IntheFLINTstudy, 72weeksof provided valuableinsightsintotheeffectsofFXR the intestine( metabolic dysfunctions might differ between the liver and indicate thattheroleofFXRduringpathogenesis increase inFGF19( 32 and increaseshepaticglycogensynthesis( shown thattheFXRactivationrepressesgluconeogenesis abnormalities ( protected against weight gain andimproved lipid FXR agonist,obeticholicacid,reversedinsulinresistance, intolerance andinsulinresistanceinmice( by theFXRsyntheticagonist,GW4064,restoredglucose both hepatic overexpression of FXR and FXR activation intolerance andinsulinresistance( to increase gluconeogenesis thus worsening glucose hepatic FXRdeficiencyinthemousehasbeenshown production and secretion of GLP-1 ( intracellular glycolyticpathwaysleadingtodecreased 16 Review ), perhapswiththecontributionfromFXR-mediated ). Also,inasmallJapanesestudy, 16patientswithtype ). Ursodeoxycholicacidhasbeenstudiedintensely Direct FXRantagonism(asopposedtoindirect Two clinicalstudieswithobeticholicacidhave 34 36 31 , ). Inanotherstudy, 6weeksoftreatment 35 ). Infact,severalanimalstudieshave 33 ). ). Thisapparent’FXRparadox’could 40 39 ). Intwohigh-dosetrials, ). Intriguingly, arecent D PSonne 28 37 , 29 ). However, these 14 30 ). Accordingly, ). Conversely, ). Inrats,the 26 , 28 , 38 30 41 ) , , and FXRactivationmaybeoftherapeuticvaluein apparent paradox that both inhibition of FXR signalling diseases suchasfattyliverdisease.Thisleavesuswiththe efficacious inimprovinginsulinsensitivityandmetabolic clinical evidence suggest that FXR activation may also be equally imposebenefits.Conversely, preclinicaland efficacy intype2diabetes),directFXRantagonismmay with bileacid-sequestratingtherapy(withproven deactivation ofFXR( indicating bileacid-dependentactivationofTGR5and/or secretion (evaluatedwithaliquidhigh-fatmealtest), Notably, ursodeoxycholicincreasedearlyphaseGLP-1 when ursodeoxycholicwasadministeredaftersitagliptin. sitagliptin, andHbA1c(butnotweight)alsodecreased decreases inweightandHbA1cwhenadministeredbefore or viceversa( daily) followedby12weekssitagliptin(50mgonce with 12weeksofursodeoxycholicacid(900mgonce TGR5 activationleadingto increasedGLP-1secretion as potentiallyincreasing intestinal bileacid-induced indirectly reduceintracellular FXRactivation–aswell acid transporter(ASBT)constitutes anotherwayto specific inhibitorofthe apical sodium-dependentbile be activatedevenbysequestrant-boundbileacids( FXR antagonisticsignalling( towards amorehydrophilicbileacidpool,indicating reduced FGF19secretion,increasedlipogenesisandashift corrected reductionsinplasmaglucoseconcentrations, treatment with bile acidsequestrants elicited placebo- shown, in patients with type 2 diabetes, that 2 weeks of reduce intestinalglucoseabsorption( ( increased splanchnicglucoseutilisationmayplayarole marked effectsonhepaticglucosehandling( majority ofhumanstudieshavenotbeenabletoshow be established( acid sequestrantsonglycaemicregulationremainsto The mechanismexplainingthebeneficialeffectofbile clinical studies Indirect FXRdeactivation–insightsfrom metabolic disease. GLP-1-producing Lcells( agreement withabasolaterallocalisationofTGR5on sequestrants onGLP-1secretion,whichmaybe in we have been unable to show acute effects of bile acid disease Targeting FXRinmetabolic 34 ). Also, bile acid sequestrants have been suggested to Thus, asidefromindirectFXRdeactivationinduced Inhibition ofintestinalbileaciduptakeviathe 43 44 ). Ursodeoxycholicacid-inducedsmall ). Asopposedtoanimalstudies,the 14 ). Downloaded fromBioscientifica.com at10/01/202103:48:50PM 2 , 13 , 13 22 ). AlthoughTGR5may ). 184 46 :5 ). Ourgrouphas 45 ), whereas R196 47 via freeaccess ), European Journal of Endocrinology control havereportedconflicting resultsintermsofgluco- examining theeffectofobeticholic acidonglycaemic agonist ( chenodeoxycholic acidand apotentandspecificFXR Obeticholic acidisa synthetic derivativeof FXR agonism–insightsfromclinicalstudies may playarole. which increasesintestinalmotilityandGLP-1production, reduced FXR activation. Additionally, TGR5 activation, absorption kinetics and hepatic utilisation of glucose via the enterohepaticlevelwheretheymayinfluence sequestrants andASBTinhibitorsworkprimarily at extent asGSK672( volixibat reducedplasmaglucoseandinsulintothesame type 2 diabetes or non-alcoholic steatohepatitis. Of note, effects onplasmaGLP-1concentrationsinpatientswith potent andselectiveASBTinhibitor, didnotdemonstrate However, morerecentclinicaltrialswithvolixibat,ahighly of TGR5intheterminalileumandcolon( mediated byincreasedbileacid-dependentactivation plasma glucose concentrations, an effect most likely inhibition elicitsincreasedplasmaGLP-1andreduced with chronicconstipationdemonstratingthatASBT this findingstandsoppositetoapreviousstudyinpatients glucose-lowering mechanismofthisdrug.Interestingly, GSK672, whichmightpointtoaninsulin-independent reduced insulinconcentrationsfollowingtreatmentwith diarrhoea (22–100%).Ofnote,bothstudiesdemonstrated common adverseeventassociatedwithGSK672was of GSK672 alsoreducedLDLcholesterol(uptoamaximum effects seen after treatment with sitagliptin (third arm). glucose-lowering impactofGSK672wassimilartothe of 1.33 mmol/L (95% CI: 0.35–2.30) ( CI: 0.28–2.14)andweightedmean24-hplasmaglucose baseline infastingplasmaglucoseof1.21mmol/L(95% metformin) elicitedplacebo-correctedreductionsfrom treatment with GSK672 10–90 mg twice daily (add-on to study ( compared withplacebo( 24-h plasmaglucoseof1.93mmol/L(95%CI:0.82–3.04) caused abaseline-correctedreductioninweightedmean ASBT inhibitor, GSK672(titratedto90mgtwicedaily), 7 daysoftreatment(add-ontometformin)withthe phase 2studyinpatientswithtypediabetes( ( 48 Review ∼ , Taken together, mostdataindicatethatbileacid 40%) and apolipoprotein concentrations. The most 49 n ). Inarandomised,placebo-controlledcrossover

= 54

75) inpatientswithtype2diabetes,14daysof ). Asmentioned,thetwo available studies 52 , 53 ). 50 ). Inasecondparallel-group D PSonne 50 ). The observed ). The observed 48 , 49 n

= , 15), 51 ). placebo-controlled phase2trialofobeticholicacid with caution.Theotherstudy(FLINT)wasarandomised, induced increase in insulin sensitivity be interpreted rates, which suggest that thefinding ofobeticholic acid- level glucose infusion glucose levels, HbA1c and entry there weresomebaselineimbalanceregardingfasting absolute increaseinglucoseinfusionrateswassmall,and point toimprovedinsulinsensitivity. However, the rate inthetwoobeticholicacidtreatmentgroups,which reported approximately 25% increase in glucoseinfusion additional glycaemicoutcomeswerereported).Thestudy sensitivity beforeandaftera6-weektreatmentperiod(no euglycaemic clampmethodwasusedtoassessinsulin alcoholic fatty liver disease ( placebo ( 50 mg( examined theeffectoftreatmentwith25mg( proof-of-concept, phase2trialbyMudaliar metabolic effects.Therandomised,placebo-controlled in placebo-treatedpatients wereabsentorreversedon on alkalinephosphatase,lipids andbloodglucoseseen demonstrated that the favourable effects of weight loss study population.Surprisingly, the baseline characteristics compared with the complete acid and98treatedwithplacebo)hadsimilar were includedintheanalysis(102treatedwithobeticholic plasma glucoseandHOMA-IR)( liver histology)onvariousglycaemicparameters(HbA1c, (i.e. additive reduction of alanine aminotransferase and combined effectsofweightlossandobeticholictreatment sensitivity. Asubsequent corroborate Mudaliar with obeticholicacid.Thus,theFLINTstudycouldnot resistance (HOMA-IR)wasevidentinpatientstreated measured bythehomeostaticmodelassessmentofinsulin placebo-corrected deteriorationofinsulinsensitivityas daily weredemonstrated.Infact,astatisticallysignificant 72 weeks of treatment with 25 mg once HbA1c orbasalplasmaglucoseconcentrationsfollowing type 2diabetesbutnoplacebo-correctedimprovementsin the placebogroup( endpointcomparedto23(21%)of109in met theprimary (45%) of110patientsreceiving25mgobeticholicaciddaily score withoutworseningoffibrosis.After72weeks,50 improvement innon-alcoholicfattyliverdiseaseactivity endpoint was aminimumtwo-point histological primary inflammation and fibrosisscores onrepeat biopsy( showed aclearbenefitwithimprovedsteatosis,lobular (without cirrhosis).Thestudywasstoppedearlywhenit including 283 patients with non-alcoholic steatohepatitis disease Targeting FXRinmetabolic n n

= = 23)inpatientswithtype2diabetesandnon-

21) obeticholicacidoncedailycomparedto P

< 0.001).50%ofthe83patientshad t al et Downloaded fromBioscientifica.com at10/01/202103:48:50PM post-hoc . ’s findingsregardinginsulin 37 ). The hyperinsulinaemic- 55 https://eje.bioscientifica.com analysisexamined the ). Two hundredpatients 184 post-hoc :5 n analysis = 20)or 36 t al. et R197 ). The via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com gallbladder refilling( arise viaFXR-stimulatedFGF19, whichisimplicatedin gallbladder and bile acid hydrophobicity, but may also may beduetoincreasedsaturation ofcholesterolinthe ( gallstones or cholecystitis (3%) compared to placebo more patientsinthe25mgobeticholicgroupdeveloped events, through the month 18. Interms of hepatobiliary cholesterol andtriglyceridesdecreaseddose-dependently obeticholic acid group). High-density lipoprotein (HDL) 10 mgobeticholicacidgroup,and336(51%)inthe25 pruritus (123(19%)intheplacebogroup,183(28%) acid group),anddose-dependentmild-to-moderate acid 10mggroup,and159(24%)inthe25obeticholic (10%) intheplacebogroup,155(24%)obeticholic reversible bymonth6inthosewhoinitiatedstatins(66 FXR agonists),whichwassuggestedtobetransientand were increase(~20%)inLDLcholesterol(aclasseffectof common adverseeventsofobeticholicacidtreatment rapidly andwasgenerallystableatmonth3.Themost marker of metabolic and cardiovascular risk ( glutamyl transferaseconcentrationinplasma,asuggested alanine and aspartate aminotransferase. Also, gamma- suchas effect onothermarkersofhepatocellularinjury ( the placebogroup,whichwasnotstatisticallysignificant patients inthe25mggroupvs(8%)of311 no worseningoffibrosis)wasachievedin36(12%)308 outcome (resolutionofnon-alcoholicsteatohepatitiswith 311 patientsintheplacebogroup( patients in 25 mg group compared with 37 (12%) of the steatohepatitis) wasachievedin71(23%)ofthe308 improvement withoutworseningofnon-alcoholic analysis. One of these outcomes (fibrosis the primary with biopsy-provenstage2–3fibrosiswereincludedin dose ofstudytreatment;931patients(539[58%]females) stage 1–3fibrosiswereenrolledandreceivedatleastone One thousandninehundredandsixty-eightpatientswith (histological assessment)withnoworseningoffibrosis. assessment) or resolution of non-alcoholic steatohepatitis worsening ofnon-alcoholicsteatohepatitis(histological as improvementoffibrosisbyatleastonestagewithno published recently( of treatment but an 18-month interim analysis has been least 4yearstoevaluatethelong-termclinicalbenefits on-going withpatientsexpectedtohavefollow-upforat 10 mgor25obeticholicaciddaily( ~2100 patientswithstage2–3liverfibrosis)toplacebo, (REGENERATE) hasrandomised~2400patients(including obeticholic acidtreatment.Thesubsequent phase 3trial < P

Review 1%) and10mgobeticholic acid(1%).Perhaps,this =

0.18). Obeticholicacidtreatmenthadabeneficial 57 59 ). The primary endpointwasdefined ). Theprimary ). D PSonne P =

0.0002). Theother 56 ). Thestudyis 58 ), declined bodyweight ofapproximately2%.Althoughweightlossis obeticholic acidresultedinadose-dependentdecrease patients withorwithouttype2diabetes.However, glycaemic homeostasisinnon-alcoholicsteatohepatitis (i.e. potentFXRagonism)doesnotseemtoimpacton from theFLINTandREGENERATE trials,obeticholicacid likely tobeclinicallyrelevant.Thus,basedonevidence 18 months.However, thesechangesweresmallandnot compared toplaceboandstayedatthislevelduringall glucose concentrationsandHbA1cwereslightlyincreased month 6.Inpatientswithouttype2diabetes,meanplasma the increaseswereshort-livedandreturnedtobaselineat obeticholic acidcomparedtoplacebotreatment.However, upontheinitiationof (from ~7to7.4%)wasobserved increase inglucose(from~7to~8mmol/L)andHbA1c study). In patients with type 2 diabetes, a transient received antidiabeticmedication(notspecifiedinthe REGENERATE trialhadtype2diabetesand,consequently, (estimated byclamp-likeindex (CLIX))improvedslightly and gamma-glutamyltransferase) andinsulinsensitivity disease ( non-diabetic patientswith non-alcoholicfattyliver in anopen-label,proofof concept phase2atrialin12 non-steroidal high-affinityFXRagonist,wasstudied more systemically( intestinal FXR, whereas obeticholic acid agonises FXR some oftheseagentsaresuggestedtoprimarilyagonise bile acid-type,andlackenterohepaticcirculation. Thus, cilofexor and ), which largely means non- FXR agonists are non-steroidal (i.e. PX-104/GS-9672/ opposed toobeticholicacid,themajorityofthesenewer treatment ofnon-alcoholicsteatohepatitis( and welltolerated. doses. Importantly, thecombinationwasgenerallysafe all treatmentgroupswithnoclinicalbenefitofhigher 8, LDL cholesterol concentrations fell below baseline in initiated fromweek4withsubsequenttitration.By treatment(10mg)was phase. Oncedailyatorvastatin obeticholic acidoncedailyduringa16-weekdouble-blind assigned (1:1:1:1)toplaceboor5mg,10mg25 non-alcoholic steatohepatitis ( controlled phase 2 study (CONTROL) in patients with been investigatedinarandomised,double-blind,placebo- obeticholic acid-inducedincreaseinLDLcholesterolhas combination ofobeticholicacidandstatinforcurbing of non-alcoholicsteatohepatitis( size isnotexpectedtoinfluencehistologicalparameters important forthispatientpopulation,aweightlossof disease Targeting FXRinmetabolic Approximately 56% of the patients in the Several otherFXRagonistsarebeingevaluatedforthe 64 ). Liverenzymes(alanine aminotransferase 62 , Downloaded fromBioscientifica.com at10/01/202103:48:50PM 63 ). PX-104,asyntheticand n

= 4 ( 84) 60 184 ). Importantly, the 61 :5 ). Patients were Table 1 R198 ). As via freeaccess European Journal of Endocrinology Review

Table 1 List of completed and ongoing clinical trials investigating FXR agonists, ASBT inhibitors and FGF19 analogues for the treatment of metabolic diseases and liver diseases.

Name Company Drug class Indication Status FXR agonists

INT-747/obeticholic acid Intercept pharmaceuticals FXR agonist (steroid scaffold) NASH, compensated fibrosis, PBC Rejected by FDA D PSonne (approved), PSC (NASH) PX-102 Gilead (Phenex FXR agonist NASH Phase 1 pharmaceuticals) LJN-452/tropifexor Novartis FXR agonist NASH and PBC Phase 2 PX-104 Phenex pharmaceuticals FXR agonist NAFLD Phase 2 (discontinued) GS-9674/cilofexor Gilead (Phenex FXR agonist NASH, PBC, PCS Phase 2/3 pharmaceuticals) INT-767 Intercept pharmaceuticals FXR/TGR5 agonist Liver fibrosis Phase 1 LMB-763/ Novartis FXR agonist NASH, diabetic nephropathy Phase 2 EDP-305 Enanta FXR agonist (steroid scaffold) NASH and PBC Phase 2 EYP001 Enyo pharmaceuticals FXR agonist NASH Phase 2

MET409 Metacrine FXR agonist NASH, IBD Phase 1 disease Targeting FXRinmetabolic TERN-101 Terns pharmaceuticals FXR agonist NASH Phase 2 ASBT inhibitors Elobixibat (A3309) Albireo ASBT inhibitor Constipation/NAFLD/NASH Phase 2 Odevixibat (A4250) Albireo ASBT inhibitor PFIC, Alagille syndrome, PBC, Phase 2/3 cholestasis Maralixibat (SHP625/LUM001/ Mirum ASBT inhibitor PFIC, Alagille syndrome, PBC syndrome, Phase 3 lopixibat PSC, PBC Linerixibat (GSK2330672)/GSK-672 GSK ASBT inhibitor PBC, T2D, cholestasis Phase 2/3 Volixibat (SHP626/LUM002) Mirum ASBT inhibitor NASH, T2D Phase 2

Downloaded fromBioscientifica.com at10/01/202103:48:50PM FGF19 analogues/other NGM-282/alderfermin NGM biopharmaceuticals FGFR4 agonist/FGF19 variant T2D, PBC, NASH, cirrhosis Phase 2 NGM-313/MK-3655 NGM biopharmaceuticals Beta-Klotho/FGFR1c receptor Obesity, insulin resistance, NAFLD/ Phase 1

https://eje.bioscientifica.com agonist NASH

FXR, farnesoid X receptor; IBD, inflammatory bowel disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PCS, primary sclerosing 184 cholangitis; PFIC, progressive familial intrahepatic cholestasis; T2D, type 2 diabetes; TGR5, Takeda G protein receptor 5. :5 R199 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com have beenreported for tropifexor, anothernon-steroidal 30 mg cilofexor (4%) and placebo (4%). Similar results receiving 100mgcilofexor(14%) thaninthosereceiving moderate tosevereprurituswas morecommoninpatients resistance. Cilofexorwasgenerally welltolerated,but − 4%), HbA1c(1.3%vs4.1%),andbodyweight( reduction in HOMA-IR ( reduction inMRI-PDFF(vs with placebo. However, in patientsachieving at least 30% insulin, HOMA-IRorHbA1cwasdemonstratedcompared regulation, noclearbenefitofcilofexoronserumglucose, HDL cholesterol or triglycerides. In terms of glycaemic no significantchangeswereseeninLDLcholesterol, bile acidsdecreasedinbothtreatmentgroups.Notably, PDFF. Serumgamma-glutamyltransferase,C4,andprimary placebo. The30mg-grouphadanegligibledecreaseinMRI- compared withanincreaseof1.9%inthosereceiving had amedianrelativedecreaseinMRI-PDFFof22.7%, in total).Atweek24,patientsreceiving100mgcilofexor randomisation was stratified by type 2 diabetes status (55% placebo ( to receivecilofexor100mg( biopsy. Onehundredandfortypatientswererandomised by magneticresonanceelastographyorhistoricalliver fraction (MRI-PDFF) steatohepatitis, diagnosedbyMRI-protondensityfat phase 2 trial in patients with non-cirrhotic non-alcoholic tested inarandomised,double-blind,placebo-controlled GS-9674, an‘intestinallyrestricted’FXRagonist( (further drugdevelopmentwasabandoned).Cilofexor/ 12 patients without replacement of previous drop-outs ruled outleadingtothetermination of thestudyafter medication andventricularextrasystolescouldnotbe patient withoutsymptoms).Arelationshipbetweenstudy contractions withasingularventriculartripletinone arrhythmia (isolatedpolymorphicprematureventricular ofcardiac but twopatientsexperiencedshortintervals and lipoproteins.Therewerenoseriousadverseevents, triglycerides or other of the measured circulating lipids no effectonserumLDLcholesterol,HDL PX-104had bilirubin concentrationswereobserved. in aspartateaminotransferase,alkalinephosphataseor treatment (specific valuesnotreported). Nochanges was significantlydecreasedfrombaselinetoendofthe change, but the AUC ofC-peptide measured by OGTT (AUC) of serum glucose, insulin or HOMA-IR did not spectroscopy) was unaffected. The area under the curves whereas hepaticsteatosis(assessedbymagneticresonance in sevenoutofeightpatientsafter4weekstreatment, 0.4%) wasdemonstrated,indicatingimprovedinsulin Review n

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The ), was combination withGLP-1receptoragonists,which pursued, with one of many treatment concepts being treatment offattyliverdiseaseareincreasinglybeing regulation werenotreported. inthe60and90μgarms.Dataonglycaemic observed in LDLcholesterolanddecreaseHDLwere arm andplacebo.However, amilddose-relatedincrease were reported to be comparable between 90 μg tropifexor as wellincreaseinFGF19.Adverseeventsandpruritus gamma-glutamyl transferaseconcentrationswasobserved with placebo.Furthermore,adose-responsedecreasein with 90μg,27.8%treated60and14.6% in33.3%ofpatientstreated MRI-PDFF wasobserved decrease inhepaticsteatosisofatleast5%assessedby alcoholic steatohepatitis( for safety, tolerability, and efficacy in patientswith non- 2 study(FLIGHT-FXR) assessingseveraldosesoftropifexor FXR agonist.Aninterimanalysisreporteddataonaphase in patientswithahighcardiovascular risk,suchpatients statin therapyforcurbingcholesterol increases,especially worrisome thatFXRagonist treatmentmaynecessitate was also seen in the FLINT trial ( and transientincreasein glycaemicparameters,as increase inplasmaLDLcholesterol,moderatepruritus, obvious downsidesofobeticholicacidtherapyarean into themetaboliceffectsofsyntheticFXRagonism: the REGENERATE trialprovidesuswithfurtherinsights vs semaglutidealone. serum alanine aminotransferase) in thecombinationarms (measured by (measured byMRI-PDFF)andliverinjury statistically significantimprovementsinhepaticsteatosis of liverhealthat24weeksin efficacyendpointsassessingbiomarkers and exploratory carboxylase inhibitor. Allregimenswerewelltolerated, agonist, withcilofexorand/orfirsocostat,anacetyl-coA evaluated combinationsofsemaglutide,aGLP-1-receptor arm trial in non-alcoholic steatohepatitis ( recently investigatedinaphase2,proof-of-concept, five- hepatic fatcontent( and furtherimprovedglucosetolerancereduced to agreaterdegree( induced obesemice,thecombinationreducedbodyweight steatosis, inflammationandfibrosis.Moreover, indiet- monotherapies intermsofreducinghepaticliverenzymes, GLP-1 receptoragonistIP118wassuperiortoeither that the co-administration of obeticholic acid and the field ( themselves constitutepromisingcandidateagentsinthe disease Targeting FXRinmetabolic FXR agonistcombinationtherapiesforthe Taken together, the18-monthinterimanalysisof 67 ). Indeed,arecentmousestudydemonstrated − 25.5%) thanIP118alone( 68 Downloaded fromBioscientifica.com at10/01/202103:48:50PM ). Thistreatmentconceptwas 66 ). At12weeks,asignificant post-hoc 36 184 , analysesshowed 55 :5 ). Indeed, it is 69 ). The trial − 12.5%) R200 via freeaccess European Journal of Endocrinology precluded clinicaldevelopment ofFGF19analoguesuntil actions ofFGF19(activation ofhepaticFGFR4)have ( also beensuggestedforthetreatment ofmetabolicdisease FGF19, thedownstreamsignalling hormoneofFXR,has FGF19-based therapyinhumans especially regardingcardiovascularriskandliverinjury. term safetyandefficacymustbeassessedthoroughly, if everapprovedfornon-alcoholicsteatohepatitis,long- as indicatedbytheFLINTandREGENERATE trials,and, metabolic consequencesofFXRagonistswarrantcaution, the Food and Drug Administration in 2018. Finally, the receiving obeticholicacidpromptedaboxedwarningby cholangitis biliary inpatientswithprimary injury event. However, postmarketreportsofseriousliver moderate pruritus being themost common adverse other FXRagonistsseemwelltoleratedwithmild-to- this regard.Thus,atfirstsight,obeticholicacidand synthetic FXRagonistscomparetosteroidalonesin At this point, clinical studies need to demonstrate how lipoprotein cholesterolchangesandpruritogeniceffects. intense discussionintheliterature,especiallyconcerning of intestinal-vsliver-specificFXRactivationisatopic in HDLcholesterolthe60and90μgarms.Theratio dose-related increaseinLDLcholesterolandadecrease less intestinallybiased,and,subsequently, yieldsamild in the liver ( still bioavailablebutmostlylackstranscriptionalactivity properties, isanintestinallybiasedFXRagonist,which to itsspecifictissuedistributionandphysicochemical at play)( patient populationsandlipidmanagementmayalsobe treatment duration,molecularstructures,potencies, systemic FXRagonism(althoughotherfactorssuchas a different balance between intestinal contra hepatic/ opposed to obeticholic acid is intriguing, and may reflect effects on serum lipids of non-steroidal FXR agonists as (non-steroidal) FXRagonists.Thelackofsignificant which havebeenreproducedinthetrialswithnewer (alanineandaspartateaminotransferase), of liverinjury well asimprovementinliverfibrosisandothermarkers serum triglycerides, and gamma-glutamyl transferase, as of obeticholicacidtherapy are adecrease in bodyweight, regarding glucose-lowering activity. On the positive sides minor effectsonlipidparametersandappearneutral steroidal FXRagonists,however, seemtoinflictonly with non-alcoholicsteatohepatitispatients.Thenon- Table 1 Review ). However, theFGFR4-dependant mitogenic 62 , 63 62 ). AccordingtoGege ). Tropifexor, on the other hand, seems D PSonne et al. , cilofexor, due 95% CI:8.0–1.9, of 7.7%vs2.7%intheplacebogroup(difference:5.0%, endpoint) reduction ofabsoluteliverfatcontent(primary fibrosis ( biopsy-proven non-alcoholicsteatohepatitisandliver serial liverbiopsies)wasconductedin78patientswith reduction. A longer phase 2 study of 24 weeks (with does notattenuatetheefficacyofNGM-282onsteatosis suggesting thattheco-administrationofrosuvastatin treatment withbothNGM-282doses,whichisconsistent cholesterol concentrationsincreased following the abdominal pain,andnausea).Asexpected,plasmaLDL grade 1adverseevents(injectionsitereactions,diarrhoea, profile wasacceptablewithmostpatientsexpediting vs 2/27(7%)intheplacebogroup.Overall,safety in absoluteliverfatcontentfrombaseline,respectively, (79%) inthe6mggroupachievedatleasta5%reduction fat fraction). 20/27 (74%) in the 3 mg group and 22/28 12 in liver fat content (assessed by MRI-proton density endpoint wastheabsolutechangefrombaselinetoweek 3 mgor6s.c.NGM-282placebo.Theprimary alcoholic steatohepatitis( phase 2studyin82patientswithbiopsy-confirmednon- tested inarandomised,double-blind,placebo-controlled variant NGM-282(alsoknownasaldaferminorM70)was effects inobesemice(fordetails,see( induce hepatocyteproliferationbutretainedantidiabetic FGF19 variantsweregeneratedwhichlackedtheabilityto the NGM-282groupvs0%in theplacebogroup( of non-alcoholicsteatohepatitis wasachievedby24%in achievement ofbothfibrosis improvementandresolution ( patients givenNGM-282vs 9% ofpatientsgivenplacebo in24%ofthe non-alcoholic steatohepatitiswasobserved 18% ofpatientsreceivingplacebo( was achievedin38%ofpatientsreceivingNGM-282 vs stage) withnoworsening of non-alcoholic steatohepatitis the previouslymentionedinitialNGM-282study( and responserateinliverfatreductionweresimilarto cholesterol inalldosegroups.Importantly, themagnitude plasma concentrationsoftotalcholesterolandLDL (week 12)resultedinrapiddecline(belowbaseline) (0.3 mg,1mgor3mg)fromweek2untilendoftreatment rosuvastatin (titratedto40mgoncedaily)withNGM-282 282 ( increase seeninpatientsreceivingtreatmentwithNGM- co-administration ofastatincouldmanagethecholesterol phase 2dosefindingstudywasinitiatedtoassesswhether reduced cholesterolcatabolism).Amulticentre,open-label, with potentFGF19-inducedinhibitionofCYP7A1(i.e. disease Targeting FXRinmetabolic P

= .0. A 0.20). 71 ). Thestudyshowedthattheco-administrationof 72 ). TheNGM-282group(1mgoncedaily)hada post-hoc P

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= 0.015). R201 70 ≥ via freeaccess ), 1 European Journal of Endocrinology https://eje.bioscientifica.com obesity, fattyliverdiseaseandinsulinresistance ( massive metabolic changes that arise as a consequence of probably of lesser importance seen in light of the type 2diabetesisaltered,thesechangesaresmalland although bileacidcompositionandmetabolism in gluco-metabolic benefit of FXR agonists. Accordingly, clinical trialshavebeenunabletodemonstratesignificant type 2diabeteshaswornofftosomedegreeasrecent initial optimismregardingclinicaleffectivenesstowards energy, glucose, and lipid metabolism. However, the indicated that FXR and bile acid signalling impact on In recent years, several animal and human studies have Conclusions significantly reducingliverfatcontent. effective inpatientswithnon-alcoholicsteatohepatitis, or type2diabetes.However, NGM-282hasprovenhighly when testedinpatientswithnon-alcoholicsteatohepatitis activity compellinglydemonstratedinanimalmodels from the field, FGF19 analogues lack the glucose-lowering glucose orHbA1c( as evidencedbythelackofsignificantchangeinplasma hyperglycaemia inpatientswithtype2diabetes( 28 daysofNGM282/aldaferminfailedtorelieve randomised, double-blind,placebo-controlledstudy, 282 treatment.Accordingly, inarecentmulticentre, in weightandBMIwerealsonotaffectedbyNGM- compared withplacebo.Placebo-correctedchanges induce changesinHbA1c,insulin,glucoseorHOMA-IR FGF19 topeakconcentrationsof0.3–2ng/mL( achieved byFXRagonists,whichelevateendogenous mL) indicatinggreaterexposurecomparedwiththat higher peakplasma NGM-282 concentrations ( with NGM-282.Thisefficacymaybeattributedtomuch group) achievedthiscombinedendpointascompared trial (4%intheobeticholicgroupvs0%placebo Interestingly, fewer patients in the REGERENATE phase 3 indirectly inhibitFXRsignalling, butsofaronlysmall only beconsideredinselected patients( and haslimitinggastrointestinal sideeffects,andshould addition, bileacidsequestrant treatmentiscumbersome LDL cholesterolandcardiovascularrisk( in HbA1c~0.5%),despitethefactthattheseagentslower low efficacyofbileacidsequestranttreatment(reduction treatment targetintype2diabetesmayalsoreflectthe The lackingoptimismwithregardtoutilisingFXRas a Review In termsofglycaemicefficacy, NGM-282didnot The ASBTinhibitorsmayrepresent anewstrategyto 74 ). Thus, contrary toexpectations ). Thus,contrary D PSonne 77 12 ). , 75 57 , , ≥ 72 n 76 10 ng/ 6 , = 81) , ). In 73 10 ). ). in metabolicphysiologyanddisease,spanningfrom of FXR.Asnoted,however, althoughFXRplaysarole are continuously gaining dominance in the targeting have moved slightly out of the limelight, FXR agonists alpha) ( peroxisome proliferator-activatedreceptoralpha(PPAR- to therepressionofPGC-1-alphaandinhibition receptor gammacoactivator-1 gluconeogenic gene peroxisome proliferator-activated induced increaseinthepromoteractivityofkey diabetes. This effect was achieved by inhibiting the FXR- and improveglucosehomeostasisinmicewithtype2 hepatocytes, suppress gluconeogenesis in mouse primary a specificFXRantagonist,HS218,hasbeenshownto examined inlargeclinicalstudiesdiabetes.However, concept ofdirectFXRantagonismhasneverbeen benefit intermsofglycaemicregulation.Theintriguing clinical studies havebeenconducted demonstrating some the public,commercialornot-for-profit sector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartiality ofthisreview. no is there that declares author The Declaration ofinterest than theirpredecessors. will gainmoresuccess,thatisconfirmativephase3trials, tropifexor), aloneorincombinationwithotheragents, whether thenon-steroidalFXRagonists(i.e.cilofexor or with non-alcoholicsteatohepatitis( rejection ofobeticholicacidforfibrosisassociated demonstrated bytheFoodandDrugAdministration’s achievement, however, isadifficulttaskasrecently – and a projected US $15 billion market ( of thelastunchartedterritoriesinpharmalandscape for the treatment of non-alcoholic fatty liver disease, one candidate agents striving to be the first approved drug numerous FXRagonistscombatagainstamultitudeof future of FXR agonists (and FGF19 analogues) lies. Here, treatment concept,suggestingthatthisiswherethe treatment of fatty liver disease constitutes a promising activation oftheFXR-FGF19signallingpathwayfor analogues) shouldfocusinsteadonliverdiseases.Indeed, the clinicaldevelopmentofFXRagonists(andFGF19 regarding theroleforFXRinglucoseregulationandthat of previousconclusionsdrawnfromanimalstudies trials remindusoftheneedforacarefulre-examination obesity tofatty liver disease and type 2 diabetes, current disease Targeting FXRinmetabolic While agentswithFXRantagonisticproperties 78 ). Downloaded fromBioscientifica.com at10/01/202103:48:50PM α (PGC-1-alpha),leading 184 80 :5 ). Time willtell 62 , 79 R202 ). 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