Pharmacotherapy for NASH: Current and emerging · Pharmacotherapy for NASH: Current and emerging...

Review

Pharmacotherapy for NASH: Current and emergingMonica A. Konerman1, Jacob C. Jones2, Stephen A. Harrison3,⇑

Summary
Keywords: Non-alcoholic stea-tohepatitis; Clinical trials; Fib-rosis; Hepatitis; Steatosis.
Received 25 September 2017;received in revised form 16October 2017; accepted 17October 2017

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liverdisease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant ofNAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbid-ity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Giventhe disease burden, there is an important unmet need for pharmacologic treatment options for thispatient population. The underlying pathophysiologic mechanisms that contribute to the developmentand progression of NAFLD and NASH are complex and reflected by the myriad of therapies, with differ-ent targets, currently under investigation. In broad strokes, drug development has focused on modula-tion of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Althoughmuch progress has been made in enhancing our understanding of NAFLD pathogenesis, developmentof pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complex-ities in clinical trial design. The compounds in phase IIa have provided promising results in terms ofpotential benefits on various aspects of histopathology. Agents in later stages of development haveshown fairly modest results in terms of reduction of hepatic steatosis, necroinflammation and fibrosis.If longer term safety and efficacy are established among heterogeneous cohorts, these medications mayhelp mitigate potential morbidity and mortality for this burgeoning patient population.� 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction
1University of Michigan,Department of Internal Medi-cine, Division of Gastroen-terology and Hepatology, AnnArbor, MI, USA2Baylor University, Waco, TX,USA3University of Oxford, RadcliffeDepartment of Medicine,Oxford, United Kingdom
⇑ Corresponding author.Address: University of Oxford,Radcliffe Department of Medi-cine, Oxford, United Kingdom.E-mail address: [email protected](S.A. Harrison).

Non-alcoholic fatty liver disease (NAFLD) hasbecome one of the most prominent forms ofchronic liver disease worldwide, as a direct resultof the obesity epidemic. The World Health Organi-zation estimates the prevalence of obesity hasmore than doubled since 1980 with >600 millionpeople (13%) having a body mass index (BMI)≥30.1 In this setting, the global prevalence of dia-betes among adults has also increased from 4.7%in 1980 to 8.5% as of 2014.2 Within the generalpopulation, the overall global prevalence of NAFLD(defined using imaging criteria) is estimated to be25% (95% CI 22.1–28.6%) though substantial vari-ability was noted across geographic regions (peakprevalence in the Middle East [31.8%] and SouthAmerica [30.4%], with the lowest rates noted inAfrica [13.5%]).3 Prevalence rates of NAFLD amongthose with metabolic disease are notably higher.Approximately a third of patients with hyperten-sion, half of patients with dyslipidaemia, up totwo-thirds of patients with type II diabetes, and>90% of patients undergoing bariatric surgeryhad evidence of NAFLD.4–10 Additional variationsin prevalence rates are attributable to gender(twice as high in men than pre-menopausalwomen) and ethnicity (higher rates in Hispanicindividuals and significantly lower rates in non-Hispanic black individuals), with ethnic variationspartly driven by genetic distributions of PNPLA3among other factors.11–13 Within the broad popu-lation of patients with NAFLD, a subset have asso-ciated inflammation and hepatocyte injury (withor without accompanying fibrosis) termed non-alcoholic steatohepatitis (NASH). The prevalence

Please cite this article in press as: Konerman MA et al. Pharmacotherapy

Journal of Hepatology 20

of NASH among patients with NAFLD is challeng-ing to assess because of the biopsy-based defini-tion. A review of liver biopsies performed inpatients with NAFLD reported NASH prevalencerates ranging from 6.7% to 59% depending onwhether the procedure was done in the absenceor presence of a specific ‘‘clinical indication”.3

Focussing on the only prospective prevalencestudy of NASH to date, the prevalence of NASHamong patients presenting for routine colon can-cer screening was 12%.14

The public health impact of NAFLD is signifi-cant given the worldwide disease burden andthe associated morbidity and mortality. Patientswith NAFLD are at higher risk of cardiovasculardisease, even when accounting for relevantmetabolic co-morbidities. In fact, cardiovasculardisease represents the leading cause of deathfor patients with NAFLD.15,16 When focussingon liver-related morbidity and mortality, NASHrepresents the third most common cause of cir-rhosis within the United States, but it is pre-dicted to become the leading cause over thenext few years.17 NASH cirrhosis is currentlythe primary aetiology for dual liver-kidney trans-plantation and is estimated to become the num-ber one indication for liver transplant by2020.18–20 Overall, the distinction between thosewith NAFLD and those with NASH is clinicallyrelevant given that multiple studies havedemonstrated that patients with NASH are athigher risk of adverse liver-related outcomes,with the degree of fibrosis contributing most sig-nificantly to this increased risk.3,21,22

for NASH: Current and emerging. J Hepatol (2017), https://doi.org/10.1016/j.jhep.2017.10.015

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https://doi.org/10.1016/j.jhep.2017.10.015

mailto:[email protected]

mailto:[email protected]

Key point

Determining optimal yetfeasible endpoints for clin-ical trials evaluating phar-macologic agents forNAFLD and NASH is com-plicated by slow progres-sion of clinically significantoutcomes.

Review

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The striking prevalence of NAFLD paired withits profound complications underscores the criti-cal need for safe, effective, and broadly applicabletherapy. Presently, there are no medicationsapproved by the Federal Drug Administration(FDA) or European Medicines Agency (EMA) forthe treatment of NAFLD or NASH, though as thisreview will detail, many agents are currently beingstudied in clinical trials. In current clinical prac-tice, vitamin E is the most commonly used medi-cation, though evidence of efficacy is limited inthose with diabetes and cirrhosis and currentAASLD and EASL guidelines recommend its usebe restricted to patients with NASH in the absenceof diabetes and cirrhosis.23,24 This recommenda-tion is largely based on data from the PIVENS trialwhere subjects randomised to 800 IU/day of vita-min E for 96 weeks demonstrated improvementsin steatosis (p = 0.005), lobular inflammation(p = 0.02) and ballooning (p = 0.01), as well asresolution of NASH (43% vs. 19% in placebo arm,p = 0.001), but no improvement in fibrosis(p = 0.24).25 There have also been subsequentsafety concerns regarding the use of vitamin E, asdata suggest a possible increased risk of overallmortality and higher rates of prostate cancer,though this remains controversial.26–28

The insulin sensitiser pioglitazone, a thiazo-lidinedione, has been well studied and prescribedby some for the treatment of NASH, usually in linewith diabetic practice guidelines. Pioglitazone hasbeen extensively evaluated in clinical trials withfairly consistent improvements in various featuresof NASH and less consistently fibrosis. When eval-uated in a meta-analysis, there was an overallimprovement in the histopathologic componentsof NASH (ballooning RR 1.62 and OR 2.11, steatosisRR 2.03 and OR 3.39, and inflammation RR 1.71and OR 2.58), with improvements in fibrosis (RR1.38 and OR 1.68).29–31 The major downside tothe use of pioglitazone is patient and physicianacceptance, given its propensity to induce weightgain (average 4.4 kg).25 It should not be used inpatients with clinically evident heart failure andmay promote post-menopausal bone loss.32,33

Given the increasing disease burden and limitedefficacy and safety of current treatment options,the development of additional pharmacologictherapies to treat NASH is critical. This review willhighlight the process of therapeutic clinical trialdesign, challenges in clinical trial recruitment,metabolic and antifibrotic agents under investiga-tion, and an overview of the future landscape ofpharmacologic design once initial agents areapproved.

Endpoints in clinical trials on NAFLD andNASHDetermining optimal yet feasible endpoints forclinical trials evaluating pharmacologic agents forNAFLDandNASH is complex, because of the chronic

onerman MA et al. Pharmacotherapy for NASH: Current and emerging. J He

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nature of the disease, with typically slow progres-sion to clinically significant outcomes.34 Subse-quently, relevant and acceptable surrogateendpoints need to demonstrate efficacy before theonset of long-term complications. In addition, theinterconnected and dynamic nature of metabolic,inflammatory and fibrotic aspects of the disease,in response to an intervention, add to the difficultyin identifying clear andprecise endpoints. Althoughthe presence of NASH has been clearly linked withfibrosis development, an individual treatment canhave different impacts on these two endpoints(i.e. treatment with drug X can improve NASH butworsen fibrosis and vice versa). Moreover, duringdisease progression fibrosismayworsen, while fea-tures of steatohepatitis resolve or ‘‘burnout”. As aresult, NASH andfibrosis need to be evaluated inde-pendently to ensure a beneficial impact on oneparameter does not simultaneously result in a neg-ative impact on another endpoint of interest, partic-ularly given that individual treatments tend tofocus on one primary mechanism of action (i.e.metabolic or NASH disease modifier vs. antifi-brotic). Moreover, many of the outcomes of interestinvolve histological parameters, which pose aunique set of barriers and limitations. This includesinherent limitations of liver biopsy such as interob-server reliability and sampling error. Early phasetrials are investigating whether relevant or predic-tive information can be derived from shorter-termendpoints to inform future trials. The challengeremains with long-term registration trials, whichare required to demonstrate that clinically benefi-cial outcomes are in linewith FDAandEMArequire-ments. This has led to the use of surrogateendpoints for accelerated approval in the US andconditional approval in Europe.

Histological endpointsHistological endpoints to assess response to atherapeutic intervention can be broadly dividedinto those meeting a numerical reduction in oneof two accepted scoring systems: NAFLD ActivityScore (NAS) or Steatosis Activity and Fibrosis(SAF) score or the resolution of NASH as deter-mined by a qualified hepatopathologist.35,36 Whenchange in the NAS is used as a primary outcome, itis recommended that ≥2 point improvement intotal score be achieved with contribution frommultiple parameters of the NAS, alongside noworsening of fibrosis.37 For trials evaluating reso-lution of NASH, this is defined as a complete reso-lution of hepatocyte ballooning, withinflammation scores of 0 or 1, in addition to noworsening of fibrosis, though there is no specificrequirement regarding change in steatosis. Clinicaltrials with a focus on improvement in fibrosismust similarly require no worsening in NASH.

Biomarkers as potential surrogates for histologyBecause of the limitations and concerns regardinghistological endpoints, there is mounting interest

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in identifying study endpoints that utilise non-invasive technologies for assessment of fat,inflammatory and fibrotic changes in response toa therapeutic intervention (Fig. 1). Promising diag-nostic algorithms are being developed to identifypatients at risk, with a certain level of NASH sever-ity and fibrosis.38 Imaging assessments are gainingmomentum as a surrogate for liver histopathology,although it is premature to comment on when andif this technology will replace histopathology.Non-invasive methods to identify hepatic steatosisinclude controlled attenuation parameter (CAP)assessment as part of vibration controlled tran-sient elastography (FibroscanTM), and MRI basedimaging in the form of proton density fat fraction(PDFF) and multiparametric MRI (LiverMul-tiscanTM). In this scenario, FibroscanTM CAP may beeasier to obtain, but is not as accurate at quantify-ing grades of steatosis as MRI.39 Furthermore, theaccuracy with which CAP reflects histologicsteatosis improvement over time has not beendemonstrated. These novel non-invasive biomark-ers are being used in clinical trials, and will needfurther data and regulatory qualification beforethey can replace a liver biopsy, both in clinical tri-als and subsequently in clinical practice.

At present, there are a limited number of non-invasive tools to accurately assess changes in liverinflammation/ballooning. Measurements of liver-associated enzymes, particularly alanine amino-transferase (ALT) and aspartate aminotransferase(AST) have historically been utilised and shouldbe obtained. Markers of apoptosis, such as CK-18,have been studied, but may not accurately reflectchange in histology over time. Recently, multi-parametric MRI, such as LiverMultiScanTM, hasgained attention for assessment of necroinflam-mation and shows promise in this area, althoughmore confirmatory data is needed.40

Biomarker assessment of fibrosis is still lim-ited as we are unable to provide a precise assess-ment of the directionality of fibrosis over time,because of the dynamic balance between fibroge-nesis and fibrinolysis. When analysing agentsthat are focussed on modulating fibrotic path-ways, imaging based biomarkers such as tran-sient elastography, multiparametric MRI ormagnetic resonance elastography (MRE) can beapplied.39,41,42 In this setting, it appears thatMRE may be the most accurate method for fibro-sis assessment. Further study is needed to deter-mine the accuracy of each of these methods forassessing fibrosis change with therapy and thevariation with time (coefficient of variation).Among the clinical and serological or so called‘‘wet biomarkers” and other non-invasive toolsfor fibrosis assessment, pro-C3, Fibrosis-4, NAFLDfibrosis score and the enhanced liver fibrosis(ELF) score (an algorithm of hyaluronic acid,amino-terminal propeptide-of-type-III-collagen,tissue-inhibitor of matrix metalloproteinase-1)appear to have promise.43–46


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Clinical endpointsAs discussed earlier, therapies ultimately need todemonstrate efficacy on long-term clinical out-comes. Prior studies have estimated that from aclinical outcomes perspective, approximatelyone-third of patients have stable disease, one-third have progressive disease and one-third haveimproved disease stage over 14 and 7 years, forpatients with NAFLD and NASH, respectively.47

The indolent and dynamic bidirectional nature ofdisease progression poses challenges in the assess-ment of these outcome types among individualswith early stage disease. The most appropriateendpoints vary depending on the stage of diseasebeing studied. In the setting of cirrhosis, relevantendpoints include changes in degree of portalhypertension or the development of hepaticdecompensation. In clinical trials of cirrhosis, all-cause and liver-related mortality are also impor-tant and tenable outcomes.37 Changes in portalhypertension, which is tightly linked to clinicaloutcomes, can be assessed directly through mea-surement of the hepatic venous pressure gradient(HVPG) or determined by the impact of the inter-vention on liver-related events. To evaluatechanges in hepatic synthetic function and thedevelopment of hepatic decompensation, serialmonitoring of Child-Turcotte-Pugh (CTP) score,model for end-stage liver disease (MELD) score,and new onset or worsening of liver-relatedevents such as ascites, variceal bleeding, hepaticencephalopathy and HCC are needed. Other non-invasive serial monitoring tests to assess changesin liver function are being investigated, includingthe methacetin breath test and HepQuant.48,49

SafetyDrug induced liver injury and other toxicity sig-nals will make an otherwise viable therapeuticagent untenable and this needs to be determinedas early in development as possible. Therefore,early phase clinical trials must carefully assesssafety and tolerability. Since NASH is a largelyasymptomatic disease, a drug with a burdensomeside effect profile may not be acceptable. Further-more, a viable potential treatment cannotadversely impact cardiovascular risk, as this isthe most common cause of death in patients withNASH.

Determining the appropriate clinical trialdurationNASH is a chronic disease like diabetes and it islikely that any intervention will need to be poten-tially life-long, though this may depend on thedrug’s mechanism of action. Similarly, careful con-sideration of the drug’s mechanism of action andtarget endpoint in the context of the phase ofdevelopment will determine the appropriate triallength. As a result, determining the appropriateduration of clinical trial length is a balancebetween having sufficient time to reach the


Hepatology 2017 vol. xxx j xxx–xxx 3


Outcomes Hard endpoints Surrogate endpoints

Clinicaloutcomes

Metabolicoutcomes

Fibrosisoutcomes

• All cause mortality• Liver-related mortality• Hepatic decompensation• Progression to cirrhosis

• Reduction in hepatic fat content• Improvement in insulin resistance• Impact on lipids• Change in weight/BMI

Inflammatoryoutcomes

• Change in fibrosis stage

• Change in necro-inflammation• Change in hepatocyte ballooning

Δ FS kPa and MREΔ Wet biomarkers-pro-C3, FIB-4, NFS, ELF

Δ CTP and MELD scoresΔ HVPGΔ FS kPa and MREΔ Wet biomarkers-pro-C3, FIB-4, NFS, ELF

Δ Multiparametric MRIΔ Liver enzymes

Δ MRI-PDFF, multiparametric MRI, CAPΔ HbA1c, fasting glucose, HOMA-IR

Fig. 1. Endpoints in clinical trials on NAFLD and NASH. BMI, body mass index; CAP, controlled attenuation parameter; CTP,Child-Turcotte-Pugh; ELF, enhanced liver fibrosis; FS, fibroscan; HOMA-IR, homeostatic model assessment and insulinresistance; HVPG, hepatic venous portal gradient; MELD, model for end-stage liver disease; MRE, magnetic resonanceelastography; NFS, NAFLD fibrosis score; PDFF, proton density fat fraction.

Key point

The design of each phase ofa clinical trial for a poten-tial therapeutic agent isstrongly influenced by thedrug’s mechanism ofaction.

Review


4

efficacy endpoint and the need to continuallyassess the risk of chronic exposure over longerperiods. In general terms, phase II trials are ofshorter duration since they are meant to providean efficacy signal before proceeding to a pivotaltrial. Subsequently, phase III trials typically testmore definitive endpoints for a longer duration,often extending multiple years. Post marketapproval, surveillance of patients on long-termtherapy will be critical to ensure long-term safety,tolerability and sustained effect. There are manyunknowns regarding the natural history of liverdisease progression in NASH, thus determiningthe time course for overall outcomes assessment(including liver-related outcomes, adverse eventprofiles and safety) may be imprecise until morerobust data are available.

Developmental pathway: phase IIA, IIB,and IIIIn NASH, the developmental pathway fortherapeutic agents involves navigating multiplecomplexities that include the non-linear, hetero-geneous nature of disease progression, bi-directionality of disease state and the limitationsin identifying clinically relevant shorter-term out-comes, as previously outlined. The design of eachphase of a clinical trial for a potential therapeuticagent is strongly influenced by the drug’s mecha-nism of action (Fig. 2). In addition, characteristicsof the patient population under study heavilyinfluence trial design. In this review, we have onlyfocussed on adult studies as paediatric drug devel-opment pathways differ significantly. Phase IIa tri-als focus on proof of concept (POC) and short-termsafety. As a result, phase IIa trials have truncatedtime courses of evaluation. This creates challenges



for the selection of relevant endpoints given thatpharmacologic agents for the treatment of NASHand especially fibrosis have a low likelihood ofinducing clinically significant improvements overthis short time frame. In addition, paired liverbiopsies performed at short intervals can raiseethical concerns given the potential risk to thepatient. In the absence of histology, phase IIa stud-ies should employ early surrogate endpoints thatare aimed at confirming target engagement ofthe experimental compound, in addition to safety.It is important to understand that these non-invasive markers are currently unapproved surro-gates for histology and simply allow for initial POCtesting for target engagement.

Assuming that phase IIa trials provide encour-aging results, subsequent phase IIb and phase IIIstudies should focus on confirming therapeuticdose, verifying clinical efficacy via histologyand assessing long-term clinical outcomes ofNASH patients. Large clinical trials with pairedbiopsy designs provide an invaluable opportunityto test non-invasive disease surrogates that maysomeday supplant histology or provide an earlyefficacy or futility signal. Surrogate non-invasiveendpoints could be assessed along the way withpaired histology as well. After initial approval,subsequent phase IIIb clinical outcome studiescontinue to evaluate longer term safety and effi-cacy. Adaptive trial designs may be a feasibleoption to overcome some of the existing com-plexities in clinical trial design for NASH. Adap-tive designs allow for planned modifications inone or more aspects of the study design basedon response in earlier phases. This approachcan potentially limit the total number of patientsneeded to enroll over the entire process of indi-vidual drug development, by allowing patients to


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Phase IIa

Phase IIb

Phase III

· Multiple time points for assessment

· Interim analysis to consider dropping study arms and re-randomisation

· Cover aims of phase II and III trials sequentially

· Proof of concept

· Short term safety

· Clarify target engagement

Truncated:12-24 wk

· Assess efficacy

· Safety and adverse events

· Therapeutic dosing

Intermediate:24-72 wk

Longer term:years

Liver biopsynot required

Δ hepatic fat viaMRI-PDFF or CAP

· Δ liver enzymes and other biomarkers

· Multiparametric MRI

· Δ biomarkers

· MRE, FS kPa

Paired liverbiopsy

Δ hepatic fat viahistology

± MRI-PDFF/CAP

· Δ inflammation and ballooning (NAS)

· Resolution of NASH w/o worsening of fibrosis


· Δ fibrosis stage w/o worsening of NASH

· MRE, FS kPa

· Progression to cirrhosis· Hepatic decompensation· Overall mortality· Liver-related mortality· HCC· Transplantation

Δ hepatic fat viahistology

± MRI-PDFF/CAP

· Δ inflammation and ballooning (NAS)

· Resolution of NASH w/o worsening of fibrosis


Focus

· Confirm efficacy

· Longer term safety and efficacy· Clinical outcomes

Timeline Endpoints

Paired liverbiopsy

Metabolic Inflammatory Fibrosis

· Δ fibrosis stage w/o worsening of NASH

· MRE, FS kPa

Clinical

Adaptive

Paired liverbiopsy

· Δ hepatic fat via MRI-PDFF or CAP early part of trial

· Δ hepatic fat via histology later part of trial

· Δ liver enzymes and other biomarkers or multiparametric MRI early part of trial

· Δ histology later part of trial

· Δ biomarkers, MRE and FS kPa early part of trial

· Δ histology later part of trial

· Assess clinical outcomes at end of trial

Fig. 2. Clinical trial design for studies on NAFLD and NASH. CAP, controlled attenuation parameter; FS, fibroscan; HCC, hepatocellular carcinoma; MRE,magnetic resonance elastography; MRI, magnetic resonance imaging; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholicsteatohepatitis; PDFF, protein density fat fraction.


transition through multiple phases of the study(Fig. 2).37,50,51 Based on results of interim analy-ses, preplanned adaptations such as discontinu-ing specific study arms, randomising additionalpatients, or stopping the study entirely can beimplemented.

Current challenges in clinical trialrecruitmentPharmacologic treatment trials in NASH are enrol-ling patients at a slower pace than treatment trialsin other disease states. This is explained by severalpotential factors including low disease awarenessamong patients and providers, as well as barriersto enrollment such as complex enrollment criteriaand the need for multiple liver biopsies. Untilawareness on many levels improves, most patientswill go undiagnosed. NAFLD/NASH disease stateawareness at the patient, primary care and spe-cialty provider level is very low. Survey studiesof knowledge about NAFLD among the generalpopulation have consistently shown low levels ofawareness. This remains true even in patients withmultiple metabolic risk factors who have a highlikelihood of having underlying NAFLD.52,53 Fur-ther complicating this is the fact that many provi-ders perceive NAFLD as a benign entity andsubsequently, many patients with a high likeli-hood of NAFLD do not complete formal evaluationto confirm the diagnosis and are not subsequentlyreferred to specialists who are involved in clinicaltrial recruitment.54,55 Primary care physicians,endocrinologists, gynaecologists, cardiologistsand to some extent gastroenterologists lack


Journal of

awareness of NAFLD/NASH progression and itsassociated risk factors. Once patients have theopportunity to enroll in a clinical trial, multiplebarriers complicate patient acceptance and subse-quent enrollment. Because of a lack of reliable sur-rogates and reliance on histology, many studiesrequire multiple liver biopsies, particularly in themore advanced phase trials. The sheer volume ofclinical trials in this disease space has also con-tributed to slow enrollment. Finally, due to thecomplex and heterogeneous nature of the disease,the inclusion and exclusion criteria for enrollmentin NAFLD/NASH clinical trials have made it chal-lenging to enroll. Many trials have restrictions onage, BMI, ALT, AST, haemoglobin A1c and bilirubinelevations. Restrictions on patients with a historyof cancer or bariatric surgery, as well as on thosetaking concomitant medications have furtherhampered enrollment.

Once patients with established NAFLD are iden-tified, there are additional challenges in identify-ing the subset of patients with NASH and fibrosisthat are eligible for enrollment in current treat-ment trials. Liver biopsy is infrequently performedin clinical practice and many patients without apre-existing biopsy are hesitant to have one per-formed. One potential option for streamliningenrollment and limiting screening failures is toapply a risk stratification approach, that uses datagleaned from studies investigating risk factors forthe presence of NASH with fibrosis in the largerpool of patients with NAFLD (Fig. 3).56–58 Whilethe ideal algorithm to identify patients with NASHremains to be found, this approach provides somegeneral guidance that may help to stratify patients




High likelihood of

NASH and fibrosis

Intermediate likelihoodof NASH and fibrosis

Low likelihood of NASH and fibrosis

Age >50, Hispanic, DM, obesity, HTN, FS kPa >8.5, AST >40, AST/ALT ratio ≥1, NFS >0.676, FIB-4 >2.67

Age >40, well-controlled DM, obesity, HTN, FS kPa >7.0, AST >20

Age <40, non-DM, non-obese, FS kPa <7, AST <20, NFS <-1.455, FIB-4 <1.30

Pre-screening criteria for NASH clinical trials

Fig. 3. Pre-screen criteria for NASH clinical trials. AST, aspartate aminotransferase; ALT,alanine aminotransferase; DM, diabetes mellitus; FS, fibroscan; HTN, hypertension; NASH,non-alcoholic steatohepatitis; NFS, non-alcoholic fatty liver disease fibrosis score.

METABOL

↓VLDL

↑SHP

↑FXR/TGR5

Bile acids

BMS-

FG

↓Adip↑T↑

↑SREPB

FGF-1

NGM 28

FXR ago

Volixiba

Fig. 4. Mechanism of action ofApoptosis signal-regulating kinareceptor; IL, interleukin; LPS, lipelement binding proteins; TGF,response; Jun N-terminal kinase

Key point

Only a small proportion ofpharmacologic treatmentsevaluated in phase II pro-gress to phase III and evenfewer progress to market.

Review


6

into high, intermediate and low likelihood ofmeeting enrollment criteria.

NASH is a heterogeneous disease with a corre-spondingly complex pathophysiology, whichincludes redundant pathways that may not be uni-form across patients. This heterogeneity and

IC

986026

F-21

onectinNFαFFA

Aramchol

PPAR agonists

MGL-3196

Insulin resistance

↑Insulin/glucose

↑Lipogenesis

↑FFA↑DNL-1

9

2

nist

t

TRβ

Insulinsensitizers

MSDC 0602k

ACC inhibitors

ER stress

↑UPR ↑JNKCollagendeposition

LPS

Mitochondrialdysfunction

ROS

Anti-fibroticSIM

GR-MD-02

ACC

pharmacologic treatments for NAFLD and NASH. ACC, Acetyl-Cse; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FGF, fiopolysaccharide; ROS, reactive oxygen species; SIM, simtuzumTransforming growth factor; TLR, toll like receptor; TNF, tumors; VLDL, very low density lipoprotein.



complexity has made finding a single agent toeffectively treat most patients a challenge. How-ever, its complex pathophysiology permits thedevelopment of a wide array of potentially viabletherapeutic targets (Fig. 4). A concise summaryof the efficacy of pharmacologic agents in laterstages of development is displayed (Fig. 5), withmore detailed description of the individual agentsand clinical studies provided later.

Phase IIB and IIA pharmacologic agentsThere are currently multiple agents in phase IIaand IIb clinical trials. However, only a small pro-portion of pharmacologic treatments evaluated inphase II progress to phase III and even fewer pro-gress to market. The following section attempts tosummarise the many compounds in developmentwith the caveat that this is a rapidly evolving land-scape and this represents a snapshot in time.Available published data are summarised belowand in cases where preliminary human data arenot yet in published form, these studies are sum-marised (Table 1). It is important to note the sig-nificant differences in inclusion and exclusioncriteria that, as mentioned, are largely driven by

EmricasanASK-1 inhibitor

Hepatic stellatecell activation

CCR2/5inhibitors

↑TGF-β↑TNF-α

↑IL-6

↑TLR-4

Kupffer cell

JKB-121

AOC3Inhibitors

Immune celltrafficking

IMM-124E

RegulatoryT cells

ANTI-INFLAMMATORY

SGLT

LIK066

ANTI-FIBROTIC

Apoptosis

oA Carboxylase; AOC, amine oxidase, copper containing; ASK,broblast growth factor; FFA, free fatty acids; FXR, Farnesoid Xab; SHP, small heterodimer partner; SREBP, Sterol regulatorynecrosis factor; TR, thyroid receptor; UPR, unfolded protein


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100

90

80

70

60

50

40

30

20

10

0

Improvement in hepatic steatosis 100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

Per

cent

age

of p

atie

nts

Vitamin

E25

Pioglita

zone

25

OCA84

Elafibr

anor

90

Vitamin

E25

Pioglita

zone

25

OCA84

Elafibr

anor

90

Vitamin

E25

Pioglita

zone

25

OCA84

Cenicr

iviroc

97

Per

cent

age

of p

atie

nts

Per

cent

age

of p

atie

nts

Resolution of NASH Improvement in fibrosis

SEL^10

0

p = 0.005 p <0.001 p = 0.001 p = 0.10

p = 0.05 p = 0.001 p = 0.08 p = 0.01 p = 0.24 p = 0.12 p = 0.004 p = 0.02 p = n.s.

A B C

54

31

69

61

3835

18

3136

21

47

22

13

29

5

21

41

31

44

35

19 20

10

37

20

31

43/80

22/72

48/70

22/72

62/102

37/98

11/31

7/39

29/80

15/72

33/70

15/72

22/102

13/98

9/31 2/39

33/80

22/72

31/70

22/72

36/102

19/98

29/145

15/144

21/57

2/10n

DrugPlacebo

Fig. 5. Improvement with pharmacologic agents.* (A) On hepatic steatosis (B) resolution of NASH and (C) Fibrosis. *Results are from separate studies and nota reflection of head to head direct comparison of listed agents on outcomes of interest. Trials for individual treatment agents employed different enrollmentcriteria and durations of therapy, and the primary endpoint definitions were not identical. ^SEL study compared SEL ± SIM to SIM alone, not placebo. Data herereflects arms with SEL compared to SIM arm alone. NASH, non-alcoholic steatohepatitis; n.s., not significant; OCA, obeticholic acid; SEL, selonsertib.


the mechanism of action employed by each treat-ment agent being investigated.

Phase IIAThere are many pharmacologic agents in phase IIaclinical trials, but only a few have presented orpublished preliminary results. NGM282 is an engi-neered variant of human fibroblast growth factor(FGF)-19 that works via FGFR4 and FGFR1c tomodulate bile acid synthesis and affect multiplemetabolic pathways. A recent phase IIa, ran-domised, placebo-controlled trial enrolled 82patients with biopsy confirmed NASH (NAS ≥4with one point in each component, with fibrosisstage 1/2/3) with a minimum of 8% absolute liverfat content by MRI-PDFF and abnormal ALT (≥19IU/L females, ≥30 IU/L in males). Subjects wererandomised to 3 mg of NGM 282 (n = 27), 6 mgof NGM 282 (n = 28), or placebo for 12 weeks.The primary endpoint was change in hepaticsteatosis (decrease in absolute liver fat ≥5%).59

There was a significantly higher proportion ofpatients in the treatment arm who achieved theprimary outcome than in the placebo arm (79%vs. 7%). Of those in the treatment arm, 34%achieved normal (<5%) liver fat content (comparedto none in placebo). ALT also normalised in 35%and 37% of subjects in the 3 mg and 6 mg armscompared to an average 2% reduction in theplacebo arm (p <0.001), reductions that correlatedwith decreases in liver fat content.

BMS-986026 is a recombinant pegylated FGF21analogue that has also been identified as having aneffective role in metabolic regulation. This FGF21analogue has beneficial effects on metabolism via


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increased adiponectin expression, improved insu-lin sensitivity and decreased lipogenesis. A phaseIIa, double-blind, placebo-controlled study,enrolled patients with biopsy proven NASH withfibrosis stage 1–3, BMI ≥25, and hepatic fat frac-tion ≥10% on MRI-PDFF. Patients were randomisedto 10 mg of BMS-986026 daily (n = 25), 20 mgevery week (n = 23), or placebo (n = 26) for 16weeks and assessed for decreases in hepatic fatfraction.60 Patients in the treatment arms had sig-nificantly reduced absolute hepatic fat fraction(�6.8 in the 10 mg daily arm, �5.2 in the 20 mgweekly arm, vs. �1.3 in the placebo arm; p =0.008) and improvements in serum ALT. Therewere also some improvements in surrogate mark-ers of fibrosis measured by MRE (36% and 33% ofpatients in the 10 mg daily and 20 mg weeklyarms, respectively, had ≥15% reduction in liverstiffness compared to 7% in the control arm) andpro-C3, as measured by adjusted percent improve-ment from baseline (30%, 21% and 1.9% in the 10mg daily, 20 mg weekly, and placebo arm, respec-tively). Improvements in metabolic parameters(adiponectin and lipids) were also seen.

Glucagon-like peptide-1 (GLP-1), a member ofthe glucagon peptide family, promotes severalbeneficial traits, including reduced hepatic steato-sis and insulin resistance, as well as increasedweight loss.61GLP-1 analogues such as liraglutideand semaglutide are currently being utilised forthe treatment of type 2 diabetes, and are beingevaluated in NASH. The LEAN trial, a phase II, ran-domised, placebo-controlled trial evaluated sub-cutaneous injections of liraglutide (1.8 mg daily)(n = 23) compared to placebo (n = 22) for 48 weeks




Table 1. Pharmacologic agents in Phase IIa studies for treatment of NAFLD/NASH.

Mechanism of action Company (Product name) Condition and stage Primary endpoint(s) N Duration (wk)

FXR agonist non-bile acidNovartis (LJN452) NASH, stage 0–3, elevated ALT, OR

PDFF >10%, obesity, DM2Adverse event profile, safety, improvement in ALT 250 12

Novartis (LMB763) NASH, stage 0–3, elevated ALT, ORPDFF >10%, obesity, DM2

Adverse event profile, safety, improvement in ALT 100 12

FXR agonist non-bile acid + ACC inhibitorGilead (GS-9674) MRE >2.5 kPa, PDFF >10% Safety and tolerability 140 24Gilead (GS-976 + GS-9674) MRE ≥NASH 2.88 kPa, PDFF ≥10%, OR

MRE >4.67 kPa, not compensated, ORNASH, stage 2–3

Safety and tolerability 110 12

PPAR-a/y agonistZydus (saroglitazar) NAFLD stage 0–3, ALT >1.5 ULN Percent change in ALT 104 16

PPAR-a/d/y agonistInventiva Pharma (IVA337) NASH, SAF fibrosis score <4 Improvement in SAF without worsening fibrosis 225 24

GLP-1 analogueNovo Nordisk (liraglutide) NASH, fibrosis 1–4, compensated Resolution of NASH without worsening of fibrosis 52 48Novo Nordisk (semaglutide) NASH, stage 2–3 fibrosis Resolution of NASH without worsening of fibrosis 372 72

ACCiGilead (GS-0976) NAFLD OR NASH without cirrhosis Safety and tolerability 127 12Pfizer (PF-05221304) MRE ≥2.5 kPa, PDFF ≥8%

NASH, stage 1–3Change in hepatic fat 360 16

FGF-19 agonistNGM BIO (NGM282) NASH, stage 1–3 Change in hepatic fat 140 12

Recombinant FGF-21BMS (BMS986036) NASH, stage 1–3 Change in hepatic fat 74 16

TLR-4 antagonistTAIWAN J (JKB-121) NASH, stage 1–3 Improvement in ALT and change in hepatic fat 66 24

Thyroid hormone receptor-B agonistMadrigal (MGL-3196) NASH, stage 1–3 Change in hepatic fat 125 36

ASBT inhibitorShire (volixibat) NASH, stage 0–3 Improvement in NAS without fibrosis worsening 266 48

mTOT modulating insulin sensitizerCirius (MSDC 0602k) NASH, stage 1–3 Improvement in NAS without fibrosis worsening 380 48

Sodium glucose cotransporter 1 and 2 inhibitorNovartis (LIK066) NASH, stage 1–3 Percent change in ALT 110 12

AOC3 inhibitorBoehringer Ingelheim (BI 1467335) NASH stage 1–3, OR

MRE ≥3.64 kPa, PDFF ≥5%Target enzyme activity relative to baseline in percent, 24 h post dose 150 Up to 16

Induction of regulatory T cellsIMMURON (hyperimmune bovine colostrum) NASH, stage 0–3 Change in hepatic fat 130 24

ACC, acetyl-coA carboxylase; ALT, alanine aminotransferase; AOC3, amine oxidase copper containing-3; ASBT, apical sodium dependent bile acid transporter; DM2, type 2 diabetes; FGF, fibroblast growth factor; FXR, farnesoid Xreceptor; GLP-1, glucagon-like peptide-1; MRE, magnetic resonance elastography; mTOT, mitochondrial target of thiazolidinediones; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PDFF, protondensity fat fraction; PPAR, peroxisome proliferator-activated receptor; TLR, toll-like receptor.

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in overweight subjects with NASH. The primaryendpoint was resolution of NASH without worsen-ing of fibrosis. In the treatment arm, resolution ofNASH was observed (p = 0.019) and ballooningimproved (p = 0.05), but fibrosis worsened (p =0.04).62 Based on these results, semaglutide, butnot liraglutide, is now being assessed in a largerphase IIa multi-centre study.

Acetyl-CoA carboxylase (ACC) inhibitors are ofinterest given that ACC activation promotes lipidstorage via stimulation of lipogenesis and inhibi-tion of lipid oxidation.63 Mouse models of ACCinhibitors have shown that these agents canreduce liver triglycerides, but were also noted toincrease plasma triglycerides.64 Two ACC inhibi-tors are currently in phase IIa trials (GS-0976and PF-05221304).65 Preliminary data from a 12-week clinical phase IIa trial of GS-0976 is avail-able. In this trial, 10 patients with NASH weregiven 20 mg of GS-0976 daily. There were statisti-cally significant improvements in liver fat contentand non-invasive markers of fibrosis. Specifically,there was a median relative decrease in liver fatcontent measured by MRI-PDFF (15.7% to 9%, p =0.006), and a reduction in median liver stiffnessfrom 3.4 to 3.1 kPa (p = 0.049) assessed byMRE.66 A separate phase II, randomised, placebo-controlled trial evaluating GS-0976 in 127 subjectswith NASH is underway to further assess safetyand efficacy.67

Hyperimmune bovine colostrum has beendemonstrated to regulate the body’s immuneresponse via induction of regulatory T cells, whichin turn impact inflammation and insulin resis-tance.68 Data from an initial trial of 10 patientswith NASH and insulin resistance treated withIMM-124E for 30 days resulted in improvementsin insulin resistance and lipid profiles andincreased levels of T regulatory cells.69 This isbeing further investigated in a randomised,placebo-controlled, phase II trial in 130 patientswith NASH.70

Phase IIB: AramcholAramchol is a novel synthetic fatty acid/bile acidconjugate that impacts lipogenesis. Aramcholupregulates the ABCA1 reverse cholesterol trans-porter and functions as a partial inhibitor ofstearoyl-CoA desaturase 1 (SCD1), a rate-limitingenzyme in the biosynthesis of monounsaturatedfatty acids in the liver. In a phase II, randomised,placebo-controlled trial, six patients with biopsyproven NASH and 60 patients with NAFLD wereevaluated. The primary endpoint was a change inhepatic steatosis by nuclear magnetic resonancespectroscopy (NMRS). In this trial, patients wererandomised 1:1:1 to aramchol 300 mg/day, 100mg/day, or placebo for 12 weeks.71 Evaluation atmonth three showed a relative improvement inliver fat content of 12.57% ± 22.14 compared to 6.39% ± 36.27 in the placebo group (p = 0.02). Thesefindings are being further evaluated in a phase IIb,


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randomised, placebo-controlled trial in over-weight/obese adults with biopsy confirmed NASH,and type II diabetes/prediabetes. In this trial,patients were randomised 2:2:1 to aramchol 400mg/day, 600 mg/day, or placebo for 52 weeks withan additional 13-week follow-up period. The pri-mary outcome was percentage change in livertriglyceride content measured by NMRS. Second-ary outcomes of interest included: the proportionof patients with a NAS improvement, withoutworsening of NASH; the proportion with a NASimprovement ≥2, without worsening of fibrosis;the proportion with SAF score improvement ≥2,without worsening of fibrosis; the proportion withNASH resolution (ballooning 0, inflammation 0 or1), without worsening of fibrosis and change inALT.72

Phase IIB: EmricasanEmricasan is a pan-caspase inhibitor that hasbeen shown to decrease portal hypertension byblocking apoptotic and inflammatory caspaseactivation involved in hepatocyte cell death.73 Ina phase IIa study of patients with a baselineHVPG of 12 mmHg, patients treated with emric-asan over 28 days had a 17.2% decrease in HVPGand a significant decrease in AST and ALTlevels.74 These findings are being further exploredin multiple phase IIb studies. ENCORE-NF is amulticentre, randomised, placebo-controlled trialof patients with biopsy proven NASH and fibrosis,but not cirrhosis, that has completed enrollment.In this study, patients were randomised to 5 mgvs. 50 mg vs. placebo for 72 weeks, with a pri-mary endpoint of improvement in fibrosis ≥1stage without worsening of steatohepatitis.75

Two subsequent phase IIb trials are also under-way in NASH patients with either cirrhosis andsevere portal hypertension (HVPG ≥12 mmHg)or decompensated cirrhosis. These studies willlook for improvement in HVPG over 24 weeksor improving event-free survival relative to pla-cebo, respectively.76,77

Phase IIB: GR-MD-02Galectin-3 is a protein expressed in immune cellsthat has been shown to play a key role in fibroge-nesis. GR-MD-02 is a carbohydrate that functionsas a galectin-3 protein inhibitor. Animal studiesusing galectin-3 protein inhibitors have demon-strated a decrease in fibrosis which has subse-quently been replicated in phase I humanstudies.78 An initial phase IIa trial of GR-MD-02given over 16 weeks assessed change in fibrosisby MRI in 30 patients with biopsy proven NASHand stage 3 fibrosis.79 Although this study didnot achieve its primary endpoint, this agent isundergoing subsequent evaluation in a longerterm (one year), randomised, placebo-controlled,phase IIb trial in patients with compensated NASHcirrhosis and portal hypertension (HVPG ≥6mmHg). Patients receive GR-MD-02 IV every two




Key point

Currently OCA is beingevaluated in a large phaseIII, randomised, placebo-controlled trial.

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weeks or placebo for 52 weeks.80 Enrollment hascompleted and results are expected towards theend of 2017.

Pharmacologic agents currently in phaseIII of developmentObeticholic acidObeticholic acid (OCA) is a semi-synthetic deriva-tive of the primary human bile acid chenodeoxy-cholic acid (CDCA) and functions as an agonist ofthe farnesoid X receptor (FXR). OCA downregu-lates hepatic glucose and lipid metabolism bydownregulating SREPB-1c and reducing endoge-nous bile acid production, via upregulation ofFGF19 which then inhibits CYP7A1, the rate-limiting enzyme for the conversion of cholesterolto bile acids.81 In addition to these primary meta-bolic effects, OCA may also decrease portal pres-sure by increasing iNOS and displaying a widerrange of anti-inflammatory and antifibrotic activ-ity.82,83 The FXR Ligand Obeticholic Acid in NASHTreatment (FLINT) trial was a randomised,placebo-controlled, phase IIb trial to evaluate thesafety and efficacy of OCA in NASH. Patientsenrolled in the trial had biopsy proven NASH/bor-derline NASH (NAS ≥4) without cirrhosis (n = 283).Patients were randomised 1:1 to either OCA 25 mgdaily or placebo for 72 weeks. In this study, 45% ofpatients in the treatment arm had at least a 2-point improvement in the NAS without worseningof fibrosis, compared to only 21% in the placeboarm (p = 0.0002). Of note, the proportion ofpatients who achieved resolution of NASH(defined as either not NAFLD or NAFLD but notNASH) was not statistically different (22% forOCA vs. 13% for placebo, p = 0.08). Interestingly,OCA did have a beneficial impact on fibrosis (35%of patients in the treatment arm vs. 19% in the pla-cebo arm had improvements in fibrosis, p = 0.004),though this did not translate into significant reso-lution of advanced fibrosis in those receivingOCA.84 Two adverse events occurred more com-monly in those receiving OCA compared to pla-cebo; pruritus (23% vs. 6%, p <0.0001) and anunfavourable alteration in lipid profile, with anincrease in low-density lipoprotein (LDL) anddecrease in high-density lipoprotein (HDL). Thesepotential metabolic effects will need to be furthercharacterised given the risk profile of the patientpopulation of interest. Currently OCA is beingevaluated in a large phase III, randomised,placebo-controlled trial termed REGENERATE.The aim of this trial is to evaluate longer termsafety and efficacy of OCA for improvement ofNASH and fibrosis. This long-term trial has targetenrollment of around 2,000 patients with biopsyconfirmed NASH and fibrosis stage 1–3 (with theexception of stage 1c). Individuals are randomised1:1:1 to OCA 25 mg/day vs. 10 mg/day vs. placebo.For the purpose of FDA subpart H approval, at 18months, a histopathologic interim analysis will be



performed on the first 750 enrolled patients withfibrosis stage 2–3, to assess for fibrosis improve-ment ≥1 point without NASH worsening, or NASHresolution without worsening of fibrosis. Subse-quent analysis via liver biopsy will occur at 48months, with final assessment based on an esti-mated number of outcome events at year six. Out-come events of interest include time to:histological progression to cirrhosis, uncontrolledascites, HCC, liver transplantation/transplant eligi-bility, and hospitalisation for hepatic decompensa-tion or death.85

ElafibranorElafibranor is another agent currently in phase IIIfor the treatment of NASH. Elafibranor is a dualperoxisome proliferator-activated receptor(PPAR)-a/d agonist and as such has effects on theregulation of metabolic homeostasis, inflamma-tion, cellular growth, and differentiation.86 PPAR-a is a regulator of fatty acid transport and a majorinducer of b-oxidation of fatty acids. In animalmodels, PPAR-a expression significantly reducescholesterol, triglycerides, and free fatty acidswhile increasing HDL cholesterol levels anddecreasing overall hepatic inflammation, thoughostensibly peroxisomes are less abundant inhumans.86,87 PPAR-d reduces fatty acid uptake,and alters glucose homeostasis, energy metabo-lism and hepatic inflammation in the liver. PPAR-d is also highly expressed in adipose tissue whereit controls adipocyte differentiation and plays acrucial role in increasing insulin sensitivity andpromoting fatty acid uptake into adipocytes.88,89

The phase IIb trial of elafibranor, GOLDEN-505,was an international, randomised, placebo-controlled trial of 276 patients with biopsy provenNASH in the absence of cirrhosis, with a primaryoutcome of resolution of NASH defined by disap-pearance of steatosis, ballooning or lobular inflam-mation. Patients were stratified by presence ofdiabetes and randomised to elafibranor 80 mgdaily vs. 120 mg daily vs. placebo for 52 weeks.90

The difference in primary outcome was not statis-tically significant across treatment arms (23%, 21%and 17% respectively, p = 0.28). However, when re-evaluated using the more stringent definition ofNASH resolution now recommended by regulatoryauthorities (disappearance of ballooning, none ormild persistence of lobular inflammation) therewas a significant difference across treatment armsfor the 120 mg dose (13% vs. 19% vs. 12%, p =0.045). Changes in ballooning and lobular inflam-mation were also noted to correlate with changesin fibrosis stage.91 Elafibranor significantlydecreased total cholesterol, LDL-cholesterol,triglycerides, and increased HDL-cholesterol, andsignificantly improved glucose homeostasis (sig-nificant reductions in HbA1c and free fatty acidsin diabetic patients). Elafibranor was well toler-ated, but did produce a mild, reversible increasein serum creatinine. These findings are being


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Key point

It is likely that combiningtherapies that engage dif-ferent targets may providea synergistic histopatho-logic benefit.


investigated further in a randomised, placebo-controlled, phase III trial of patients with biopsyproven NASH (NAS ≥4) and fibrosis stage 1–3,RESOLVE-IT. A targeted 2,000 patients will be ran-domised 2:1 to elafibranor 120 mg daily vs. pla-cebo. Interim analysis, at week 72, of 1,000patients with fibrosis stage 2–3 will assess forthe primary endpoint of NASH resolution withoutworsening of fibrosis, for the purposes of FDA sub-part H approval. The study is estimated to lastuntil accrual of a pre-specified number of eventsof interest: all-cause mortality, cirrhosis develop-ment, and liver-related clinical outcomes (esti-mated duration four years of treatment).92

CenicrivirocCenicriviroc (CVC) is a dual CCR2/CCR5 chemokinereceptor antagonist that has been shown to playkey roles in hepatic inflammation and fibrosis.93,94

In the setting of hepatocyte injury, kupffer cellssecrete C-C chemokine ligand type 2 (CCL2) trig-gering CCR2 receptors to initiate an inflammatoryresponse. This inflammatory process involvesmacrophage secretion of pro-inflammatory cytoki-nes, platelet-derived growth factor, and interlukin-1b. This also activates pro-inflammatory mediatorsin adipose tissue which together ultimately acti-vate hepatic stellate cells.94–96 CVC was evaluatedin a phase IIb, randomised, placebo-controlled,multinational study of 289 patients with biopsyproven NASH (NAS ≥4, with fibrosis stage 1–3)and diabetes or metabolic syndrome (CENTAUR).Patients were randomised to CVC 150 mg dailyfor two years, vs. placebo for one year followedby 150 mg daily in year two, vs. placebo for twoyears. The primary endpoint was a 2-pointimprovement in the NAS without worsening offibrosis. In analysis of one-year data, rates ofachievement of the primary endpoint were not sta-tistically different (16% CVC vs. 19% placebo, p =0.52). Rates of resolution of steatohepatitis werealso similar (8% CVC and 6% placebo, p = 0.49),although twice as many patients in the CVC armhad improvement in fibrosis by ≥1 stage withoutworsening in steatohepatitis (20% vs. 10%, p =0.02).97 This impact on fibrosis is being furtherinvestigated in a current phase III clinical trial ofpatients with NASH and fibrosis stage 2–3. In thistwo arm trial, patients will be randomised to CVC150 mg vs. placebo for 12 months with a primaryoutcome of improvement in fibrosis by ≥1 stageand no worsening of steatohepatitis.98

SelonsertibApoptosis signal-regulating kinase 1 (ASK1) is alarge contributor to the pathogenesis of oxidativestress-related cell death, fibrosis and inflamma-tion. ASK-1 is activated by reactive oxygen species,tumour necrosis factor-a, endoplasmic reticulumstress, and lipopolysaccharide. Once activated,ASK1 in turn activates mitogen-activated proteinkinase (MAPK) that consequently activates c-Jun


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N-terminal Kinase (JNK).99 An apoptosis signal-regulating kinase 1 (ASK1) inhibitor [GS-4997-selonsertib (SEL)] is being studied in patients withNASH. The phase IIb randomised trial of 67patients with biopsy proven NASH, with NAS ≥5and fibrosis stage 2–3, evaluated change in fibrosisstage as a primary endpoint. Patients were ran-domised 2:2:1:1:1 (stratified by diabetes) to SEL6 mg daily ± simtuzumab (SIM) 125 mg subcuta-neously (sq) weekly, vs. SEL 18 mg daily ± SIM125 mg sq weekly, vs. SIM 125 mg sq weekly fora total of 24 weeks. Based on efficacy results fromprior studies, for the purpose of this trial SIM wasconsidered equivalent to ‘‘placebo”. Overall 43% ofsubjects in the SEL 18 mg ± SIM arm had improve-ment in fibrosis compared to 30% in the SEL 9 mg± SIM arm, vs. 20% in the SIM alone arm.100 Thereare currently two phase III trials of SEL, exploringits effectiveness in patients with bridging fibrosisand compensated NASH cirrhosis. In both trialsthe primary endpoint is improvement in fibrosisby ≥1 stage without worsening of NASH.101,102

Combination therapiesPresently the majority of NASH clinical trials arebeing conducted with single agent therapies.However, based on the complex pathophysiologyand presumed multiple redundant pathways, it islikely that combining therapies that engagedifferent targets may provide a synergistichistopathologic benefit. Presently the combinationof a non-bile acid FXR agonist (GS-9674) + ACCinhibitor (GS-0976) is being investigated in anearly phase II clinical trial.103 In an animal modelof NASH, treatment with this combination therapydemonstrated a greater reduction in hepaticsteatosis and genes associated with fibrosis thantreatment with either agent alone.104 Future clini-cal trials will likely use combinations of agentsthat have already produced positive results indi-vidually. Logistically, these combination therapiesare most easily studied among compounds manu-factured by the same pharmaceutical company,though combinations of promising agents acrosscompanies may also be considered to maximisethe benefit of individual therapies (i.e. combina-tions of an agent with positive metabolic effectsand an agent with significant antifibrotic effects).

Future of clinical trials once therapies areapprovedWith multiple agents currently in phase III clinicaltrials, it is important to consider how the eventualapproval of a pharmacologic agent for NASH willimpact ongoing and future clinical trials in thisarena. Potential implications include the incorpo-ration of the regulatory approved agent as a con-trol arm in future clinical trials. Alternativesinclude adjustment of primary endpoints todemonstrate improvement in metabolic and




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fibrotic outcomes above what is achieved by theapproved therapies.

ConclusionsThere are presently no approved pharmacologicagents for the treatment of NAFLD and NASH,but numerous agents are currently being investi-gated in phase II and III clinical trials. Data fromthese studies has shown promising improvementsin steatosis, inflammation and fibrosis. Because ofthe longitudinal and heterogeneous nature of dis-ease progression in NAFLD/NASH, investigationinto the long-term efficacy and safety of theseagents will be critical, particularly given concernsraised for potential adverse metabolic effects ofsome of these agents. Addressing important barri-ers to clinical trial enrollment and optimising clin-ical trial design in NAFLD/NASH will also be keyfor approval of therapeutic agents for this disease.Incorporation of non-invasive parameters toassess steatosis, inflammation and fibrosis in addi-tion to considering adaptive trial designs arepotential approaches.

Financial supportNo financial support was received for the produc-tion of this manuscript.

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Conflict of interestMAK and JCJ have no conflicts to disclose. SAH is aconsultant/advisor to Gilead, Intercept, Genfit,HistoIndex, Axcella, Cymabay, BMS, Pfizer, Madri-gal, NGM Bio, Cirius, Novartis, Novo Nordisk,Chronic Liver Disease Foundation, Echosens andPerspectum. He has received research supportfrom Gilead, Intercept, Genfit, Cirius, Madrigal,NGM Bio, Conatus, Galmed, Immuron, Tobira/Allergan, Pfizer, Boehringer Ingelheim, and Novo-Nordisk.

Authors’ contributionsMAK – drafting and critical revision of manuscript,design of figures and Table; JCJ – contribution todrafting portions of manuscript; SAH – manuscriptconcept and content, design of table and figures,review and critical revision of manuscript.

AcknowledgementThe authors would like to acknowledge Dr. MaryRinella for her detailed review of and feedback onthe manuscript.

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Please cite this article in press as: Konerman MA et al. Pharmacotherapy for NASH: Current and emerging. J Hepatol (2017), https://doi.org/10.1016/j.jhep.2017.10.015

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Review


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https://clinicaltrials.gov/ct2/show/NCT03205345?term=emricasan%26draw=1%26rank=1

https://clinicaltrials.gov/ct2/show/NCT03205345?term=emricasan%26draw=1%26rank=1

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