New clinical trials in NAFLD 김원 서울대학교의과대학보라매병원내과 Non alcoholic steatohepatitis (NASH) is an aggressive form of non alcoholic fatty liver disease (NAFL

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1 New clinical trials in NAFLD 김원 서울대학교의과대학보라매병원내과 Non alcoholic steatohepatitis (NASH) is an aggressive form of non alcoholic fatty liver disease (NAFLD) and gradually replacing hepatitis C as the leading indication for liver transplantation in Western countries. Despite this alarming trend, there has been no pharmacotherapy proven to be effective as well as safe in NASH. Currently, lifestyle modification is the therapeutic cornerstone for ameliorating clinical or histological outcomes in patients with NAFLD. However, the use of pharmacological agents as adjunctive therapy to lifestyle modification is also crucial because weight loss is often hard to achieve and maintain. Moreover, ongoing research evaluating potential pharmacological agents for NASH is critical because NASH patients are at particular risk of disease progression. Hence, there is an urgent need for safe pharmacotherapy that successfully reverses or prevents progression of liver injury and fibrosis in those with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events stemming from the liver, adipose tissue, and gut will ultimately promote the development of effective targeted therapies for NASH. Novel agents should be safe, optimally dosed, and finally pass clinical trials offering proof of concept and efficacy. With regard to NASH, trial design is not necessarily straightforward since surrogate end points to predict clinical benefit are not yet validated. There are a number of agents that are currently in clinical trials for the treatment of NASH and NASH related fibrosis. Future studies should include larger patient populations with advanced fibrosis and cirrhosis, and should include longer treatment durations to further assess the effectiveness as well as tolerability and potential long term adverse effects. This review focuses on new clinical trials currently underway to develop potential pathophysiology guided target therapies for NASH. Keywords: non alcoholic steatohepatitis, fibrosis, pharmacotherapy, clinical trial 서론 비알코올지방간질환 (non-alcoholic fatty liver disease, NAFLD) 은비만인구의증가와바이러스간염의 치료향상에따라세계에서가장흔한만성간질환의주요원인으로알려져있다 년대까지간내 지방축적은양성질환으로여겨졌고, NAFLD 라는용어도존재하지않았다. NAFLD 는병리적으로 5% 22 대한간학회 The Korean Association for study of the Liver

2 김원 New clinical trials in NAFLD 이상의간세포에지방소적 (fat droplet) 이관찰되는상태로유의한양의알코올섭취와지방간의이차적원인이배제될때진단된다. 1 NAFLD는조직학적으로단순지방간 (simple steatosis), 비알코올지방간염 (non-alcoholic steatohepatitis, NASH) 그리고간경변등을포괄하는질환군이다. NASH는단순지방간과달리잠재적으로간경변및간세포암등으로진행가능하며, 2020년까지미국에서간이식의가장흔한원인이될것으로예상된다. 2,3 미국시장조사결과, 2009년 NASH의시장규모는 5억달러이었고 년사이 16% 의연평균성장률을보이면서 2017년에 16억 5천만달러의시장규모로성장할것으로전망하였다. 4 그러나최근 NAFLD 유병률이증가함에도불구하고 NAFLD 관련제약시장의성장이더딘이유는 NASH 치료제로승인된약제가전혀없고, NASH 확진에간생검이반드시필요하여진단율이낮다는점, 드문약물처방빈도, 그리고적극적으로치료를희망하는환자들이많지않다는점등으로설명된다. 국내에서도항산화제, 항당뇨병약및항고지혈증약등이현재 NASH 환자에서가장널리사용되는 off-label 약물들이다. 최근미국간학회와미국식품의약품안전청의공동워크숍보고서에서 NASH에대한신약및바이오마커개발의미충족수요와장애요인을극복하기위해 NAFLD 분야의다양한이해집단간의의견조율이필요하고, NASH 진단법및치료제개발에서모호한분야 ( 고위험군선별방법, 연구디자인, 유효성평가지표등 ) 에대한합의가필요함을강조하였다. 5 이에본고에서는 NAFLD의치료를위해최근떠오르는새로운약제들의임상개발과현재진행중인새로운임상시험에대해간략히살펴보고자한다. 본론 NAFLD/NASH 환자에서약물치료의목표는간기능에대한치료뿐만아니라기저대사증후군의구성요소 ( 비만, 당뇨, 고혈압, 고지혈증 ) 들을교정하는것이다. 많은임상시험에서수많은약물과천연물을연구하고있지만, 아직까지완벽하게안전하면서도효과적인 NASH 치료제를개발하지못했다. NAFLD/NASH 환자들은다양한병인경로를보이기때문에기저병태생리에따른개별화된치료는필수불가결하다. 다양한기전을통해작용하는 NASH의새로운치료약물관련임상시험들이현재진행중이며결과에따라향후 NASH 치료전략에지대한영향을미칠것으로기대된다. NASH 관련임상시험은대부분 1상이나 2상개발단계에있고일부약물이 3상혹은 4상으로진행중에있다. 이하에서는 NASH 치료약물후보로향후개발될수있거나현재이미임상시험단계에진입한새로운치료타깃관련약물들을고찰하고자한다 (Table 1). 23

3 2015 대한간학회추계 Single Topic Symposium Table 1. List of emerging compounds currently in clinical development for NASH Compound Molecular target Administration route Development stage and phase Pharmaceutical company DGAT2Rx DGAT2 preclinical ISIS AM6545 CB1 receptor preclinical MAKScientific JD5037 CB1 receptor preclinical Jenrin Discovery LJPC-1010 Galectin-3 Oral Phase 1 La Jolla PXS-4728A LOXL2 Oral Phase 1 Pharmaxis LY FGF21 s.c. Phase 1 Eli Lilly GKT NOX1/4 Oral Phase 2 Genkyotex Simtuzumab LOXL2 i.v. Phase 2 Gilead Sciences Cenicriviroc CCR2/CCR5 Oral Phase 2 Tobira Emricasan Caspase Oral Phase 2 Conatus Liraglutide GLP-1 s.c. Phase 2 Novo Nordisk Sitagliptin DPP-4 Oral Phase 2 Merck Exenatide GLP-1 s.c. Phase 2 Astrazeneca Remogliflozin SGLT2 Oral Phase 2 Islet Sciences Aramchol SCD1 Oral Phase 2 Galmed Px-102 FXR Oral Phase 2 Phenex MBX-8025 PPARδ Oral Phase 2 Cymabay GR-MD-02 Galectin-3 i.v. Phase 2 Galectin GFT505 PPARα/δ Oral Phase 2 Genfit Oltipraz LXR Oral Phase 3 PharmaKing Obeticholic acid FXR Oral Phase 3 Intercept 1. 치료목표및치료전략 최선의치료타깃선택과임상연구개발후보물질의최적화등은효과적인 NASH 치료제개발을위 해필수적이지만고비용과장시간의복잡한단계를필요로하는힘든과정이기도하다. 흔히약물개발 프로그램은임상적으로타당하면서도동시에달성가능한연구종료점 (end point) 에대한진지한고민을 개발초기단계부터요구하는경우가대부분이다. 5 NASH 약물개발을위해우선질병진행과관련된 NAFLD activity score (NAS) 의호전과조직학적염증괴사의소실로정의되는지방간염의치유에우선초점을맞추어야한다. 이러한종료점은질병자연사의초기에관찰되고합당한표본크기와연구기간을통해임상연구에서수행가능한목표이기도하다. 항섬유화치료는간경변발생을예방하거나호전시키는것을목표로한다. 이렇게달성이쉽지않은종료점과관련된임상적이득여부의증명은대규모의장기간임상결과조사연구 (outcome research) 를필요로하지만현실적으로이를시행한다는것은대단히어려운일이다. 따라서개념입증단계 (proof of concept) 의단기간 1상혹은 2a상임상시험에서는신약의내약성을주로평가하고개발을계속추진할지여부를결정하기위한탐색적접근을위해구체적연구디자인을계획한다. 예를들면, MR spectroscopy (MRS) 를이용하여지방간의호전여부와간손상 24 대한간학회 The Korean Association for study of the Liver

4 김원 New clinical trials in NAFLD 의간접지표인간효소수치 (AST, ALT) 등의지속적호전이대리유효성평가지표로서이용될수있다. 6 그러나 NAFLD와 NASH 모두혈청 ALT 상승없이도존재할수있고정상 ALT를갖는일부환자에서도진행된간섬유화를동반한 NASH를갖고있을수있음을항상염두에두어야한다. 현재까지몇몇약제들이다양한디자인의임상시험에서효과가있다고입증되었지만공식적으로 NAFLD/NASH 치료제로승인된약제는아직까지없다. 따라서 NASH 치료관련연구의목적은광범위하게적용가능하면서장기간안전하게사용할있는치료제를개발하는것이다. 여러가지신호전달경로사이의복잡한상호작용과질병중증도및악화에대한개별경로의기여정도에따른 NASH 발생과간경변으로진행은환자별로다양하지만그기전은아직명확히규명되지않은상태이다. 그러므로여러경로가수렴하는지점으로의단일치료타깃의선택을집중할필요가있지만단일경로이상의다양한지점을타깃으로하는치료가보다효과적인치료가될수도있다. 즉, 염증뿐만아니라섬유화에대해효과를갖는약물들이향후지방간분야에서중요한의미를갖는치료적해결책이될수있을것이다. 2. 새로운치료적접근 NASH는간, 지방조직, 장등의다양한기관에영향을미치는복잡한대사이상을보이는전신질환이다. 질병진행은간세포손상과점진적간구조파괴와관련된조직회복및섬유화발생의함수이다. 간내혹은간외에서질병진행의주요인자들이확인되었고향후치료타깃으로활용될수있을것이다. 이하에서는이렇게매우흔한대사성간질환인 NAFLD/NASH의새로운치료제와주요병태생리기전을목표로하는새로운치료접근법에대해현재진행중인임상시험을중심으로기술하고자한다. 1) 간세포내지질축적과인슐린저항성기전지향치료지방간과 NASH의기본적병태생리인인슐린저항성은복잡한관련성이있다. 특히지방간과인슐린저항성은단순히비만의존재를반영하는것일수있고이러한점은 NASH 치료임상시험을디자인할때대단히중요한부분이다. 7 또한지방간이 NASH의선행인자일수있지만반드시간손상을유발하는것은아니다. 기실식사나지방조직에서유입된중성지방의합성과저장은유리지방산의에스테르화를통하여유리지방산이간내축적되는것을막아주며지방독성을예방한다. 8 이러한상황하에서유리지방산은인슐린신호체계를방해하고산화스트레스는보상적방어기제를능가하면서간세포손상을유도한다. 9 ISIS-DGAT2Rx 는중성지방합성의주요성분인 diacylglycerol acyltransferase-2 (DGAT-2) 를억제함으로써 NASH 환자에서간내지방량을감소시킬것으로기대된다. Aramchol은 stearoyl coenzyme A desaturase (SCD1) 을억제하는지방산-담즙산결합체 (3β-arachidyl-amido, 7α-12α-dihydroxy, 5β -cholan-24-oic acid) 이며동물모델에서간내지방제거를용이하게한다. 10 NAFLD 환자에서단기간무작위이중맹검 2상연구에따르면 MRS로측정한간내지방량의감소를보였고현재간조직검사를포함한대규모장기임상연구를계획중이다. 11 기존의 pioglitazone은인슐린저항성을개선하여당뇨병이수반 25

5 2015 대한간학회추계 Single Topic Symposium 된 NASH 환자에서사용될수있지만체중증가와장기사용시방광암발생등안전성문제로사용을신중하게따져봐야한다 Remogliflozin etabonate 에의한신장의 sodium glucose transporter 2 (SGLT2) 억제는당재흡수를차단하고포도당뇨를촉진하여고혈당증을개선한다. 16 SGLT2 억제제는인슐린과무관한 HbA1c 감소와유의미한체중감소효과를보여대사질환과경구당뇨치료제로기대를모으고있다. 17 인슐린저항성개선뿐만아니라약제고유의항산화활성으로당뇨와 NASH가있는환자에서도효과적인대안이될수있을지추가적임상시험이필요한상태이다. 2) 간세포손상기전지향간타깃치료간세포손상을유발하는신호전달체계는지방조직이나장에서시작될수있고쿠퍼세포, 단핵구, 림프구등을포함한간내국소염증기전을악화시킬수있다. 다양한신호전달체계가동시에활성화되지만질병진행에가장관련이깊은경로를확인하는것은타깃치료를개발하는데중요하다. 그중특히 C-C chemokine 수용체 2/5 (CCR2/CCR5) 에대한 CCL2/CCL5 리간드와 monocyte chemoattractant protein 1 (MCP1) 은 NASH에서활성화되고발현이증가된다 따라서 cenicriviroc과같은 CCR2/CCR5 이중길항제는항염증과항섬유화효과를보일수있다. 현재간생검에서확진된 200 여명의 NASH 환자를대상으로개념입증단계의 2b 임상시험이진행중이고 2016년결과가발표될예정이다. 일차유효성평가지표는 1년치료후간섬유화의악화없는지방간염의호전과 2년후간섬유화의악화없는지방간염의소실을분석할예정이다. 활성산소에의한산화스트레스는 NASH에서간섬유화의주요유발인자이다. 21,22 미토콘드리아는 NASH에서활성산소의주요공급원이고 nicotinamide adenine dinucleotide phosphate oxidase (NOX) 는활성산소를생성하는주요효소이다 따라서활성산소생성을억제하기위해 NOX를차단함으로써치료효과를기대할수있다. GKT137831은최초의 NOX1/4 억제제로당뇨병성신병증의치료제로동물실험이진행되었고, 향후예방및치료목적으로간세포자멸사를억제하고간섬유화를약화시킬수있을것으로기대를모으고있다. 26,27 현재이를위한 1상및 2상임상시험이준비중에있다. NASH에서세포자멸사의정도는섬유화단계와유의한상관관계가있어 pan-caspase 억제제인 VX-166과 IDN-6556 (emricasan) 은 NASH 동물모델에서간섬유화를유의하게호전시킴이증명되었다 NASH 환자에서또다른 pan-caspase 억제제인 GS-9450은간세포자멸사의지표인 cytokeratin-18 fragment 를유의하게감소시켰으나 C형간염환자에서시행한임상시험에서간효소의상승을유발해더이상의개발은중단되었다. 32 IDN-6556 은 NASH에서 2상시험이진행되었고 2015년결과가발표될예정이다. 33 Pan-caspase 억제제는암발생가능성이있어주의깊은장기간의추적관찰이요망된다. 3) 간섬유화기전지향치료다른원인의간질환의경우기저질환의치료가가장이상적인항섬유화치료일수있지만, NASH와같이질병진행과관련하여복잡한네트워크를갖는경우항섬유화치료제개발은미충족수요로남을수있다. Galectin-3는염증, 세포자멸사, 혈관신생, 세포이동등의다양한세포생리에관여하고당단백 26 대한간학회 The Korean Association for study of the Liver

6 김원 New clinical trials in NAFLD 의 galactose기에결합하는다기능단백이다. 34 주로탐식세포 (macrophage) 에서발현되며간섬유화등에관여한다. GR-MD-02는 galectin-3에결합하여그기능을억제하는 galactose기를함유한탄수화물성분이다. 동물실험결과 GR-MD-02는간염과간섬유화를줄이고간경변을치유하면서문맥압항진증을호전시킨다. 35,36 간섬유화호전기전은아직불분명하지만콜라겐을분해하는탐식세포의능력을회복시키는것이주요기전일것으로추정된다. 현재 NASH와진행된간섬유화를보이는환자에서 1상임상시험이진행되었고 2015년에 2상시험이계획되어있다. 37 GR-MD-02가 iv제제인데반해 LJPC-10은경구 galectin-3 억제제이다. Lysyl oxidase-like 2 (LOXL2) 는콜라겐과엘라스틴의교차연결에관여하는단백으로간섬유화를일으키는주요타깃으로알려져있다. 38,39 Simtuzumab (GS-6624) 은 LOXL2에대한단클론항체로서 NASH와진행성간섬유화혹은간경변환자에서 2상임상시험이진행중이다. Simtuzumab이 iv제제인데반해 PXS-4728A는경구제제로서향후임상시험결과가주목된다. 간에서 endocannabinoid 신호와관련되어 CB2과 CB2 등의두개의 G protein-coupled receptor (GPCR, TGR5) 가관심을모으고있다. CB1 수용체는지방합성을증가시킬뿐만아니라간섬유화와자멸사를촉진하고 CB2 수용체는항염증, 항섬유화특징을보이면서간보호효과를나타낸다. 40,41 따라서 CB1 수용체를억제하고 CB2 수용체를활성화시키는것은적절한 NASH 치료전략일수있다. 1세대 CB1 수용체항진제인 rimonabant는 NASH에서괄목할만한효과를보였지만혈관-뇌장벽을통과하여뇌의수용체와결합함으로써상당한정도의중추신경계부작용을유발하여 2008년시장에서퇴출되었다. 42 말초조직에선택적으로작용하는 CB1 수용체길항제인 AM6545와역CB1 항진제인 JD5037가전임상에서고무적인결과를얻어 1상임상시험이계획중이다. 4) NASH 발생에관여하는핵수용체매개기전지향치료핵수용체는지질대사, 에너지항상성유지, 염증반응에중요한역할을담당하고 NASH와인슐린저항성치료에매력적인치료타깃이다. 효능을극대화하고부작용을최소화하기위해여러핵수용체중최적의타깃을결정하고수용체선택성및결합능의바람직한균형을맞추는것이중요하다. 지질및당대사를조절하면서항염증및항섬유화활성을보이는것으로알려진담즙산의대사적활성은간과장에서고농도로발현되는핵수용체인 farnesoid X receptor (FXR) 의활성화에의해매개된다. 43 FXR 항진제인 obeticholic acid (OCA) 는간생검에서확진된 NASH환자에대한대규모 2상임상시험에서 72주간투여후간섬유화를포함한대부분의조직학적소견의호전을보고하였다. 44 그러나 subgroup 분석에서당뇨가없는 NASH 환자에서는그효과가희석되었고, 일부환자에서 LDL 콜레스테롤을높이고 HDL 콜레스테롤을낮추는등심혈관계위험을증가시킬수있다는것이보고되었다. 또다른 FXR 항진제인 Px-102도현재 NASH 환자에서 2상임상시험이진행중이다. Peroxisome proliferator-activated receptors (PPARs) 는지질과당대사를조절하고항염증및항섬유화특성을갖는핵수용체이다. Pioglitazone은 PPARγ 항진제로간생검에서입증된 NASH 환자중체중감소가있었던환자에서조직학적호전을보였 27

7 2015 대한간학회추계 Single Topic Symposium 지만장기간사용의안전성에대한우려가있다 ,45 PPARα/δ 이중항진제 (GFT-505) 는전임상시험에서인슐린저항성, 고지혈증, 간기능, 간섬유화등의호전에효과를보였다 GFT-505는현재 NASH 환자에서 2b 상임상시험이진행중이고그결과가매우주목된다. OCA와달리 GFT-505는소양감이관찰되지않고심혈관계보호효과를보이는지질의증가를보였다는점에서더욱기대를모은다. 국내에서개발중인 oltipraz는 liver X receptor (LXRα) 길항제로 adenosine monophosphate-activated protein kinase (AMPK) 와 S6K1 (S6 kinase-1) 조절을통해 sterol regulatory element-binding protein (SREBP)-1c을매개로하는간내지질합성을억제한다. 49 개념입증단계의 2상임상시험에서위약군에비해고용량투여군에서 MRS로측정한간내지방량의유의한감소를보여 3상임상시험을현재진행중이고그결과를기다리는중이다. 5) 간세포자가포식타깃치료자가포식 (autophagy) 은인슐린저항성, 간손상, 간섬유화등과밀접하게연결되어있다. 50 자가포식은지질합성뿐만아니라지질분해와관련이있다는증거가있고, 특정조직의대사적상태에따라자가포식의활성화가지질분해혹은지질합성중어느쪽을유도할지가결정된다. 51 카페인은 NAFLD 초기단계에자가포식의유도를통해지방간에서 NASH로진행을억제한다. 52 그러나지속적으로변화된자기포식플럭스 (autophagic flux) 가간세포내지질소적의중성지방을분해하여유리지방산을제공함으로써오히려후기간손상의원인이된다. 자가포식과정의생리적결함이직접적으로 NASH 발생을촉진하는것인지확실하지않지만최근연구에따르면자가포식이 NASH에서증가되어있다는증거가있다. 53 NASH의진행과정에서특정간세포내자가포식의기전과의미를이해하는것은새로운잠재적치료타깃을확인하는데도움이될수있다. 54,55 이러한견지에서최근발견된자가포식과핵수용체 (FXR과 PPARα) 의관련성은매우중요하다. 56,57 향후간의자가포식에대한조직특이적혹은전신적조절제가임상시험에진입하기위해더많은기초연구가필요하다. 6) 마이크로 RNA (mirna) 발현이상의교정 NASH 환자에서간의 mirna 발현은 NAFLD 환자와는다른양상을보인다. 58 NASH에서 mirna 조절이상이간질환의원인인지결과인지불명확하지만 mirna 발현을교정하는것은상당한치료적잠재력을갖는다. 이러한 mirna가임상시험에진입하기전에약물특이성, 투여방법, 장기효능등의미해결과제들이우선선결되어야한다. 특정 mirna를목표로하는것은 NASH를호전시킬수있지만단일 mirna가조절하는유전자네트워크의복잡성과특정 mirna 억제의부정적효과는향후추적관찰이필요한부분들이다. 59,60 7) 대사호르몬경로지향치료 Fibroblastic growth factor 21 (FGF21) 은간에서분비되어간, 지방조직, 시상하부에서의신호전달을통 28 대한간학회 The Korean Association for study of the Liver

8 김원 New clinical trials in NAFLD 해당이나지질대사뿐만아니라에너지항상성을조절하는물질로알려져있다. 61,62 FGF21의다양한효과에대한기전으로는인슐린감수성증가, 간내지방합성의감소, 에너지소비의유도, adiponectin의분비등이있다. 62 최근 FGF21의혈중농도상승이비만, 당뇨, NAFLD 환자에서보고되고있고 63,64 생리적 FGF21 상승과약리적 FGF21 효과사이의차이가알려지면서개념입증단계의 1b 상무작위대조군이중맹검시험이당뇨가있는비만환자에서시행되었다. 65,66 FGF21 변이체 (LY ) 의피하주사후 4주뒤고지혈증, 체중, 인슐린, adiponectin, 지방산의산화등이호전되었다. 따라서향후고용량의장기간 FGF21를사용한임상시험이필요하다. 동물모델에서관찰된골밀도감소와같은안전성문제에대해서도확인할필요가있다. 글루카곤유사펩티드 (glucagon-like peptide 1, GLP1) 와같은 incretin 은담즙산의 TGR5 활성화에반응하여위장관에서식후분비되는호르몬이다. 67 인슐린감수성을개선시킬뿐만아니라 GLP1은포만감증가와위장관운동감소에의해체중감소를촉진하는것으로알려져있다. 68 Incretin은간내유리지방산산화를촉진하고 FGF21의분비를억제한다. 69 직접작용 GLP1 유사체인 liraglutide (Victoza) 와합성수용체항진제인 exenatide (Byetta) 가현재당뇨치료제로사용중이고양호한안전성결과를보여향후간생검에서확진된 NASH 환자에서추가임상시험이필요한상황이다. 70,71 현재 52명의조직학적으로확진된 NASH 환자들을대상으로 48주간 liraglutide를투여한후전향적무작위대조군연구를진행중이며그결과가주목된다. 8) 장내 microbiota 타깃치료 Gut-liver axis는비만과 NAFLD와같은대사증후군의발생에중요하며장내 microbiota는환자의대사에중요한역할을담당한다. 72 장내미생물불균형 (intestinal dysbiosis) 은장의투과성과세균전이 (bacterial translocation) 를증가시키고 TNF-α의혈중농도증가가수반된다 장내미생물이나포화유리지방산으로부터 lipopolysaccharide (LPS) 와같은 pathogen-associated molecular pattern (PAMP) 이나손상된세포로부터자멸사 DNA와같은 damage-associated molecular pattern (DAMP) 이생성되며간에도달한후 toll-like receptor (TLR, pattern recognition receptor) 를활성화한다. 76 간내에서이러한결과는염증사이토카인의생성과면역세포의동원과같은염증반응을유도한다. 소규모의개념입증단계전향연구에서 Bifidobacterium longum의투여는간섬유화를악화시키지않고지방간염을조직학적으로호전시켰다. 77 프로바이오틱스를이용한장내 microbiota 조절이나대변이식은향후추가연구가필요한분야이다. NASH 환자에서 microbiome에대한지식이쌓일수록 NASH에대한타깃치료분야에서큰발전이있을것이다. 결론 지방간이 NASH 로진행하는기전이점차밝혀짐에따라수많은잠재적약물치료에대한타깃을확인 29

9 2015 대한간학회추계 Single Topic Symposium 할수있게되었다. 가장흔한대사간질환인 NASH 환자들의유병률을고려하여많은제약회사들이약물개발에대한치열한각축전을벌이고있다. NASH 치료의결과진행된간섬유화나간경변의완화, 즉간질환의진행을중단시키는것이임상적으로가장적절한최종목표이다. NASH에대한수많은약물개발프로그램이진행중이고대부분은초기임상단계에머물러있다. 그러나일부약물의경우향후임상시험의결과에따라치료에대한전망이매우밝아신약승인까지이어질가능성이높다. 새로운경구당뇨약제들에서이미경험했듯이 NAFLD/NASH에대해새롭게승인된신약의상품성이나시장성이폭발적일것이라는것은이론의여지가없다. 그러나당뇨약과는다르게 NASH의병태생리와임상상의이질성으로인해한가지약제가독점적으로시장을지배하는일은일어나지않을것으로예상되며두가지이상의병용치료나개인별맞춤치료가대세를이룰것으로전망된다. REFERENCES 1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55: Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141: Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014;59: Nonalcoholic Steatohepatitis Therapeutics - Pipeline Assessment and Market Forecasts to GlobalData, 2010; Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015; 61: Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011;54: Gruben N, Shiri-Sverdlov R, Koonen DP, Hofker MH. Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison? Biochim Biophys Acta 2014;1842: Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 2008;19: Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 2012;15: Leikin-Frenkel A, Goldiner I, Leikin-Gobbi D, Rosenberg R, Bonen H, Litvak A, et al. Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents. Eur J Gastroenterol Hepatol 2008;20: Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014;12: e Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362: Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trials (SELECT). JAMA 2011;306: Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010;341:c Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E 30 대한간학회 The Korean Association for study of the Liver

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