Novel pharmacological therapies using anti-fibrotics and others in NAFLD 김원서울대학교의과대학보라매병원내과 Won Kim Department of Internal Medicine, Seoul Metropolitan Government Seoul National University, Boramae Medical Center, Seoul, Korea Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) in the developed countries. It is a growing contributor to the burden of CLD requiring liver transplantation. Cirrhosis is also associated with an increased risk of hepatocellular carcinoma, which however may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH). The pathogenesis of NASH is poorly understood and probably multifactorial and additionally how best to manage the accompanying cardiometabolic risk is unclear. NASH progresses very slowly and the natural history of NASH is often heterogeneous and it is difficult to predict who will progress, necessitating large population-based studies. The diagnosis of NASH currently requires a liver biopsy but there are no approved therapies for NASH. Moreover, non-invasive techniques for diagnosing NASH and assessing response to treatment are not yet ready for clinical trials, thus liver biopsy continue to be required. Therefore, there is an urgent need to develop better diagnostic and therapeutic strategies for patients with NASH, targeting both those with early-stage disease as well as those with advanced liver fibrosis. NASH will not be a winner-take-all market due to the heterogeneity of the disease with diverse clinical phenotypes to be reflected by therapies that will combine two or more approved drugs. Continuous research and discovery programs should aim at identifying new targets for therapy and eventually combine those that target synergistic pathways. Individualized therapy based on severity of disease and treatment response might be a reality as soon as anti-nash and anti-fibrotic agents emerge. This review focuses on novel pharmacological therapies such as emerging anti-fibrotic drugs against NAFLD. Keywords: Non-alcoholic steatohepatitis; Fibrosis; Pharmacotherapy; Cardiometabolic risk 서론 비알코올지방간질환 (non-alcoholic fatty liver disease, NAFLD) 은선진국에서는가장흔한만성간질환 의원인으로알려져있고. 비알코올지방간염 (non-alcoholic steatohepatitis, NASH) 은향후간이식의주 54 대한간학회 The Korean Association for study of the Liver
김원 Novel pharmacological therapies using anti-fibrotics and others in NAFLD 요대상질환이면서원발성간세포암의주요전구질환이될것으로전망된다. 1-4 NAFLD 유병률의증가는비만인구의증가와관련이있고비만은 NASH 환자에서질환을악화시킬수있는위험인자인당뇨와고지혈증의발생에기여한다. 1,2 실제로 NASH 환자의주요사인은말기간부전이아닌심혈관질환이라는사실은이미주지의사실이다. 단순지방간은경과가양호하고 NASH는점진적으로진행하는고위험군으로알려져있지만최근연속적간생검결과두질환모두진행성간섬유화나간경변으로진행할수있는것으로밝혀졌다. 5,6 장기간에걸친관찰연구에서도단순지방간과 NASH의조직학적차이점보다는간섬유화자체만이유일한전체사망률과간질환관련사망률의예측인자라는것이보고되었다. 7,8 NASH 환자에서간섬유화 1단계진행에 7년정도시간이소요되는것으로추정되므로 NAFLD 환자대부분은간경변으로발전하기까지최소 30-40년정도가걸린다. 5 그러나소수의환자에서는불과 10년이내에간경변으로발전하는급격한진행군으로분류되고이러한개인별다양한진행속도는 PNPLA3 9,10 나 TM6SF2 11,12 와같은유전적혹은식이습관이나장내미생물의변화 13 와같은후천적질환조절인자에의한것으로추정된다. 급격한섬유화를유발하는인자에대한병인적기전을이해하는것이 NAFLD 치료와관련한주요미충족수요이다. 이러한유발인자들에는인슐린저항성과당뇨, 14,15 비만, 16 산화스트레스, 17 염증성사이토카인과아디포카인, 17,18 선천 19-22 및적응 23,24 면역반응등이있고이들의직접적혹은상승적상호작용 17 을통해 NASH 관련섬유화와밀접하게관련된다. 섬유화는궁극적으로간경변이나간질환관련사망으로진행되기때문에 25,26 NASH에서섬유화진행을유발하는구체적기전이나세포를확인하는것은, 이를통한잠재적항섬유화치료개발을통해이러한진행을예방하거나섬유화호전에효과적일수있다는점에서매우중요한임상적의미를갖는다. 이에본고에서는 NASH환자에서개발중인간섬유화에대한새로운파이프라인의치료제들을검토하고, 특히간섬유화호전과문맥압고혈압을주요평가지표로설정한임상시험들에초점을맞추고자한다. 본론 최근까지도간경변은비가역적상황으로알려졌었으나만성 B형간염 27-29 과 C형간염 30,31 의임상시험에서일부환자에서는간경변도되돌릴수있고유지바이러스반응을보이는 C형간염이나 HBV DNA 를지속적으로억제하는 B형간염환자에서원인질환을제거할경우간섬유화도호전될수있음을보인바있다. 조직학적으로증명된 NASH환자에대한여러무작위배정대조군연구들로부터시행된최근메타분석에서 NASH에서도간섬유화의조직학적호전이가능하다는것이알려졌다. 32,33 NASH에서알려진항섬유화전략으로는, 1) 간손상의원인제거, 2) 간내염증억제혹은조절, 3) 간보호, 4) 간성상세포활성화억제, 5) 간내기질분해촉진 34 등이있다. 이러한전략중일부 ( 상기전략중5의경우 ) www.kast.org 55
2016 대한간학회추계 Single Topic Symposium Table 1. Clinical trials for anti-fibrotic agents against NASH focusing fibrosis outcome Compound Molecular target Study phase Study design Primary outcome Secondary outcome GR-MD-02 Galectin-3 II RCT Reducing HPVG at 1 year Changes in: esophageal varices, digital collagen morphological change, Fibroscan, histological fibrosis Simtuzumab (GS-6624) Simtuzumab (GS-6624) Obeticholic acid No. of patient LOXL2 II RCT Reducing HPVG at 2 years Esophageal varices 259 LOXL2 II RCT Change from baseline in morphometric quantitative collagen on liver biopsy at year 1 FXR III RCT Fibrosis improvement with no worsening of NASH and NASH resolution with no worsening of fibrosis Cenicriviroc CCR2/CCR5 II RCT Improvement of NAS score with no concurrent worsening of fibrosis stage at 1 year GS-4997 & Simtuzumab ASK1 & LOXL2 II RCT Adverse event profile of GS-4997 156 222 Resolution of fibrosis 2000 Changes in histological fibrosis, hepatic tissue fibrinogen protein, morphometric quantitative collagen (a-sma), APRI, FIB-4, FibroTest, NFS, ELF 289 Not provided 70 는섬유화경로에대한직접적효과이지만, 나머지전략의대부분은간내지방침착의감소혹은염증의 치유를통한간접적효과들이다. 본고에서는 NASH 환자를위해최근떠오르는항섬유화치료전략 ( 상기 전략중특히 2-5) 에초점을맞추고자한다. 1. 항염증, 항산화스트레스치료제산화스트레스 17 와염증성사이토카인과아디포카인 17,18 은 NASH 관련섬유화와연결되어있고, 염증성매개물질은간성상세포의활성화에관여하고, NASH에서염증과산화스트레스성분을차단하는약제들은섬유화예방이나호전에효과적일것으로추정된다. 34 1) NOX-1과 NOX-4 억제제간섬유화에서 NADPH oxidase (NOX) 는간성상세포에서활성산소를생성하는주요효소이다. 35 NOX1과 NOX2 및 NOX4는간성상세포에서발현되고간섬유화에기여한다는것이동물실험에서알려졌다. 35-37 동물모델에서최초의 NOX1/4 억제제인 GKT137831은활성산소생성과 NOX 및섬유화유전 56 대한간학회 The Korean Association for study of the Liver
김원 Novel pharmacological therapies using anti-fibrotics and others in NAFLD 자발현을억제하고간섬유화를호전시키며산화스트레스및염증인자들을감소시켰다. 35 이러한결과는 NOX1과 NOX4의이중억제가 NASH에서간섬유화를호전시키기위한적절한치료전략임을시사한다. 2) Galectin-3 길항제 Galectin-3는염증, 세포자멸사, 혈관신생, 세포이동등의다양한세포생리에관여하고당단백의 galactose기에결합하는다기능단백이다. 38 주로탐식세포 (macrophage) 에서발현되며간섬유화등에관여한다. Galectin-3 억제제인 GR-MD-02 (Galectin Therapeutics) 는 galectin-3에결합하여그기능을억제하는 β-galactose와 arabinose기를함유한다당류이다. 39 동물실험결과 GR-MD-02는간섬유화에중요한면역세포인, 활성화된탐식세포에작용하여 galectin-3의발현을감소시키고결국간내지방축적, 풍선변형, 염증세포침윤, 콜라겐침착등을포함한 NASH의호전과관련된다. 39 Thioacetamide처치동물모델에서 GR-MD-02은섬유화를줄이고간경변을되돌리며 galectin-3를발현하는문맥역과중격의탐식세포를감소시키면서간문맥고혈압을호전시켰다. 이러한결과는 GR-MD-02가간섬유화와간경변의호전에영향을줄뿐만아니라간경변의병태생리결과도호전시킬수있음을시사한다. 40 간섬유화호전기전은아직불분명하지만콜라겐을분해하는탐식세포의능력을회복시키는것이주요기전일것으로추정된다. 현재 NASH간경변환자에서간섬유화와간문맥고혈압의치료를위한 GR-MD-02의효능과안전성을평가하기위한 2상임상시험이진행중이다 (ClinicalTrials.gov Identifier: NCT02462967). 3) CCR2/5 이중길항제간세포손상을유발하는신호전달체계는지방조직이나장에서시작될수있고쿠퍼세포, 단핵구, 림프구등을포함한간내국소염증기전을악화시킬수있다. 다양한신호전달체계가동시에활성화되지만질병진행에가장관련이깊은경로를확인하는것은타깃치료를개발하는데중요하다. 그중특히 C-C chemokine 수용체 2/5 (CCR2/CCR5) 에대한 CCL2/CCL5 리간드는 NASH에서활성화되고발현이증가된다. 41-43 또한 CCR2/5는 chemokine 수용체로서단핵구, 탐식세포, 쿠퍼세포, 간성상세포, 자연살세포와 T세포등에서발현되며간성상세포의활성화와섬유화진행에중요한역할을담당하고있다. 44 따라서 cenicriviroc (CVC, Tobira) 과같은 CCR2/CCR5 이중길항제는 NASH 관련염증과섬유화를호전시킬수있다. CVC는식이유발 NASH 혹은 thioacetamide유발간손상동물모델에서간섬유화를감소시키는것으로밝혀졌다. 45,46 현재진행중인 CENTUAR 임상시험은 CVC 매일 150 mg 투여가간섬유화 (F1-3) 를갖는, 조직검사에서확진된 NASH의치료에효과적이고안전한지평가하는것이다 (ClinicalTrials.gov Identifier: NCT02217475). www.kast.org 57
2016 대한간학회추계 Single Topic Symposium 2. 간보호제 1) 항자멸사약물 NASH에서세포자멸사의정도는섬유화단계와유의한상관관계가있어 pan-caspase 억제제인 emricasan (Conatus Pharmaceuticals) 은 NASH 동물모델에서간섬유화를유의하게호전시킴이증명되었다. 47-50 Caspase는세포자멸사경로에서중요한역할을담당하고 IL-1β와 IL-18과같은사이토카인의분비를촉진하므로매력적인치료타깃이될수있다. 여러종류의 caspase 억제제들을이용한이전의전임상 51,52 과임상연구 53 들은이러한치료적접근이효과적임을입증해왔다. Emricarsan은 NASH의전임상모델에서실험적 NASH와관련된자멸사와염증뿐만아니라간섬유화도억제함을보여왔다. 일부 NASH환자를포함한 NAFLD 환자 38명에서시행된 2상임상시험에서 25 mg emricarsan을 1일 2회경구투여시 ALT의유의미한감소뿐만아니라혈청 cck18도현저히감소시킴을관찰할수있었다. 특히, cck18의감소는 NAFLD/NASH 환자에서염증과증가된자멸사를감소시킴을시사한다. 54 Emricarsan은특별한용량제한독성이나약제관련중대이상반응없이안전하게투약이가능하였다. 2) 지방산 -담즙산결합체 Aramchol (Trima Israel Pharmaceutical Products Ltd.) 은 stearoyl coenzyme A desaturase (SCD1) 을억제하는지방산-담즙산결합체이며간내지방량을감소시킨다. 55 SCD1은간내지방산대사를조절하는핵심효소이다. SCD1억제는지방산합성을감소시키고지방산산화를증가시킴으로써결과적으로간내중성지방과지방산함량을감소시킨다. 최근시행된임상시험에서조직학적으로확진된지방간 60명환자 (6명의 NASH 환자포함 ) 에게 aramchol을매일 100 mg 혹은 300 mg 3개월간투여하였다. 56 300 mg 용량으로간내지방량이유의하게감소하였지만, 단기간내반복적간조직검사는추천되지않기때문에간섬유화에대한효과는평가받지못하였다. 현재진행중인 2b임상시험은조직검사로확진된 240 명의 NASH 환자에서고용량 aramchol (400 mg과 600 mg) 의간내지방량감소효능과안전성을평가하고있다. 염증과섬유화지표가평가에포함될예정이다 (ClinicalTrials.gov Identifier: NCT02279524). 3) ASK1 억제제 Apoptosis-signal-regulating kinase 1 (ASK1) 은고혈당, TGF-β 및활성산소등을포함한여러자극에의해활성화되는인산화효소이다. 57 ASK1은자멸사, 섬유화, 그리고 p38과 JNK1 경로를활성화함으로써대사이상을유발한다. ASK1 경로는인간 NASH의간조직에서활성화되어있는것으로밝혀졌다. 58 NASH (F1/2 섬유화 ) 동물모델에서선택적소분자 ASK1 억제제인 GS-4997은지방간과간섬유화를유의하게호전시키고 NASH 관련주요대사지표들을유의미하게호전시켰다. 58 GS-4997 치료는체중, 공복혈당 (17%), 인슐린 (13%), AST, ALT, 콜레스테롤, 간내지방량 (68%), 간내 hydroxyproline (44%), α- 평활근액틴, 인산화 p38 발현, 섬유성콜라겐면적 (84%), 용해성및비용해성콜라겐의합성등을유의 58 대한간학회 The Korean Association for study of the Liver
김원 Novel pharmacological therapies using anti-fibrotics and others in NAFLD 미하게감소시켰다. 또다른동물모델에서 ASK1 억제는간섬유화, 지방간및인슐린저항성을감소시켰고, 지방산합성과지질대사를정상화시켰다. 57 ASK1 억제제로처치한동물은지방합성이 26%, SCD1이 21% 감소하였고, delta-5 desaturase의 78% 증가를보였다. 지방산합성, 지질대사및콜레스테롤생합성을조절하는유전자네트워크가 ASK1 억제제를치료받은동물에서는지방간이있는동물과다르게발현된다는것이밝혀졌다. 즉, ASK1 억제후혈청 osteopontin (35%), 하이알유론산 (33%), TIMP-1 (41%) 및 IL-6 (50%) 가현저히감소하였다. GS-4997은현재중등도에서중증의간섬유화를보이는 NASH환자에대해 2상임상시험이진행중이다 (ClinicalTrials.gov Identifier: NCT02466516). 3. 간성상세포활성화억제제 Hedgehog 신호억제제인 vismodegib은영양소과잉 NASH 동물모델에서 TNF-related apoptosis-inducing ligand (TRAIL) 매개간손상을감소시킴으로써간내염증과섬유화를호전시켰다. 59 이모델에서 vismodegib 치료는간세포에지질과부하에도불구하고간세포손상을줄이고탐식세포의축적과활성화와관련간내지표를감소시켰으며 death receptor (DR5) 과발현과 DR5 매개간손상을억제하였고결국간섬유화의감소등을가져왔다. Hedgehog 경로가 NASH에서매우중요하기때문에 Hedgehog 신호억제제를사용한임상시험을향후시행할가치가있을것으로보인다. 4. 간내기질분해촉진제 Lysyl oxidase-like 2 (LOXL2) 는세포외기질내간질성콜라겐의교차연결에관여하는효소로, 콜라겐분해를저해함으로써간섬유화를일으키는주요타깃으로알려져있다. 60 LOXL2는섬유화된간조직에서발현이증가하고 LOXL2에대한단클론항체는여러실험모델에서상당한섬유화호전효과를보였다. 61 현재진행중인임상시험에서 LOXL2에대한단클론항체인 simtuzumab (GS-6624; Gilead Sciences) 이 NASH 환자에서간섬유화의조직학적진행과간경변으로의진행을예방할수있는지를연구하고있다 (ClinicalTrials.gov Identifier: NCT01672866). 다음으로진행중인임상시험은 NASH에서이차적으로발생한대상성간경변환자에서간경변의치료를위한 simtuzumab의안전성과효능을평가하는중이다 (ClinicalTrials.gov Identifier: NCT01672879). LOXL2 항체는간섬유화에대한직접적효과를갖는치료제로예상된다. 5. 병용치료전략 NASH 에서간섬유화는서로관련된발생기전과신호경로를통해다양한위험인자들의상호작용으로 유도된다. NASH 에서손상의원인은이질적일수있지만결과적인반응은콜라겐의축적과간섬유화의 www.kast.org 59
2016 대한간학회추계 Single Topic Symposium 악화라는공통된반응으로귀결된다. 그러므로다양한타깃에대한목표지향치료는종국에 NAFLD에서간경변과간섬유화를호전시키는것이필요하다. 원인을제거하는것이간섬유화를호전시키는가장효율적인방법이며이러한사실은이미만성 B형간염과 C형간염의사례에서확인된바있다. 단일약제로모든측면의병인을효과적으로타격하기란쉽지않으며따라서 NASH치료의현주소는병용치료 전략을지향하는단계로접어들었다고해도과언이아니다. 62,63 다가오는수년간 NASH 치료는순수하게 간섬유화단계에기반해서결정될것이다. 예컨대, 2, 3단계의 NASH 섬유화치료를위해서는지방간, 간내염증및산화스트레스를차단하는간보호제와심장대사기능을호전시키는약제의병용이반드시필요하다. 반면에 4단계의대상성간경변은간내염증과산화스트레스를차단하는간보호제뿐만아니라기질분해를촉진하는약제의병용과같은보다공격적인접근이필요할수있다. 최근탐색적병용치료가시작되었는데그실례로 NASH와 2-3단계의간섬유화를보이는성인환자에서 ASK1 억제제 (GS-4997) 단독혹은 simtuzumab (LOXL2 단클론항체 ) 과의병용치료의안전성과내약성을평가하는임상시험이진행중이다 (ClinicalTrials.gov Identifier: NCT02466516). NASH와간섬유화분야에항섬유화치료제는계속개발중이며, 머지않은장래에간섬유화의병인에대한이해도증진될것으로기대된다. 결론 최근 NASH에서간섬유화의진행을이끄는특정기전의확인과관련된연구들에서큰진전이있었고, 그결과로섬유화진행을예방할뿐만아니라간섬유화나간경변을정상상태로되돌릴수있는목표지향치료제후보물질의개발이가능하게되었다. 진행성간섬유화나간경변으로고통받는 NASH환자들의치료가현재로서는가장큰미충족수요라할수있다. 따라서 NASH에대한단독혹은병용치료로서몇가지의항섬유치료전략들이시험무대에올라있다. 이러한항섬유화치료전략들이성공적으로개발된다면향후 NASH에서간섬유화진행에대한이해를크게증진시키고, 가까운장래에이러한질환으로고통받는환자들에게큰도움이될것이라고낙관할수있을것이다. 색인단어 : 비알코올지방간염 ; 섬유화 ; 약물치료 ; 심장대사위험 REFERENCES 1. 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;141:1249-1253. 2. 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;59:2188-2195. 60 대한간학회 The Korean Association for study of the Liver
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