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1 Korean J Gastroenterol Vol. 71 No. 2, pissn eissn REVIEW ARTICLE 가까운미래에사용할수있는유망한치료약제 서검석, 이성희 1 원광대학교의과대학내과학교실및소화기질환연구소, 원광대학교약학대학약품연구소 1 Emerging Therapies: What Are Promising in the Near Future? Geom Seog Seo and Sung Hee Lee 1 Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University School of Medicine, Institute of Pharmaceutical Research and Development, Wonkwang University College of Pharmacy 1, Iksan, Korea The treatment of inflammatory bowel disease has evolved with the development of anti-tnf agents. In spite of long-term effectiveness, many patients do not respond or no longer responds to these drugs. Therefore, the development of new drugs that act on different inflammatory pathways has become necessary. Vedolizumab, a gut-specific biological agent, inhibits interaction α4β7 integrin with mucosal addressin cell adhesion molecule-1 without inhibiting systemic immune responses. Long-term vedolizumab therapy in patients with Crohn s disease and ulcerative colitis was safe and effective. Additionally, vedolizumab can be used in patients already failed an anti-tnf therapy. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23. Ustekinumab will be a clinically effective agent to use in medically-refractory Crohn s disease especially as a second line drug. Tofacitinib is an oral, small molecule that inhibits JAK1, JAK3 and in a lesser extent, JAK2. Perhaps the most attractive things of these JAK inhibitors is that they are given orally instead of parenterally. Early results showed that patients with moderately to severely active ulcerative colitis receiving tofacitinib were more likely to achieve remission at 8 weeks than those receiving placebo. However, these results have not been as robust in Crohn s disease. Much of the positioning will depend on the safety profile such as opportunistic infection and atherogenic risk. The challenges for the future are to determine the therapeutic drug monitoring-guided dose optimization, optimal timing and drug combinations to produce the most effective, and safest outcomes for IBD patients. (Korean J Gastroenterol 2018;71:81-88) Key Words: Ulcerative colitis; Crohn s disease; Vedolizumab; Ustekinumab; Tofacitinib 서론 궤양성대장염과크론병의치료에있어서 infliximab, adalimumab, golimumab, certolizumab pegol과같은항-tnf 제제의사용은기존의고식적치료에비해서임상적호전을보여주었으나, 여전히많은환자에서반응을하지않거나사용도중에반응소실및내약성의감소등과같은문제점이제기되고있다. 1-6 대한장연구학회주관하에염증성장질환환자를대상으로한 2017년해피바울캠페인의설문조사에의하면환자들이진료실에서가장궁금해하는내용이완치치료제및신약개발여부일정도로현재진행중인신약개발연구는치료자와환자모두에게공통된관심사항이다. 따라서항-TNF 이외에다른기전을가지는약제의개발이필요하게되었는데, vedolizumab (VDZ), etrolizumab ( 인테그린의 β7 아형에세포부착분자의결합억제제로써궤양성대장염에대해 3상연구진행 Received December 30, Revised February 12, Accepted February 14, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 서검석, 54538, 익산시무왕로 895, 원광대학교의과대학내과학교실및소화기질환연구소 Correspondence to: Geom Seog Seo, Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University School of Medicine, 895 Muwangro, Iksan 54538, Korea. Tel: , Fax: , medsgs@wonkwang.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 71 No. 2, February

2 82 서검석, 이성희. 가까운미래에사용할수있는유망한치료약제 중 ) 등과같은인테그린차단제, ustekinumab (UST), risankizumab (IL-23 의 p19 아형억제제로써크론병에대해 2상연구진행중 ) 과같은항-인터루킨제제, tofacitinib, upadacitinib ( 선택적 Janus kinase [JAK]1 억제제로써크론병과궤양성대장염모두 3상연구진행중 ), ozanimod (sphingosine-1-phosphate 수용체길항제로써크론병및궤양성대장염에대해각각 2상, 3상연구진행중 ), mongersen (SMAD7 안티센스올리고뉴클레오타이드로써크론병의경우임상 3상에서연구중단, 궤양성대장염에대해서 2상연구진행중 ) 등과같은약제의임상연구가활발히진행중에있다. 7,8 본고에서는최근사용가능한약제인 VDZ와가까운미래에사용할수있는 UST, tofacitinib에국한하여알아보고자하며, 추가적인약제부작용및임신에미치는영향에대해서는염증성장질환보다먼저연구가이루어진피부질환 ( 건선 ), 관절질환 ( 류마티스관절염 ) 관련임상자료를통해상세히소개하고자한다. 본론 1. Vedolizumab (Kynteles, Entyvio ) VDZ는 α4β7 인테그린에대한 IgG1 단클론항체로써, 염증세포의 α4β7 인테그린과내피세포 (endothelium) 의부착분자 (adhesion molecule) 인 mucosal addressin cell adhesion molecule-1과의결합을억제시킨다. 9 이로인해염증세포가혈관밖으로이동할수없게되어장점막으로의림프구의귀환 (lymphocyte homing) 이되지않기때문에, 크론병과궤양성대장염에서염증반응을줄이는효과를보이게된다. VDZ 사용후 6주째임상반응을보인궤양성대장염환자를대상으로위약군 (126명), VDZ 8주간격사용군 (122명), VDZ 4주간격사용군 (125명) 으로나누어 52주후점막치유를비교한 GEMINI 1 연구에서메이요내시경점수 0 또는 1점이각각 19.8%, 51.6%, 56% 로유의한차이를보였다 ( 모두 p<0.001). 또한메이요내시경점수 0인경우도각각 8.7%, 28.7%, 33.6% 로유의한차이를보였다 ( 모두 p<0.001). 10 중등도및중증궤양성대장염에서항-TNF제제를사용하지않았던환자 (60%) 와이전에항-TNF제제를사용하였던환자 (40%) 군으로나누어서 6주후 VDZ의임상반응을알아본 GEMINI 1 사후분석결과에서는, 항-TNF제제를사용하지않았던군 ( 위약군 76명에서 26.3%, VDZ 130명에서 53.1% 로두치료군간차이의절대값은 26.4%; 95% confidence interval [CI], ) 이항-TNF제제를사용하였던군 ( 위약군 63명에서 20.6%, VDZ 82명에서 39.0% 로두치료군간차이의절대값은 18.1%; 95% CI, ) 에비해치료효과가더높았다 주후에항-TNF제제미사용군에서 VDZ와위약 군의임상관해는각각 46.9%, 19.0% 였고 ( 두군간차이의절대값은 28.0%; 95% CI, ), 항-TNF제제사용군에서 VDZ와위약군의임상관해는각각 36.1%, 5.3% 였다 ( 두군간차이의절대값은 29.5%; 95% CI, ). 11 궤양성대장염환자에서 VDZ의장기적관해 (long lasting remission) 를알아보기위한 GEMINI long-term safety 연구 (VDZ를 4주간격사용 ) 에서 104주째 88% (120/136), 152주째 96% (70/73) 로높은관해유지율을보였다. 12 크론병환자를대상으로한 GEMINI 2 연구에서 VDZ 사용후 6주째임상반응을보인환자들중 52주째위약군, VDZ 8주간격사용군, VDZ 4주간격사용군의스테로이드미사용임상관해를보았을때, 각각 15.9%, 31.7%, 28.8% 를나타내어 VDZ군에서더효과적임을알수있었다. 13 GEMINI 2와 3의사후분석에서 52주째임상관해비율은항-TNF제제미사용군에서 48.9%, 항-TNF제제사용군에서 27.7% 를나타내어 ( 위약군은각각 26.8%, 12.8%) 위약군에비해서 VDZ군의임상관해율이더높았고, 이러한효과는항-TNF제제에노출되지않았을때더현저하였다. 14 크론병환자에서 VDZ의장기적관해를알아보기위한 GEMINI long-term safety 연구 (VDZ를 4주간격사용 ) 에서 104주째 83% (100/120), 152주째 96% (62/70) 로높은관해유지를입증하였다. 15 크론병및궤양성대장염환자에서 VDZ 300 mg을 4주간격으로정맥주입하였을때점막치유및조직학적치유를알아보기위해 GEMINI long term safety 연구에등록된환자들에대해전향적으로감시대장내시경을시행하였는데, 추적기간은 1년이상이었고 ( 년, 평균 3.2년 ), 크론병의경우궤양이없는점막치유가 29% (7/24) 를, 궤양성대장염의경우메이요점수가 1 이하인점막치유가 50% (17/34) 를나타내었다. 조직학적치유까지관찰된경우는크론병과궤양성대장염에서각각 20.8% (5/24), 2.4% (11/34) 였다. 16 크론병에서 VDZ의누공폐쇄율에미치는긍정적효과를기대해볼수있지만, 현재진행중인 ENTERPRISE 4상임상시험 ( 누공성크론병에서 VDZ를 22주까지투여후, 30주째누공치유평가 ) 결과를기다려보아야한다. 17 병합치료에대해서는아직까지증례보고수준으로이루어지고있는데, 궤양성대장염환자에서발생한심한낭염 (pouchitis) 및척추관절염 (spondyloarthritis) 이 VDZ와 etanercept 병합치료에의해효과적으로조절이된다는보고 18 및치료에불응하는궤양성대장염환자에서 VDZ, certolizumab pegol을병합사용하고 21개월관찰하였을때임상관해및점막치료를보고한바있다. 19 고위험크론병환자에서세가지약물 (VDZ 300 mg, adalimumab 160/80/40 mg, methotrexate 15 mg) 에대한병합치료효과를알아보기위한 4상공개임상시험이진행되고있어우리가궁금해하는점에대해답을줄수있을것으로기대된다. 20 The Korean Journal of Gastroenterology

3 Seo GS and Lee SH. Emerging Therapies: What Are Promising in the Near Future? 83 동물모델에서치료용량을넘어서는 VDZ를투여하였음에도기형, 사산, 자궁내성장장애등은없었고, 출산 6개월까지관찰하였을때성장장애또한없었기때문에, 임신기간동안에사용하는것은안전할것으로생각되었지만, 년부터 2013년까지 6개의 VDZ 연구에참여하였던지원자를대상으로분석한결과 27명에서임신이있었고, 이중 4명은자연유산을경험하였다. VDZ를투여받고있는남성환자 19명의배우자에서임신이발생하였는데, 이중 2명에서자연유산이있었다. 22 VDZ 시판후에는 81예의임신중에 11예의자연유산이있다고보고하고있어, 22 현재 VDZ를사용하고있는염증성장질환환자에서임신결과를알아보기위해진행되고있는임상시험의결과를확인할필요가있다. 23 GEMINI 1과2에등록된환자를 52주간관찰하였을때, VDZ를투여받은환자의자가항체생성률은 4% (56/1,434) 였고, 이중에 1% 만이지속적으로양성을나타내었다. VDZ 약제사용초기에면역조절제를같이투여하는경우에는 VDZ의자가항체생성률이 4% 에서 3% 로 1% 가량더감소되었다. 24 치료에더심하게불응하는환자군의등록, 유병기간의차이, 더높은기저크론병활성지수 (Crohn s disease activity index, CDAI), 면역조절제의허용여부, 관해유지를평가하는기간의차이로인해 infliximab, adalimumab, certolizumab pegol 임상연구와 GEMINI 임상연구의결과를직접비교하기는어렵지만, 년까지 2,830명에대한 VDZ의투여에도불구하고위약군에비해심각한감염의증가소견은없었다 년부터 2013년까지 VDZ에대한 6 개의임상연구 ( 위약대조군연구 C13002, GEMINI 1, 2, 3과개방형연구인 C13004, GEMINI long term safety) 를종합해보았을때, 총 18예의암발생이있었다. 24 위장관암 (6예), 피부암 (5예), 폐암 (2예), 비뇨기계암 (2예), 유방암 (2예), B-세포림프암 (1예) 이었고, 이중에서대장암발생 (1.1/100 PYs) 이위장관암중에서가장많았지만, HealthCore Integrated Research Database 에서관찰된염증성장질환환자에서의암발생률 (2.1/1,000 PYs; 95% CI, ) 보다더낮게관찰되었다. 24,25 VDZ는뇌척수액의 T-림프구면역표현형 (immunophenotype) 에영향을미치지않으므로 natalizumab (α4β7과 α4β1 인테그린길항제 ) 에서보고되었던진행성다초점백질뇌병증 (progressive multifocal leukoencephalopathy) 의발병건수가없어안전성이보장된약제라고할수있다. 26 국내에서염증성장질환환자에서 VDZ의사용은 2차약제로승인이이루어진상태이고, 최초투여일로부터 2주및 6주경과시점에 300 mg씩정맥주입하고, 관해유지를위해 8주간격으로 300 mg씩투여한다. 미국의 VICTORY 컨소시엄에서중등도및증증크론병환자에대한 VDZ의효과및안정성에대한연구결과를발표하였는데, 이후향코호트연구에포함된크론병환자의 90% 이상 (193/212) 에서항-TNF제제를사용하였으므로국내에서 2차약제로허가된 VDZ의효과를간접적으로가늠해볼수있는연구로생각된다. 사용 6개월, 12개월, 18개월후에임상관해는각각 18%, 35%, 54% 였고, 반응소실은 6-12개월사이에가장많이발생되었다. 6개월과 12개월후의점막치유는각각 21%, 67% 였다. 질병활성도, 활동성항문주위질환, 흡연력, 항-TNF제제의사용력등은 VDZ의치료효과를감소시키는인자로작용하였다. 중증부작용또는심각한감염이 8-10% 의환자에서발생되었지만, 대부분은약제의중단없이해결할수있는정도였다. 27 국내에서는 2017년 8월 1일부터 VDZ이염증성장질환환자에서보험급여를적용받게되었다. 보험급여기준및유지요법인정에대해알아보면, 먼저궤양성대장염에서투여대상은 1종이상의항-TNF제제치료에반응을나타내지않거나반응이없어지는환자, 또는내약성이없는중등도-중증의궤양성대장염환자이고, 중등도- 중증궤양성대장염환자는메이요점수 6-12점이면서내시경점수가 2점이상인경우로정의하였다. 유지요법인정은약제를 14주투약후다음두가지조건을모두충족하여야하는데, 첫째, 메이요점수가최초투여시점보다 30% 이상감소하고 3점이상감소한경우, 둘째, 직장출혈점수가 1점이상감소또는직장출혈점수가 0점또는 1점인경우로하였다. 크론병에서투여대상은 1종이상의항-TNF제제치료에반응을나타내지않거나반응이없어지는환자, 또는내약성이없는중등도-중증의활성크론병 (CDAI 220 이상 ) 을대상으로하였다. 유지요법인정은첫투약후 14주이내에 CDAI가 70점이상감소또는총 CDAI score의 25% 이상감소된경우로하였다. VDZ에효과가없거나부작용으로투약을지속할수없어이전에투여한적이없는다른항-TNF 제제 (adalimumab, infliximab, golimumab 주사제 ) 로교체투여 (switch) 하는경우급여를인정하며, 이경우에는교체투여에대한투약소견서를첨부하도록하였다. VDZ의사용에있어초기반응이느리다는우려가있지만, 실제궤양성대장염및항-TNF제제미사용크론병환자에서는해당되지않을것으로생각되고, 향후병합치료의효능에대한연구가진행되면이에대한문제는해결될것으로생각된다. 항-TNF제제의사용이지난 20년간이루어졌지만, 아직까지도수술전항-TNF제제의사용이수술후합병증에미치는영향에대해명확한결론이나지않을정도로복잡한임상상황임을알수있다. 28 VDZ의사용기간이짧아서 VDZ의수술후합병증에미치는영향에대해서논하기는아직이르지만, 수술전 VDZ의사용은수술후합병증에영향을미치지않는다는보고와 29,30 수술부위의감염이증가한다는상반된보고가있어서, 31,32 향후전향적다기관연구가필요할것으로생각된다. Vol. 71 No. 2, February 2018

4 84 서검석, 이성희. 가까운미래에사용할수있는유망한치료약제 결론적으로 VDZ는증등도및증증의염증성장질환환자에서항-TNF제제의사용여부와관계없이안전하게사용할수있는약제이고, 점막치유효과도기대할수있으며, 감염및암발생의부작용측면에서도비교적안전한약물이라할수있다. 또한항-TNF제제의사용금기인동반질환이있는상황 ( 탈수초질환, 울혈성심부전, 림프종 ) 에서도사용할수있다는장점이있다. 2. Ustekinumab (STELARA ) UST는 IL-12와 IL-23의 p-40 subunit에대한인간단백질로재조합된 IgG1-κ 단클론항체로써 p-40이세포표면의 IL-12, IL-23 수용체에결합하는것을선택적으로차단시켜 T-세포활성화를감소시킨다. 33 UST에대한 2개의크론병관해유도연구가있는데, UNITI-1은항-TNF제제치료에실패한군을대상으로하였고, UNITI-2는고식적치료에실패한군을대상으로진행하였다. UNITI-1과2에반응을보였던군을대상으로관해유지연구 (IM-UNITI) 를시행하였고, UST 90 mg 8주간격사용군 (133명), UST 9 0mg 12주간격사용군 (132명), 위약군 (132명) 으로배정하였다. UNITI-1 연구에서 6주및 8주째 UST의임상반응은, 위약군 (247명), UST 130 mg 군 (245명), UST ~6 mg/kg군 (249명) 에서각각 21.5/34/3/33.7 (%), 20.2/33.5/37.8 (%) 를보였고, 임상관해는각각 8.9/ 16.3/18.5 (%), 7.3/15.9/20.9 (%) 로 UST군에서모두유의하게높았다. 34 UNITI-2 연구에서도 6주및 8주째임상반응은위약군 (209명), UST 130 mg군 (209명), UST ~6 mg/kg군 (209명) 에서각각 28.7/51.7/55.5 (%), 32.1/47.4/57.9 (%) 였고, 임상관해는각각 8.9/16.3/18.5 (%), 7.3/15.9/20.9 (%) 로 UST군에서모두유의하게높았다. UNITI-1과 2 연구에서위약군과 UST군간에부작용의차이는보이지않았다. 34 관해유지연구에서도 44주째 UST군에서임상반응, 임상관해및스테로이드사용이없는관해유지에더효과적이었고, 유지치료기간동안에안전성에있어위약군과의차이는없었다. 34 UNITI-1 (n=56), 2 (n=26) 및 IM-UNITI (n=21) 에등록되었던, 일본의크론병환자를대상으로 UST의효과를알아본연구에서 6주째 UST 130 mg, UST ~6 mg/kg군이위약군보다더높은임상반응을보였다 (UNITI-1에서각각 36.8%, 31.6%, 27.8%, UNITI-2에서각각 37.5%, 55.6%, 11.1%). 44주째임상관해는 UST 90 mg 12주간격사용군, UST 90 mg 8주간격사용군, 위약군에서각각 50.0%, 55.6%, 25.0% 였다. 위약군과비교하였을때약제안전성측면에서도의미있는차이를보이지않아, 항-TNF제제나고식적치료에실패한중등도및중증크론병환자의관해도입및유지치료에모두효과가있을것으로보고하였다. 35 UST를사용한캐나다인크론병환자 (95.2% [159/167] 는이전항-TNF제제실패환자 ) 를 대상으로한다기관후향코호트분석에서, UST 약제투여 3개월 (90 mg 8주간격사용또는 12주간격사용 ) 후임상반응및관해는각각 38.9% (65/167), 15.0% (25/167) 였고, 6개월후에는각각 60.3% (91/151), 27.9% (31/111) 였다. 내시경또는영상의학적반응은 6개월째 54.5% (67/123), 12개월째 55.8% (48/86) 였고점막치유는 25% 였다. 심각한부작용은 11건 (6.6%) 발생하였는데, 호흡기감염 (1명) 및췌장염 (1명) 으로인한입원, 약물주입반응, 관절통, 피로감및치아농양등과같은조절되지않는부작용 (8명) 과함께사망 (1명, 86세환자로약제관련성으로보기어려운심폐질환으로인해 ) 이있었다. 그외에암, 결핵은관찰되지않았다. 36 크론병환자의수술후합병증에미치는영향을알아보기위해 UST 사용군 (n=44) 과항-TNF제제사용군을비교해보았을때, 수술후 30일내수술부위감염률 ( 각각 13%, 20%, p=0.61) 및재입원률 ( 각각 18%, 10%, p=0.14) 에차이를보이지않았지만재수술을하는경우 ( 각각 16%, 5%, p=0.01) 는 UST군에서더높았다. 37 하지만여러기관자료를후향적으로분석하였고, UST가 2016년에미국식품의약국 (Food and Drug Administration) 허가를받은이유로인해 UST 사용대상군이상대적으로적었으므로, 향후전향적다기관연구가필요하다. UST를사용한후건선환자에서임신결과에문제를일으킬수있다는제한된보고가있었지만, 크론병과관련해서는아직결론을내리기가어렵다 건선환자에서 UST 의사용용량보다는크론병환자에서의사용용량이더높고, 아직다기관전향연구결과가없기때문에 UST의임신안전성에대한연구가향후필요하다. 이상의결과를종합해보았을때 UST는난치성크론병에서대안이될수있는약제일것으로생각된다. IL-23의 p19 subunit 억제제인 risankizumab과 UST는효능및안전성에있어어떠한차이를보일지향후연구결과를통해확인이필요하다. 41,42 3. Tofacitinib (XELJANZ ) Tofacitinib은염증에관여하는모든 JAK를억제하는소분자물질로써 IL-2, 4, 6, 7, 9, 15, 21 및인터페론감마를차단할수있다. JAK-signal transducers and activators of transcription (STAT) 신호전달이차단되어세포외화학신호가세포핵으로전달이되지않기때문에 DNA 전사및유전자발현에영향을미쳐면역, 세포증식및분화, 세포자멸사에영향을준다 증등도및중증의궤양성대장염환자에서 tofacitinib의효용성과안전성을평가하기위해 3상임상연구가진행되었는데, 2개의관해유도연구 (OCTAVE 1, 2) 가 8주간시행되었고 (10 mg BID군, 위약군 ), 반응을보인환자들은 52주동안에 OCTAVE Sustain (10 mg BID, 5 mg BID The Korean Journal of Gastroenterology

5 Seo GS and Lee SH. Emerging Therapies: What Are Promising in the Near Future? 85 군, 위약군 ) 을그리고이후에는 OCTAVE Open으로전환되었다. OCTAVE 1에서약물투여 8주후임상관해를알아보았을때 tofacitinib과위약군은각각 18.5%, 8.2% 를보였고, OCTAVE 2 연구에서는각각 16.6% 와 3.6% 를나타내었으며 ( 각각 p값이 0.007, <0.001), 이러한효과는항-TNF제제를사용하지않았던군뿐만아니라이미사용하였던군에서도일정하게보여주었다. Tofacitinib 사용군과위약군의점막치유율차이를비교해보았을때, 점막치유의도입및유지정도의차이는각각 15.9% (29.6% vs. 13.7%), 32.6% (45.7 vs. 13.1%) 였다. 46 모집군과연구디자인의차이때문에점막치유의직접적인비교는할수없지만, infliximab의경우각각 28.8%, 27.3%, VDZ의경우각각 16.1%, 31.8% 를보고하고있다. 47 반면에심각한감염발생률은위약군과 tofacitinib군간에차이가없었다 주째임상관해를알아본 OCTAVE Sustain 연구에서보면, 중앙에서분석하였을때위약군 (198명), tofacitinib 5 mg군 (198명), tofacitinib 10 mg군 (197명) 의임상관해는각각 11.1/34.3/40.6 (%) 이었다. 이를항-TNF제제사용유무에따라서임상관해정도를알아보았을때, 항-TNF제제사용군에서는각각 12.0/26.7/36.6 (%), 항-TNF제제미사용군은각각 10.4/40.7/44.8 (%) 로항-TNF제제미사용군에서관해정도가더높았고, 점막치유측면에서도각각 13.1/37.4/45.7 (%) 로 tofacitinib군에서유의하게높았다 (p<0.0001). 46 대상포진감염에대한분석을보면, 위약군 1예 (1/198), tofacitinib 5 mg BID군 3예 (3/198), tofacitinib 10 mg BID군 10예 (10/196) 에서대상포진이발생하였는데, 모두치료를중단할 Table 1. Characteristics and Positioning of Vedolizumab, Ustekinumab and Tofacitinib in the Treatment of Inflammatory Bowel Disease Indication Patient profiles Route of administration and dosage in clinical trials Induction of remission at week 6 or 8 Sustained clinical remission who had a clinical response to induction therapy Mucosal healing Summary of clinical efficacy results Vedolizumab Ustekinumab Tofacitinib Moderate-to-severe UC and CD Moderate-to-severe CD Moderate-to-severe UC (second-line biologic agent in Korea) 1. Concerns about infection and cancer 2. Uncontrolled heart failure, a history of lymphoma, or multiple sclerosis IV induction (300 mg, q0-2-6w) and maintenance (300 mg q8w) % (anti-tnf naïve)/39.0% (anti-tnf failure) in UC % (anti-tnf naïve)/13.3% (anti-tnf failure) in CD % (anti-tnf naïve)/36.1% (anti-tnf failure) in UC at week % (anti-tnf naïve)/27.7% (anti-tnf failure) in CD at week % (VDZ q8w)/47.5% (VDZ q4w) in anti-tnf failure group at week % in CD 1. Highest as first-line agent for induction of remission and mucosal healing in moderate-to-severe UC 2. The effectiveness of VDZ in anti-tnfα-naive populations tended to be greater than that in anti-tnfα-experienced populations 1. EIM 2. Children a 3. Anti-TNF induced psoriaform lesions IV or sc induction b (130 mg or 6 mg/kg), sc maintenance (90 mg q8w or q12w) 15.9% (130 mg)/20.9% (6mg/kg) in anti-tnf failure group 30.6% (130 mg)/40.2% (6 mg/kg) in conventional therapy failure group 48.8% (90 mg q12w)/53.1% (90 mg q8w) at week 44 Approximately one quarter (endoscopic or radiologic response; %) Consistent benefit of induction regimens, irrespective of previous treatment or response to a TNF antagonist Safety profile Favourable safety profile Contraindicated in patients with hypersensitivity and clinically important active infection (e.g. active TB) 1. Intolerable injection side effects 2. Prefer oral medication over injectable administration Oral induction (10 mg BID) and maintenance (5 mg BID or 10 mg BID) 18.5% (10 mg BID) 34.3% (5 mg BID), 40.6% (10 mg BID) at week % in OCTAVE 1, 28.4% in OCTAVE % (5 mg BID)/45.7% (10 mg BID) in OCTAVE sustain Similar efficacy in UC patients regardless of whether or not they have received prior anti-tnf therapy (highest second-line agent for induction of remission and mucosal healing in moderate-to-severe UC) 1. Increased risk of herpes zoster 2. Risk of dyslipidemia UC, ulcerative colitis; CD, Crohn s disease; EIM, extraintestinal manifestation; TNF, tumor necrosis factor; VDZ, vedolizumab. a Pediatric CD patients; only case series of UST use are available; b Various dosage was used. Vol. 71 No. 2, February 2018

6 86 서검석, 이성희. 가까운미래에사용할수있는유망한치료약제 정도로중증감염소견은없었지만, 향후 tofacitinib을사용할계획에있는경우에는대상포진백신을미리접종하는것이바람직할수있다. 48,49 염증성장질환에서 tofacitinib의병합치료에대한대규모, 전향연구는아직이루어지고있지않으나, methotrexate 치료에불충분한반응을보인류마티스관절염환자를대상으로한연구를살펴보았을때, tofacitinib 단독치료군은 tofacitinib+methotrexate, adalimumab+methotrexate 병합치료군에비해관절염활성도의개선율 (50% 이상호전 ) 은약간감소하였지만, 부작용으로인한약제중단률은가장낮은정도를보여주었다. 50 향후궤양성대장염환자를대상으로한 tofacitinib의병합치료에대한효능및안전성에대한전향적연구가필요할것이다. OCTAVE 연구의경우추적관찰기간이짧고, 대상군이상대적으로적어서결론을내리기는어렵지만장기간사용할때지질이상의가능성을배제할수없다. 비록많은수의류마티스관절염또는건선환자를장기간추적관찰하였을때심혈관계문제를일으키지않았고, 심지어는류마티스관절염환자에서혈중콜레스테롤을상승시킴에도불구하고동맥경화를호전시킨다는보고가있지만, 55 향후궤양성대장염환자를대상으로한 tofacitinib의고지혈증이상이심혈관계에미치는영향에대해서전향적연구가필요하다. Tofacitinib 약제사용에따른이득과위험성에대한결과는현재진행중인개방표지 (open-label) 연장연구를통해얻을수있을것으로기대된다. 56 류마티스관절염및건선환자에서 tofacitinib의사용은일반집단및염증성장질환환자에서생물학제제를사용한경우와동일한임신결과를보고하고있다. 57 하지만유럽류마티스학회에서는임신과관련해서 tofacitinib이아직태아에대한안정성여부에대한근거가충분하지않기때문에, 임신을계획하고있는경우라면약제의사용을중단할것을권고하고있으므로, 58 향후궤양성대장염환자에서 tofacitinib이임신에미치는영향에대한연구결과를지켜볼필요가있다. OCTAVE 연구를통해몇가지알수있는사실은이전에항-TNF제제치료를받았던또는치료실패인환자모두에서효과가있고, 투여 2주째에도부분메이요점수에호전을가져올정도로치료효과가빠르며, 관해도달여부와관계없이평균약물농도는유사하므로치료약물농도측정은큰의미가없다는것이다. 59 Tofacitinib, VDZ, UST 약물전반에대한특성, 효능및부작용에대한내용을 Table 1에정리하였다. Tofacitinib은저분자이므로고분자단백질에비해자가항체형성이거의없어반응소실에대한가능성이상대적으로적을것으로예상되고, 급성중증궤양성대장염환자에서신속한치료효과를나타낼것으로기대된다. 성인이나소아의 궤양성대장염환자에서의 tofacitinib의위험성-효과에대한비교분석뿐만아니라, 선택적 JAK1 억제제인 upadacitinib 과 tofacitinib의효능및부작용측면에대한비교가필요할것이다. 42 결 론 궤양성대장염및크론병에서항-TNF제제의도입은기존의고식적인치료보다더많은임상반응, 임상관해및점막치유를보여주었지만, 반응소실을포함한여러이유로인해새로운약제개발의개발이필요하게되었다. 항-TNF제제보다효과및안정성면에서더우월하거나, 항-TNF제제에불응하는환자에서구제치료제로써의역할을할수있는약제의개발이임상에서중요하다고할수있다. VDZ, UST, tofacitinib은상기조건을상당부분만족시키는약제로써향후임상에서널리사용될가능성이높지만, 약제치료모니터링, 약제용량결정, 병합치료및부작용에대한연구가더필요하고, 이러한과정을이해함으로써임상에서더효과적으로사용될수있을것으로기대된다. 또한 3상임상시험단계이전의여러약물도현재지속적으로효과및안정성검증을진행하고있기때문에향후이러한약제의임상시험결과를예의주시할필요가있다. REFERENCES 1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359: Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007;132: Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007;357: Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-tnf therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis 2010;4: D'Haens GR, Panaccione R, Higgins PD, et al. The London position statement of the world congress of gastroenterology on biological therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106: Seo GS, Chae SC. Biological therapy for ulcerative colitis: an update. World J Gastroenterol 2014;20: Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J The Korean Journal of Gastroenterology

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