Mendelian Randomization Studies Promise to Shorten the Journey to FDA Approval.
Mendelian Randomization Studies Promise to Shorten the Journey to FDA Approval.
复制标题
DOI：
10.1016/j.jacbts.2018.08.001
复制
发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Roberts R
中科院分区：
文献类型：
--
作者：
Roberts R
一直缺乏批准用于心血管疾病的新药。费用高昂，平均为25亿美元，需要12.5年。这在很大程度上是由于高失败率，只有5%的批准由食品和药物管理局。尽管临床前研究显示出潜在的安全性和有效性，但大多数药物在进入I至III期临床试验时都失败了。失败的一个原因是药物靶点，通常发现它是一种生物标志物，而不是疾病的病因。孟德尔随机化（MR）研究将确定药物靶点是否是致病性的，可以节省数百万美元和时间，并防止不必要的药物不良反应。这在3项临床试验中得到证实，其中2种药物veraspladib和darapladib均为阴性。试验期间的MR研究表明，分泌型和脂蛋白相关磷脂A2的靶点不是冠状动脉疾病的病因，并预测阴性结果。MR研究的要求是功能改变的遗传风险变异，在受孕时随机化，并在一生中保持固定。它不受饮食、生活方式或社会经济因素的影响。它比随机对照试验更敏感，因为暴露于风险因素是终身固定的。MR研究表明，血浆高密度脂蛋白胆固醇不是冠状动脉疾病的致病靶点，尿酸、C反应蛋白等也不是。磁共振研究在确定药物靶点是否是病因方面具有高度敏感性，并且相对容易，廉价且不耗时。建议药物靶点在进行随机对照试验前进行MR研究。
There has been a dearth of new drugs approved for cardiovascular disorders. The cost is prohibitive, averaging to $2.5 billion, and requiring 12.5 years. This is in large part due to the high failure rate, with only 5% approval by the Food and Drug Administration. Despite preclinical studies showing potential safety and efficacy, most fail when they go to clinical trials phase I to III. One cause for failure is the drug target, often discovered to be a biomarker rather than causative for the disease. Mendelian randomization (MR) studies would determine whether the drug target is causative and could save millions of dollars and time, and prevent unnecessary exposure to adverse drug effects. This was demonstrated in 3 clinical trials that were negative with 2 drugs, veraspladib and darapladib. MR studies during the trials showed the targets of secretory and lipoprotein-associated phospholipids A2 are not causative for coronary artery disease and predicted negative results. The requirement for MR studies is a genetic risk variant with altered function, randomized at conception that remains fixed throughout one’s lifetime. It is not confounded by dietary, lifestyle, or socioeconomic factors. It is more sensitive than randomized controlled trials because exposure to the risk factor is fixed for a lifetime. MR studies showed plasma high-density lipoprotein cholesterol is not a causative target of coronary artery disease, and neither is uric acid, C-reactive protein, and others. MR studies are highly sensitive in determining whether drug targets are causative, and are relatively easy, inexpensive, and not time consuming. It is recommended that drug targets undergo MR studies before proceeding to randomized controlled trials.
登录
查看更多内容
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
30.8
作者：
Howson JMM;Zhao W;Barnes DR;Ho WK;Young R;Paul DS;Waite LL;Freitag DF;Fauman EB;Salfati EL;Sun BB;Eicher JD;Johnson AD;Sheu WHH;Nielsen SF;Lin WY;Surendran P;Malarstig A;Wilk JB;Tybjærg-Hansen A;Rasmussen KL;Kamstrup PR;Deloukas P;Erdmann J;Kathiresan S;Samani NJ;Schunkert H;Watkins H;CARDIoGRAMplusC4D;Do R;Rader DJ;Johnson JA;Hazen SL;Quyyumi AA;Spertus JA;Pepine CJ;Franceschini N;Justice A;Reiner AP;Buyske S;Hindorff LA;Carty CL;North KE;Kooperberg C;Boerwinkle E;Young K;Graff M;Peters U;Absher D;Hsiung CA;Lee WJ;Taylor KD;Chen YH;Lee IT;Guo X;Chung RH;Hung YJ;Rotter JI;Juang JJ;Quertermous T;Wang TD;Rasheed A;Frossard P;Alam DS;Majumder AAS;Di Angelantonio E;Chowdhury R;EPIC-CVD;Chen YI;Nordestgaard BG;Assimes TL;Danesh J;Butterworth AS;Saleheen D
通讯作者：
Saleheen D
DOI：
10.1016/s2213-8587(15)00034-0
发表时间：
2015-04
期刊：
The lancet. Diabetes & endocrinology
影响因子：
--
作者：
Interleukin 1 Genetics Consortium
通讯作者：
Interleukin 1 Genetics Consortium
影响因子：
30.8
作者：
Deloukas, Panos;Kanoni, Stavroula;Willenborg, Christina;Farrall, Martin;Assimes, Themistocles L.;Thompson, John R.;Ingelsson, Erik;Saleheen, Danish;Erdmann, Jeanette;Goldstein, Benjamin A.;Stirrups, Kathleen;Koenig, Inke R.;Cazier, Jean-Baptiste;Johansson, Asa;Hall, Alistair S.;Lee, Jong-Young;Willer, Cristen J.;Chambers, John C.;Esko, Tonu;Folkersen, Lasse;Goel, Anuj;Grundberg, Elin;Havulinna, Aki S.;Ho, Weang K.;Hopewell, Jemma C.;Eriksson, Niclas;Kleber, Marcus E.;Kristiansson, Kati;Lundmark, Per;Lyytikainen, Leo-Pekka;Rafelt, Suzanne;Shungin, Dmitry;Strawbridge, Rona J.;Thorleifsson, Gudmar;Tikkanen, Emmi;Van Zuydam, Natalie;Voight, Benjamin F.;Waite, Lindsay L.;Zhang, Weihua;Ziegler, Andreas;Absher, Devin;Altshuler, David;Balmforth, Anthony J.;Barroso, Ines;Braund, Peter S.;Burgdorf, Christof;Claudi-Boehm, Simone;Cox, David;Dimitriou, Maria;Do, Ron;Doney, Alex S. F.;El Mokhtari, NourEddine;Eriksson, Per;Fischer, Krista;Fontanillas, Pierre;Franco-Cereceda, Anders;Gigante, Bruna;Groop, Leif;Gustafsson, Stefan;Hager, Joerg;Hallmans, Goran;Han, Bok-Ghee;Hunt, Sarah E.;Kang, Hyun M.;Illig, Thomas;Kessler, Thorsten;Knowles, Joshua W.;Kolovou, Genovefa;Kuusisto, Johanna;Langenberg, Claudia;Langford, Cordelia;Leander, Karin;Lokki, Marja-Liisa;Lundmark, Anders;McCarthy, Mark I.;Meisinger, Christa;Melander, Olle;Mihailov, Evelin;Maouche, Seraya;Morris, Andrew D.;Mueller-Nurasyid, Martina;Nikus, Kjell;Peden, John F.;Rayner, N. William;Rasheed, Asif;Rosinger, Silke;Rubin, Diana;Rumpf, Moritz P.;Schaefer, Arne;Sivananthan, Mohan;Song, Ci;Stewart, Alexandre F. R.;Tan, Sian-Tsung;Thorgeirsson, Gudmundur;van der Schoot, C. Ellen;Wagner, Peter J.;Wells, George A.;Wild, Philipp S.;Yang, Tsun-Po;Amouyel, Philippe;Arveiler, Dominique;Basart, Hanneke;Boehnke, Michael;Boerwinkle, Eric;Brambilla, Paolo;Cambien, Francois;Cupples, Adrienne L.;de Faire, Ulf;Dehghan, Abbas;Diemert, Patrick;Epstein, Stephen E.;Evans, Alun;Ferrario, Marco M.;Ferrieres, Jean;Gauguier, Dominique;Go, Alan S.;Goodall, Alison H.;Gudnason, Villi;Hazen, Stanley L.;Holm, Hilma;Iribarren, Carlos;Jang, Yangsoo;Kahonen, Mika;Kee, Frank;Kim, Hyo-Soo;Klopp, Norman;Koenig, Wolfgang;Kratzer, Wolfgang;Kuulasmaa, Kari;Laakso, Markku;Laaksonen, Reijo;Lee, Ji-Young;Lind, Lars;Ouwehand, Willem H.;Parish, Sarah;Park, Jeong E.;Pedersen, Nancy L.;Peters, Annette;Quertermous, Thomas;Rader, Daniel J.;Salomaa, Veikko;Schadt, Eric;Shah, Svati H.;Sinisalo, Juha;Stark, Klaus;Stefansson, Kari;Tregouet, David-Alexandre;Virtamo, Jarmo;Wallentin, Lars;Wareham, Nicholas;Zimmermann, Martina E.;Nieminen, Markku S.;Hengstenberg, Christian;Sandhu, Manjinder S.;Pastinen, Tomi;Syvanen, Ann-Christine;Hovingh, G. Kees;Dedoussis, George;Franks, Paul W.;Lehtimaki, Terho;Metspalu, Andres;Zalloua, Pierre A.;Siegbahn, Agneta;Schreiber, Stefan;Ripatti, Samuli;Blankenberg, Stefan S.;Perola, Markus;Clarke, Robert;Boehm, Bernhard O.;O'Donnell, Christopher;Reilly, Muredach P.;Maerz, Winfried;Collins, Rory;Kathiresan, Sekar;Hamsten, Anders;Kooner, Jaspal S.;Thorsteinsdottir, Unnur;Danesh, John;Palmer, Colin N. A.;Roberts, Robert;Watkins, Hugh;Schunkert, Heribert;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
Tanaka, T