Roberts Robert
Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona.
JACC Basic Transl Sci. 2018 Nov 12;3(5):690-703. doi: 10.1016/j.jacbts.2018.08.001. eCollection 2018 Oct.
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.
获批用于治疗心血管疾病的新药一直匮乏。成本高得令人望而却步，平均达25亿美元，且需要12.5年时间。这在很大程度上是由于失败率高，美国食品药品监督管理局的批准率仅为5%。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期临床试验时都会失败。失败的一个原因是药物靶点，常常发现其是一种生物标志物而非疾病的病因。孟德尔随机化（MR）研究将确定药物靶点是否为病因，这样可以节省数百万美元和大量时间，并防止不必要的药物不良反应暴露。这在3项针对两种药物（维拉司帕迪布和达普拉迪布）的阴性临床试验中得到了证明。试验期间的MR研究表明，分泌型和脂蛋白相关磷脂A2的靶点并非冠状动脉疾病的病因，并预测了阴性结果。MR研究的要求是存在功能改变的基因风险变异，在受孕时随机产生且在一个人的一生中保持不变。它不受饮食、生活方式或社会经济因素的干扰。它比随机对照试验更敏感，因为对风险因素的暴露是终身固定的。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病因靶点，尿酸、C反应蛋白等也不是。MR研究在确定药物靶点是否为病因方面高度敏感，且相对简便、廉价且不耗时。建议在进行随机对照试验之前，先对药物靶点进行MR研究。
