Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval.,PLOS Genetics

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Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-12 , DOI: 10.1371/journal.pgen.1008489
Emily A King ₁ , J Wade Davis ₁ , Jacob F Degner ₁

Affiliation

Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.

中文翻译：

具有遗传支持的药物靶标被批准的可能性是两倍吗？关于药物机制的遗传支持对药物批准可能性影响的订正估计数。

尽管对疾病的活动进行了强烈的审查，但最终在早期临床试验中只有10％的候选新分子实体被批准。分析历史管道数据，Nelson等。2015年（Nat。Genet。）得出结论，具有人类疾病关联遗传证据的管道药物靶标产生批准药物的可能性是其两倍。利用最新的临床开发进展和GWAS数据集的快速增长，我们使用更新的数据扩展了原始工作，测试了遗传证据是否可以预测未来的成功，并引入了针对目标和适应症水平属性进行调整的统计模型。我们的工作证实，具有遗传支持目标的药物更有可能在第二阶段和第三阶段获得成功。当因果基因清晰时（与编码变体相关的孟德尔特征和GWAS关联），我们发现，人类遗传证据的使用使认可度提高了两倍以上，对于孟德尔协会，积极协会具有前瞻性。我们的发现表明，对基因组学和遗传学的投资可能对采用该策略的公司有利。

更新日期：2019-12-13

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