The genetics of drug efficacy: opportunities and challenges

• Published in: Nature reviews. Genetics Vol. 17; no. 4; pp. 197 - 206
• Main Authors: Nelson, Matthew R., Johnson, Toby, Warren, Liling, Hughes, Arlene R., Chissoe, Stephanie L., Xu, Chun-Fang, Waterworth, Dawn M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2016; Nature Publishing Group
• Subjects: 631/154/109; 631/154/309/2144; 631/154/436/434; 631/208/212/1728; Agriculture; Animal Genetics and Genomics; Biomarkers, Pharmacological - analysis; Biomedicine; Cancer Research; Drug Discovery - trends; Drug metabolism; Gene Function; Genetic aspects; Genotype; Human Genetics; Humans; Identification and classification; Pharmacogenetics - trends; Precision Medicine - trends; review-article; Treatment Outcome
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg.2016.12

Key Points To date, there have been at least 76 genome-wide association studies and a large number of candidate gene studies of drug efficacy. From these, there are at least 12 drugs with high-confidence genetic predictors of drug efficacy. Genetic predictors of drug efficacy are mostly common variants with a range of effect sizes; most have been discovered through studies of sensitive quantitative measures of drug response, and all but one were discovered following drug approval. Less than 20% of drugs are estimated to have common genetic predictors of efficacy that are large enough to inform clinical decision making. There are limited scenarios in which genetics can 'rescue' a trial that fails owing to lack of efficacy. However, advances in genetic technologies can allow for cost-effective screening for genetic predictors with potential clinical utility during the course of clinical development. Pharmaceutical and academic researchers should combine resources to study the efficacy pharmacogenetics of marketed drugs. In this Review, the authors highlight the potential for efficacy genetics to drive drug development and guide treatment options. They argue for the integration of routine pharmacogenetic screening into clinical development and propose strategies for identifying efficacy loci for marketed drugs. Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.