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

Abstract

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.

Fig 1. Estimated effect of evidence from human genetic studies on the probability of advancing in clinical development.

A: Partitioning Pharmaprojects, OMIM, and GWAS Catalog into training data available to Nelson et al. 2015 and validation sets. We use validation set Pipeline Progression, consisting of target-indication pairs assigned a clinical phase in 2013, to determine whether gene target-indication pairs with genetic evidence were more likely to advance to the next pipeline phase from 2013-2018. Pharmaprojects target-indication pairs absent from or assigned an unknown clinical phase in the Nelson et al. dataset form the New Pipeline replication set. Pharmaprojects target-indication pairs approved prior to 2013 or with unknown phase in our dataset are not part of any replication set. B: Our estimates of the effect of genetic evidence on gene target-indication pair progression compared to values reported by Nelson et al. 2015 [3] in validation sets New Pipeline (drugs and indications > 2013, 2013 inactive drugs) New Genetic (only new genetic information > 2013) Pipeline Progression, and in the full updated dataset (Full Data). Estimates falling close to the identity line (shown in black) are consistent between the two analyses.

Fig 2. Estimated odds ratio of gene target-indication pair attaining approval, as a function of similarity between drug indication and the most similar trait associated with the target.

A: Left: All genetic associations. Right: Only genetic associations reported after 2013 download. B: Effect of LD expansion threshold R² on the estimated approval odds ratio of a drug gene target-indication pair supported by a GWAS high-moderate deleterious variant. Posterior median and pointwise 95% credible interval from Bayesian logistic regression.