Study: Drug Candidates Targeting Disease Genetics More Likely to Gain Approval

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FDA-approval is more likely to be successful for a potential new drug if it known to target a specific gene already known to be linked to the disease. Researchers from AbbVie confirmed earlier findings that when causal genes are clearly established, such as in diseases with Mendelian traits and GWAS associations linked to coding variants, the use of this genetic evidence increases FDA-approval by more than two-fold.

Their findings are published in a paper in PLOS Genetics.

“Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III,” the authors write.

Currently, between 5 and 10 percent of potential new drugs that enter early stage clinical trials are ultimately approved. A 2015 study from Nelson et al at GlaxoSmithKlinepreviously showed the pipeline drug targets with human genetic evidence of disease are twice as likely to lead to approved drugs.

In this study, lead researcher Emily King and her AbbVie researchers extended this analysis a further five years to see if and how genetic evidence predicts future FDA successes. “Using the estimated impact of genetics from the 2015 study, increasing the fraction of new molecular entities (NMEs) in development with genetic support from the current value of 15 to 50 percent is predicted to decrease the direct R&D cost per launched drug by 22 +/- 13 percent,” they write.

Specifically, they analyzed the last five years of drug development data to assess which types of genetic evidence are more likely to be useful in guiding drug discovery.

“Here we report the revised estimates of the impact of genetic evidence on drug target success…into a model that can be deployed by other companies and academics to predict the likelihood of success of targets of interest to them,” the authors say.

In the 2015 analysis, Nelson, et al mapped common variant genetic associations from GWASdb and rare Mendelian traits from the Online Mendelian Inheritance in Man (OMIM)database to Medical Subject Heading (MeSH) terms.They also used the Informa Pharmaprojects database to generate a set of target-indication pairs.

In their replication analysis, AbbVie researchers used updated data subsets from the GWAS Catalog, OMIM, and Informa Pharmaprojects.  Similar to the 2015 study, they aggregated data at the level of gene target-indication pair, the unit on which genetic evidence is computed.

“A gene target-indication pair is said to have genetic evidence if there is human genetic evidence of association between the gene and a trait sufficiently similar to the indication,” they write.

In this analysis, they included 21,934 gene target-indication pairs linked to a highest pipeline phase. They found that historically, drugs designed to target proteins with amino acid sequence changes linked to the disease they are intended to treat, have the best chance of being approved.

Similar to the Nelson et alpaper, AbbVie researchers found a strong association between genetic evidence and progression through clinical development or drug approval.

“GWAS genetic evidence is generally positively associated with progressing in clinical development,” they write. “GWAS-supported target-indication pairs are more likely to be approved than those without a GWAS-linked gene target.”

Additionally, the research demonstrated that drugs targeting proteins genetically linked to a disparate disease are more likely to be halted before approval, perhaps due to off-target, negative side effects.

“Our analysis of the last five years of drug development data indicates that the positive association between genetic evidence and drug success is not just a historical phenomenon,” they conclude.

The research team has developed a Shiny app others may use to evaluate target-indication pairs of interest.

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