Pharmacogenetic targeting of drugs for heart failure

Abstract

Pharmacogenetic drug development represents an ideal approach to enhance a drug's response rate in a disease indication cohort, thereby increasing the therapeutic index. The most straightforward way to develop a pharmacogenetically targeted drug is to identify a functionally important genetic variant in the drug's target(s), or in a target modifier. There are two general ways to detect such genetic variation, the candidate gene variant hypothesis testing approach, and genome wide scanning "hypothesis free" methods. In order to impact drug development either approach needs to be implemented early in the drug development process, with the candidate strategy having the advantage that it can be introduced earlier, during preclinical development. Contrary to conventional wisdom, a pharmacogenetic approach does not increase the overall efficiency of drug development, because the required additional genetic and biologic function discovery work will be layered onto standard regulatory steps. However, identification of a hyper-responsive subpopulation by a genetic biomarker does increase the chance of success in Phase 3, which may lower the cost of pivotal trials. Perhaps most importantly from a commercial standpoint, pharmacogenetics use patents, typically submitted relatively late in the development process, can greatly extend a drug's exclusivity period. This will recoup the extra cost inherent to pharmacogenetic drug development, and increase the product's return on investment by providing a longer period for branded exclusivity. Most importantly, pharmacogenetic targeting will result in a therapeutic agent with a greater therapeutic index and a better pharmacoeconomic profile than would be possible with pan-genetic, entire cohort positioning.