Developing a drug from early screening stages to regulatory approval is a cost and time consuming process that can take 12-15 years and has been estimated to cost 2.6 billion US$ . Importantly, lowest success rates are seen in clinical stages of development (Fig. 1a). If compounds fail in the clinics this is due to either efficacy or safety and “both of these are often the direct result of sloppy early target validation," says David Szymkowski, director of biotherapeutics at the biopharmaceutical company Xencor .
As the development a drug against a certain target is a big commitment in terms of time and money, target validation is of paramount importance in the drug-discovery process. Therefore, model systems are needed to test whether the chosen target is instrumental in the given disease of interest in humans.
The novel physiological and pathophysiological hepatic in vitro systems offer the possibility to test and validate targets before committing vast monetary and temporal resources to a promising lead compound. The system allows to use sense reversal strategies by which modulation of expression of the gene(s) of interest and monitor its effects on the efficacy of the drug candidate using a multitude of biochemical and molecular endpoints. Thereby, we can provide proof-of-concept data that directly demonstrates whether the potential target is indeed implicated in drug action, thus bolstering confidence and reducing the likelihood of expensive failures of poorly-chosen candidates (Fig. 1b,c).
- Smith C., Nature, 2003
- Paul et al., Nat Rev Drug Disc, 2010