Between 1999 and 2008, more First in Class drugs were discovered using Phenotypic Screens than with Target-based approaches (Swinney & Anthony Nat Rev Drug Disc. 2011)
Phenotypic screening or Phenotypic drug discovery (PDD) is an approach that measures functional characteristics of the model used, whether it be a whole organism or a cell culture. Functional characteristics may include the morphology of the cells, their ability to synthesize a particular molecule, or even their ability to proliferate.
Essentially, phenotypic approaches treat the biological system as a black box where compounds are added and a change in the behavior of the model is quantified.
Phenotypic screening is the oldest method of drug discovery and even during the recent era of focus on target-based approaches, phenotypic screening led to more first-in-class drugs.
For follow-up discoveries where the molecular target has been elucidated in prior studies, target-based approaches have been shown to be relatively efficient.
Phenotypic screens are typically more difficult to develop than target-based screens since they involve complex cellular systems rather than cell-free biochemistry.
Until recently, it has been argued that a drawback of phenotypic screens has been the difficulty associated with target identification. However, advances in RNAi and in silico approaches have significantly reduced this concern.
The biggest advantage of Phenotypic Screening is the potential to find first-in-class drugs via discovery of novel pathways or targets. Because Phenotypic Screening isn’t limited by prior knowledge of specific molecular targets, compounds may be discovered that act on previously unreported molecules or pathways.
Mark Fishman, President of the Novartis Institutes of Biomedical Research (NIBR); “For me it’s a discovery tool. The single biggest impediment to drug discovery is the small number of new, validated targets that we have. Phenotypic screening is one way of moving beyond well-defined targets from the literature to discover new therapeutic targets and new disease biology” (Kotz, J. SciBX 5(15, 2012).
Another major advantage of Phenotypic Screening is in discovering compounds whose efficacy is maintained in more complex downstream models. Since modern phenotypic screens involve use of advanced cell systems (i.e. primary cells, stem cell derived cultures, 3D cultures) their complexity more closely recapitulates human disease physiology. In contrast, the relative simplicity of target-based screens, which are often cell-free biochemical assays, leads to early attrition of leads.
Recent evidence based on FDA filings between 1999 and 2008 suggest that phenotypic screening is most well-suited to drug discovery in the CNS therapeutic area. During this time period, when target based approaches were a major focus in the pharmaceutical industry, 7 new first-in-class drugs were discovered via phenotypic screens while only 1 was discovered via a target based approach (Swinney & Anthony, Nature Reviews Drug Discovery vol. 10 July 2011 p507).
Between 1999 and 2008, 50 first-in-class small molecules were approved by the FDA. Five of these small molecules were imaging agents, of the remainder 28 (67%) were discovered via phenotypic screens. It is interesting to note that the dominance of phenotypic screens occurred during an era when target-based approaches were the focus (Swinney & Anthony, Nature Reviews Drug Discovery vol. 10 July 2011 p507).
Phenotypic approaches led to the highest number of first-in-class drugs to be approved by the FDA between 1999 and 2008 (figure adapted from Swinney & Anthony, Nature Reviews Drug Discovery vol. 10 July 2011 p507).
Below is a list of first-in-class drugs approved by the FDA between 1999-2008 that were discovered using phenotypic screening. A wide range of therapeutic areas have been sucessfully addressed using a phenotypic approach. In particular, phenotypic screening has led to a relatively large number of new molecular entities (NMEs) approved in the therapeutic areas of CNS and Infectious Disease (Swinney & Anthony, Nature Reviews Drug Discovery vol. 10 July 2011 p507).