The discovery of first-in-class drugs: origins and evolution

Abstract

Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…Of all new FDA‐approved NCEs between 1999 and 2013, almost one third are first‐in‐class compounds, as modulators of an until then unprecedented target or biological pathway,369 and the share of potentially first‐in‐class drugs in the current global pipeline has been estimated to be on average 70 % 370. India's past and current discovery pipeline is far from reaching comparable figures, as the vast majority of modes of action have been extensively targeted previously by other companies, such as PDE4 inhibitors, DPP‐IV inhibitors, kinase inhibitors, or oxazolidinone and fluoroquinolinone antibiotics.…”

Addressing the Right Targets in Oncology: Challenges and Alternative Approaches

“…110 A similar analysis performed in 2011 using data from 1999-2008 claims that 56% (28 of 50) of first-in-class small-molecule approvals were derived from phenotypic screening. 111 Although there are many advantages to screening in a more physiologically relevant setting, there are also significant obstacles associated with this approach, such as chemistry optimization and molecular target deconvolution (see Table 2 for comparison between target-based and target-agnostic approaches).…”

The utility of target-based discovery

“…Of 113 first in class drugs approved by the US FDA from 1999 to 2013, 70% were identified through targetbased drug discovery [2]. The approach is not limited to smallmolecule drug discovery.…”