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

Key Points

  • Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2013, which shows that the majority (78) of these drugs were discovered through target-based approaches (45 small-molecule drugs and 33 biologics).

  • Only eight of the 33 drugs identified in the absence of a target hypothesis were found by what we define here as 'phenotypic screening': the testing of a large number of compounds in a target-agnostic assay that monitors phenotypic changes. The discovery of the other 25 non-target-based drugs occurred through a chemocentric approach in which compounds with known pharmacology served as the starting point.

  • The median time from first disclosure of the concept (target, pathway or chemotype) to FDA approval was 25 years for non-target-based drugs and 20 years for target-based drugs. All but four of the non-target-based drugs had their origins before 1985, the time around which the technologies necessary for target-based approaches were introduced.

  • We conclude that target-based drug discovery is successful and recognize that high-throughput screening and other innovations applied in the past 25 years have only recently started to have a major impact on new approvals. We further suggest viewing phenotypic screening as a logical evolution of target-based approaches and consider it a novel discipline rather than a neoclassical approach.

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.

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Figure 1: Discovery of first-in-class drugs approved by the FDA between 1999 and 2013.
Figure 2: Chronology of the discovery of first-in-class drugs approved between 1999 and 2003.
Figure 3: Chronology of the discovery of first-in-class drugs approved between 2004 and 2008.
Figure 4: Chronology of the discovery of first-in-class drugs approved between 2009 and 2013.
Figure 5: Distribution of first-in-class drugs according to the molecule type and target family.

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Acknowledgements

The authors are grateful to I. Jones for expert help in statistical analysis, and thank their colleagues at the Novartis Institutes for Biomedical Research for the stimulating discussions related to this work. The authors also thank M. C. Fishman for making valuable suggestions on the content and scope of the analysis, and U. Eder for important insights into general aspects of pharmaceutical research.

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Correspondence to Jörg Eder.

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All authors are employees of Novartis Pharma AG.

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Supplementary information S1 (table)

Characteristics and origins of first-in-class drugs approved by the US FDA: 1999–2013 (PDF 1759 kb)

Supplementary information S2 (box)

Approval times for target-based and systems-based first-in-class drugs: 1999–2013 (PDF 274 kb)

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DATABASES

Drugs@FDA

Glossary

First-in-class drugs

Drugs that modulate an as-yet unprecedented drug target or biological pathway.

Phenotypic screening

The testing of a large number of — in most cases randomly selected — compounds in a systems-based assay.

Target-based approaches

Hypothesis-based approaches that aim to manipulate a biological system bypharmacologically modulating a specific component or target (an enzyme, receptor, and so on).

Small-molecule drugs

Drugs with a low molecular mass (typically <1,000 Da); this includes synthetic drugs, natural products (or derivatives) and natural substances (or derivatives).

Systems-based approach

Hypothesis-agnostic assay or approach that monitors or is based on a phenotypic change in vitro or in vivo.

Chemocentric approaches

Drug discovery approaches based around a specific compound or compound class. Chemocentric approaches have made a substantial contribution both to drugs originating from systems-based approaches and to drugs originating from target-based approaches.

Natural substance (or derivative)

A chemical substance (or derivative thereof) produced by a living organism found in nature that usually has pharmacological or biological activity. For this article we arbitrarily excluded natural products from natural substances to keep the former as a separate class of compounds.

Biologics

Defined here as all drugs approved under a biologics license application (BLA) by the US Food and Drug Administration (FDA); usually antibodies and other proteins.

Chemotype

A family of molecules that possess the same core structure or scaffold.

Natural product (or derivative)

Secondary metabolites (or derivatives thereof) that are extracted from tissues of plants, marine organisms or microorganism fermentation broths.

Pharmacophore

The steric and electronic features of a ligand that are necessary to ensure optimal interactions with a biological target structure and to trigger (or to block) its biological response.

Low-molecular-mass synthetic drug

Low-molecular-mass drugs that are not derived from natural products or natural substances.

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Eder, J., Sedrani, R. & Wiesmann, C. The discovery of first-in-class drugs: origins and evolution. Nat Rev Drug Discov 13, 577–587 (2014). https://doi.org/10.1038/nrd4336

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