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Research ArticleDrug Discovery and Translational Medicine

Development of Human Target Validation Classification that Predicts Future Clinical Efficacy

Cecilia Karlsson, Peter J. Greasley, David Gustafsson and Karin Wåhlander
Journal of Pharmacology and Experimental Therapeutics February 2019, 368 (2) 255-261; DOI: https://doi.org/10.1124/jpet.118.250894
Cecilia Karlsson
Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden (C.K., P.J.G.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); Emeriti Pharma, AZ Bioventure Hub, Gothenburg, Sweden (D.G.); and KW Translational Medicine AB, Västra Frölunda, Sweden (K.W.)
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Peter J. Greasley
Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden (C.K., P.J.G.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); Emeriti Pharma, AZ Bioventure Hub, Gothenburg, Sweden (D.G.); and KW Translational Medicine AB, Västra Frölunda, Sweden (K.W.)
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David Gustafsson
Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden (C.K., P.J.G.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); Emeriti Pharma, AZ Bioventure Hub, Gothenburg, Sweden (D.G.); and KW Translational Medicine AB, Västra Frölunda, Sweden (K.W.)
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Karin Wåhlander
Cardiovascular, Renal and Metabolism Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden (C.K., P.J.G.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); Emeriti Pharma, AZ Bioventure Hub, Gothenburg, Sweden (D.G.); and KW Translational Medicine AB, Västra Frölunda, Sweden (K.W.)
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Abstract

Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late-phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase that later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience in drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation [(HTV); the relevance of the target from a human perspective]. The elements were consolidated into a 10-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using 50 years of legacy research and development data, the ability of the 10-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium, or high HTV at the time of candidate drug selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk.

Footnotes

    • Received May 24, 2018.
    • Accepted November 13, 2018.
  • This work was funded by AstraZeneca.

  • https://doi.org/10.1124/jpet.118.250894.

  • The primary laboratory used in this study was at AstraZeneca (Gothenburg, Sweden).

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 2
1 Feb 2019
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Research ArticleDrug Discovery and Translational Medicine

Human Target Validation Classification Predicts Efficacy

Cecilia Karlsson, Peter J. Greasley, David Gustafsson and Karin Wåhlander
Journal of Pharmacology and Experimental Therapeutics February 1, 2019, 368 (2) 255-261; DOI: https://doi.org/10.1124/jpet.118.250894

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Research ArticleDrug Discovery and Translational Medicine

Human Target Validation Classification Predicts Efficacy

Cecilia Karlsson, Peter J. Greasley, David Gustafsson and Karin Wåhlander
Journal of Pharmacology and Experimental Therapeutics February 1, 2019, 368 (2) 255-261; DOI: https://doi.org/10.1124/jpet.118.250894
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