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The state of the art in secondary pharmacology and its impact on the safety of new medicines

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.

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Fig. 1: Current industry practice for secondary pharmacology screening.
Fig. 2: Selectivity of kinase-targeted and non-kinase-targeted compounds against kinases.
Fig. 3: Composition of the small-molecule portfolio of phase I–III drug candidates with respect to primary target class for the top ten large pharmaceutical companies in 2023.

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Acknowledgements

The authors thank the following individuals for their valuable contributions: K. A. Henderson from Amgen, C. J. B. Larner from AstraZeneca, A. Fekete from Novartis, E. Pawluk from UCB Biopharma and the entire membership of the IQ-DruSafe In vitro Secondary Pharmacology Working Group. J.-P.V., R.J.B. and S.J. are the Chair and Co-Chairs of the IQ-DruSafe In vitro Secondary Pharmacology Working Group, respectively.

Author information

Author notes

  1. Stephen Jenkinson

    Present address: Metrion Biosciences, San Diego, CA, USA

  2. Malar Pannirselvam

    Present address: GSK, Waltham, MA, USA

  3. Mohan Rao

    Present address: Neurocrine Biosciences, San Diego, CA, USA

  4. Lyn Rosenbrier Ribeiro

    Present address: Grunenthal, Berkshire, UK

  5. Duncan Armstrong

    Present address: Armstrong Pharmacology, Macclesfield, UK

  6. Russell Naven

    Present address: Novartis Biomedical Research, Cambridge, MA, USA

  7. Ravikumar Peri

    Present address: Alexion Pharmaceuticals, Wilmington, DE, USA

  8. These authors contributed equally: Richard J. Brennan, Stephen Jenkinson, Jean-Pierre Valentin.

Authors and Affiliations

  1. Sanofi, Cambridge, MA, USA

    Richard J. Brennan

  2. Pfizer, La Jolla, CA, USA

    Stephen Jenkinson

  3. GSK, Stevenage, UK

    Andrew Brown

  4. UCB Biopharma, Braine-l’Alleud, Belgium

    Annie Delaunois, Lyn Rosenbrier Ribeiro, Alicia Sibony & Jean-Pierre Valentin

  5. Novartis Biomedical Research, Basel, Switzerland

    Bérengère Dumotier

  6. Vertex Pharmaceuticals, Boston, MA, USA

    Malar Pannirselvam

  7. Janssen Research & Development, San Diego, CA, USA

    Mohan Rao

  8. AstraZeneca, Cambridge, UK

    Lyn Rosenbrier Ribeiro

  9. Sanofi, Frankfurt, Germany

    Friedemann Schmidt

  10. Novartis Biomedical Research, Cambridge, MA, USA

    Yoav Timsit & Duncan Armstrong

  11. Takeda Pharmaceuticals, Cambridge, MA, USA

    Vicencia Toledo Sales, Russell Naven & Ravikumar Peri

  12. Merck, North Wales, PA, USA

    Armando Lagrutta

  13. AbbVie, North Chicago, IL, USA

    Scott W. Mittlestadt

  14. Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland

    Sonia Roberts

  15. Faegre Drinker Biddle and Reath, LLP, Washington, DC, USA

    James M. Vergis

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  1. Richard J. Brennan
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Contributions

R.J.B., S.J., A.B., A.D., B.D., M.P., M.R., L.R.R., F.S., A.S., Y.T., V.T.S., D.A., A.L., S.W.M., R.N., R.P., S.R., J.M.V. and J.-P.V. researched data for the article. R.J.B., S.J., A.B., A.D., B.D., M.P., M.R., L.R.R., F.S., A.S., Y.T., V.T.S., A.L., S.W.M., R.P., S.R., J.M.V. and J.-P.V. reviewed and/or edited the manuscript before submission. R.J.B., S.J., A.B., A.D., B.D., M.P., M.R., L.R.R., F.S., A.S., Y.T., V.T.S., D.A., A.L., S.W.M., R.P., S.R. and J.-P.V. made a substantial contribution to discussion of content. R.J.B., S.J., A.B., A.D., B.D, M.P., L.R.R., F.S., A.S., Y.T., V.T.S., S.W.M., S.R. and J.-P.V. wrote the article.

Corresponding author

Correspondence to Richard J. Brennan.

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Competing interests

A.B., A.D., B.D., M.P., M.R., L.R.R., F.S., A.S., Y.T., V.T.S., A.L., S.W.M., R.N., R.P., S.R. and J.-P.V. are employees of pharmaceutical companies. R.J.B. is a Director/Trustee and Scientific Advisory Board member of Lhasa Ltd., which manages the Effiris consortium. S.J. is an employee of a CRO providing screening services to pharmaceutical companies. D.A., R.J.B., S.J., A.B., A.D., M.P., M.R., L.R.R., F.S., A.S., Y.T., V.T.S., A.L., S.W.M., R.N., R.P., S.R. and J.-P.V. hold shares, share rights and/or stock options in pharmaceutical companies. J.M.V. declares no competing interests.

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Nature Reviews Drug Discovery thanks Wolfgang Jarolimek and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Adverse drug reactions

Harmful, unintended results caused by the act of taking a medication. An adverse drug reaction is a special type of adverse event in which a causative relationship can be demonstrated.

Adverse event

(AE). Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.

Assay hit rate

The number of compounds showing activity in a specific assay as a proportion of the total number of compounds evaluated in the assay.

Compound promiscuity rate

Promiscuity is defined as the specific interaction of a small molecule with multiple biological targets (as opposed to nonspecific binding events) and represents the molecular basis of polypharmacology. The promiscuity rate of a compound refers to the number of off-target hits as a proportion of the total number of targets assayed.

DruSafe

A leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development with the mission to advance nonclinical safety sciences and impact the global regulatory environment.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

(ICH). An initiative that brings together regulatory authorities and the pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product development and registration. The mission of the ICH is to promote public health by achieving greater harmonization through the development of technical guidelines and requirements for pharmaceutical product registration.

New drug application

A document through which drug sponsors formally propose that the US Food and Drug Administration (FDA) approve a new pharmaceutical for sale and marketing in the USA.

New molecular entities

New drugs containing active ingredients not previously approved by the FDA or marketed as drugs in the USA.

Off-target activity

 Pharmacological activity of a drug against a target other than its intended therapeutic target.

Primary pharmacology studies

These studies aim to investigate the mode of action and/or effects of a substance in relation to its desired therapeutic target.

Safety pharmacology studies

These studies aim to investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. Safety pharmacodynamic effects may result from activity at the primary molecular target, secondary targets or nonspecific interactions.

Secondary pharmacology studies

These studies aim to investigate the mode of action and/or effects of a substance not related to its desired therapeutic target.

Side effects

Unintended pharmacological effects of a drug, frequently used to describe adverse effects, but this term may also apply to additional beneficial consequences.

The International Consortium for Innovation and Quality in Pharmaceutical Development

(IQ). A not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community.

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Brennan, R.J., Jenkinson, S., Brown, A. et al. The state of the art in secondary pharmacology and its impact on the safety of new medicines. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-00942-3

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