An analysis of the attrition of drug candidates from four major pharmaceutical companies

Waring, Michael J.; Arrowsmith, John; Leach, Andrew R.; Leeson, Paul D.; Mandrell, Sam; Owen, Robert M.; Pairaudeau, Garry; Pennie, William D.; Pickett, Stephen D.; Wang, Jibo; Wallace, Owen B.; Weir, Alex. McCook

doi:10.1038/nrd4609

Cited by 1,108 publications

(796 citation statements)

References 27 publications

(31 reference statements)

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“…This is illustrated by the sharp reduction in drug withdrawal over the last decade because of arrhythmogenic events, largely attributable to the widespread introduction of compulsory hERG channel assays (Stockbridge et al , 2012). What sometimes goes almost unnoticed though is the concomitant fall in the approval rate of new drugs despite the unprecedented increase in R&D investment in the last 10 years (Kola and Landis, 2004; Bunnage, 2011; Hay et al , 2014; Waring et al , 2015). This indicates that current methods are still not meeting needs, perhaps providing negative indications for drugs that could be of clinical benefit.…”

Section: Cardiotoxicity Caused By Electrical Disruptionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Cardiotoxicity Caused By Electrical Disruptionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

View full text Add to dashboard Cite

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“…[1][2][3][4][5] Prior to clinical testing, all clinical candidates are evaluated in animals to define the spectrum of toxicities that might occur in human subjects and safe doses for clinical testing. 6 However, continued occurrences of clinical safety terminations calls into question the value of nonclinical testing in predicting human risk.…”

Section: Introductionmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…Apart from efficacy and toxicity, many failures during drug development are related to pharmacokinetics, i.e., the fate of the compound in the organism 1. Nowadays, by monitoring physicochemical profiles of lead compounds it is possible to increase the quality of clinical candidates 2. The individual consideration of absorption, distribution, metabolism and excretion (ADME) behaviors at the early stages of drug discovery has decreased the fraction of global pharmacokinetics‐related failures in later phases of development.…”

mentioning

confidence: 99%

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

2016

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Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED‐Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED‐Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

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An analysis of the attrition of drug candidates from four major pharmaceutical companies

Cited by 1,108 publications

References 27 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

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