Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework

Cook, David; Brown, David; Alexander, Robert; March, Ruth; Morgan, Paul; Satterthwaite, Gemma; Pangalos, Menelas N.

doi:10.1038/nrd4309

Cited by 1,159 publications

(878 citation statements)

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“…A second form of cardiotoxicity, commonly evident in the early phases of drug discovery, is the acute and direct, detrimental effect of drugs on the electrophysiological properties of CMs (Cook et al ., 2014). Electrical homeostasis is crucial for coordinating synchronous and functional contraction of the heart, and its disruption significantly reduces cardiac output.…”

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

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“…7,8 Nonetheless, when confidence in nonclinical safety data is high compounds are more likely to be safe in humans. 9 Uncertainty regarding safety predictions occurs at three major transition points in biopharmaceutical testing: (1) the transition inherent in using simple in vitro models to predict in vivo nonclinical (animal) results early in discovery; (2) the transition from nonclinical testing to human clinical trials; and (3) the transition from testing in well-controlled clinical trials to the larger diverse patient population post approval. In other work, we addressed the first transition by associating chemical properties with toxicity early 10 and by developing a systems level framework using co-expression networks to evaluate how well mechanisms extrapolate from primary cell cultures to the same organ in vivo.…”

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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“…Success rates and time spent by development phase have been widely used as parameters to quantify efficiency in pharmaceutical R&D 373, 374, 375. Current success rates by phase are defined as the number of development compounds that advance to the next phase, divided by the number of compounds that entered the phase from which is subtracted the number of compounds of yet unknown fate, for example, those in ongoing studies.…”

Section: Resultsmentioning

confidence: 99%

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

Differding¹

2017

ChemMedChem

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This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid‐2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India.

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Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework

Cited by 1,159 publications

References 61 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

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

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