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

Nature Reviews Drug Discovery

Volumn 13, Issue 6, 2014, Pages 419-431

  Cook, David ^a   Brown, Dearg ^a   Alexander, Robert ^a   March, Ruth ^a   Morgan, Paul ^a   Satterthwaite, Gemma ^a   Pangalos, Menelas N ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID PRECURSOR PROTEIN; ANTIVITAMIN K; APLAVIROC; ATECEGATRAN METOXIL; AZD 1981; AZD 3778; AZD 5672; AZD 6765; AZD 8529; BAPINEUZUMAB; BENRALIZUMAB; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CORTICOSTEROID; HORMONE RECEPTOR BLOCKING AGENT; KETAMINE; LEBRIKIZUMAB; MARAVIROC; MEPOLIZUMAB; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR AGONIST; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; OLAPARIB; PF 592379; PLACEBO; RISPERIDONE; SOLANEZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; XIMELAGATRAN;

ALZHEIMER DISEASE; ANTIDEPRESSANT ACTIVITY; ASTHMA; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL (TOPIC); DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG EXPOSURE; DRUG HALF LIFE; DRUG INDUSTRY; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESEARCH; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; EMBOLISM; GOOD LABORATORY PRACTICE; HUMAN; INTERVIEW; MAJOR DEPRESSION; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; PRODUCT DEVELOPMENT; QUALITY CONTROL; QUESTIONNAIRE; REVIEW; RHEUMATOID ARTHRITIS; SCHIZOPHRENIA; SINGLE DRUG DOSE; TRANQUILIZING ACTIVITY;

ANIMALS; BIOMEDICAL RESEARCH; CLINICAL TRIALS AS TOPIC; DECISION MAKING, ORGANIZATIONAL; DRUG DESIGN; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; DRUG INDUSTRY; DRUGS, INVESTIGATIONAL; EFFICIENCY, ORGANIZATIONAL; HUMANS; MODELS, ORGANIZATIONAL; ORGANIZATIONAL CULTURE; RESEARCH SUPPORT AS TOPIC; TECHNOLOGY, PHARMACEUTICAL;

EID: 84901946024     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4309     Document Type: Review

References (71)

1. Pammolli, F., Magazzini, L. & Riccaboni, M. The productivity crisis in pharmaceutical R & D. Nature Rev. Drug Discov. 10, 428-438 (2011).
2. Paul, S. M. et al. How to improve R & D productivity: the pharmaceutical industry's grand challenge. Nature Rev. Drug Discov. 9, 203-214 (2010).
3. Herper, M. The truly staggering cost of inventing new drugs. Forbes [online], http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly- staggering-cost-of-inventing-new-drugs/(10 Feb 2012).
4. Munros, B. Lessons from 60 years of pharmaceutical innovation. Nature Rev. Drug Discov. 8, 959-968 (2009).
5. Scannell, J. W., Blanckley, A., Boldon, H. & Warrington, B. Diagnosing the decline in pharmaceutical R & D efficiency. Nature Rev. Drug Discov. 11, 191-200 (2012).
6. Handen, J. S. The industrialization of drug discovery. Drug Discov. Today 7, 83-85 (2002).
7. Linder, M. D. Clinical attrition due to biased preclinical assessments of potential efficacy. Pharmacol. Ther. 115, 148-175 (2007).
8. Ringel, M., Tollman, P., Hersch, G. & Schulze, U. Does size matter in R & D productivity? If not, what does? Nature Rev. Drug Discov. 12, 901-902 (2013).
9. Arrowsmith, J. & Miller, P. Trial Watch: Phase II and Phase III attrition rates 2011-2012. Nature Rev. Drug Discov. 12, 569 (2013).
10. Redfern, W. et al. Impact and frequency of different toxicities throughout the pharmaceutical life cycle. The Toxicologist 114, 231 (2010).
11. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711-716 (2004).
12. Picker, S. M. In-vitro assessment of platelet function. Transfus. Apher. Sci. 44, 305-319 (2011).
13. Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507-3512 (2013).
14. de Jong, M. & Maina, T. Of mice and humans: are they the same?-Implications in cancer translational research. J. Nucl. Med. 51, 501-504 (2010).
15. Wendler, A. & Wehling, M. The translatability of animal models for clinical development: biomarkers and disease models. Curr. Opin. Pharmacol. 10, 601-606 (2010).
16. Jucker, M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nature Med. 16, 1210-1214 (2010).
17. Pangalos, M. N., Schechter, L. E. & Hurko, O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nature Rev. Drug Discov. 6, 521-532 (2007).
18. Prahalad, S. Negative association between the chemokine receptor CCR5-Δ32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun. 7, 264-268 (2006).
19. Vierboom, M. P. et al. Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5. Arthritis Rheum. 52, 627-636 (2005).
20. Okamoto, H. & Kamatani, N. CCR-5 antagonist inhibits the development of adjuvant arthritis in rats. Rheumatology 45, 230-232 (2006).
21. Fleishaker, D. L. et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res. Ther. 14, R11 (2012).
22. van Kuijk, A. W. et al. CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial. Ann. Rheum. Dis. 69, 2013-2016 (2010).
23. Gerlag, D. M. et al. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 62, 3154-3160 (2010).
24. Wehling, M. Assessing the translatability of drug projects: what needs to be scored to predict success? Nature Rev. Drug Discov. 8, 541-546 (2009).
25. Morgan, P. et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov. Today 17, 419-424 (2012).
26. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351-354 (2000).
27. Aan Het Rot, M. et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 67, 139-145 (2010).
28. Quirk, M. et al. Abstract P-09-045. Effects of low-trapping NMDA channel blocker AZD6765 on gamma-band EEG and psychotomimetic liability: a comparison to ketamine in freely behaving rats. Int. J. Neuropsychopharmacol. 15 (Suppl. S1), 153 (2012).
29. Skolnick, P., Popik, P. & Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563-569 (2009).
30. Mealing, G., Lanthorn, T. H., Murray, C. L., Small, D. L. & Morley, P. Differences in degree of trapping of low-affinity uncompetitve N-methyl-d-aspartic acid receptor antagonists with similar kinetics of block. J. Pharmacol. Exp. Ther. 288, 204-210 (1999).
31. Zarate, C. A. et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol. Psychiatry 71, 939-946 (2012).
32. Lip, G. Y. et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomised doseguiding, safety and tolerability study of four doses of AZD0837 versus vitamin K antagonists. Eur. Heart J. 30, 2897-2907 (2009).
33. Olsson, S. B. et al. Safety and tolerability of an immediate-release formulation of the oral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Thromb. Haemost. 103, 604-612 (2010).
34. Pehrsson, S., Johansson K., Kjaer, M. & Elg, M. Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats. Thromb. Haemost. 104, 1242-1249 (2010).
35. Wolzt, M. et al. Effect on perfusion chamber thrombus size in patients with atrial fibrillation during anticoagulant treatment with oral direct thrombin inhibitors, AZD0837 or ximelagatran, or with vitamin K antagonists. Thromb. Res. 129, e83-e91 (2012).
36. Olsson, S. et al. Stroke preventions with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised clinical trial. Lancet 362, 1691-1698 (2003).
37. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 293, 690-698 (2005).
38. Uppoor, R. S. et al. The use of imaging in the early development of neuropharmacological drugs: a survey of approved NDAs. Clin. Pharmacol. Ther. 84, 69-74 (2008).
39. 11 C-l-Deprenyl and PET. J. Nucl. Med. 46, 1618-1624 (2005).
40. Thebault, J. J., Guillaume, M. & Levy, R. Tolerability, safety and pharmacodynamics and pharmacokinetics of rasagiline: a potent, selective and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy 24, 1295-1305 (2004).
41. Ramsey, S. J., Attkins, N. J., Fish, R. & van der Graaf, P. H. Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo. Br. J. Pharmacol. 164, 992-1007 (2011).
42. Qureshi, Z. P., Seoane-Vazquez, E., Rodriguez-Monguio, R., Stevenson, K. B. & Szeinbach, S. L. Market withdrawal of new molecular entities approved in the United States from 1980 to 2009. Pharmacoepidemiol. Drug Safety 20, 772-777 (2011).
43. King, A. Prevention: neuropsychiatric adverse effects signal the end of the line for rimonabant. Nature Rev. Cardiol. 7, 602 (2010).
44. Tralau, T. & Luch, A. Drug-mediated toxicity: illuminating the 'bad' in the test tube by means of cellular assays? Trends Pharmacol. Sci. 33, 353-364 (2012).
45. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 434, 917-921 (2005).
46. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123-134 (2009).
47. Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). J. Clin. Oncol. Abstr. 31, 5505 (2013).
48. Jack, C. R. et al. Evidence for ordering of Alzheimer disease biomarkers. JAMA Neurol. 68, 1526-1535 (2011).
49. Poirier, J. et al. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 2, 697-699 (1993).
50. Holgate, S. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches? J. Allergy Clin. Immunol. 128, 495-505 (2011).
51. Izuhara, K. et al. [Clarification of the pathogenesis and development of clinical examination for allergic disease]. Rinsho Byori 55, 369-374 (in Japanese) (2007).
52. Izuhara, K. & Saito, H. Microarray-based identification of novel biomarkers in asthma. Allergol. Int. 55, 361-367 (2006).
53. Izuhara, K. et al. IL-13: a promising therapeutic target for bronchial asthma. Curr. Med. Chem. 13, 2291-2298 (2006).
54. Woodruff, P. G. et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Natl Acad. Sci. USA. 104, 15858-15863 (2007).
55. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088-1098 (2011).
56. Thomson, N. C., Patel, M. & Smith, A. D. Lebrikizumab in the personalized management of asthma. Biologics 6, 329-335 (2012).
57. Wenzel, S. E. et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 160, 1001-1008 (1999).
58. Pavord, I. D. et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651-659 (2012).
59. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144-2148 (2000).
60. Visser, S. et al. Model-based drug discovery: implementation and impact. Drug Discov. Today 18, 746-775 (2013).
61. Lisman, J. E., Raghavachari, S. & Tsien, R. W. The sequence of events that underlie quantal transmission at central glutamatergic synapses. Nature Rev. Neurosci. 8, 597-609 (2007).
62. Moghaddam, B. & Javitt, D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 4-15 (2012).
63. Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102-1107 (2007).
64. Geyer, M. A. & Moghaddam, B. in Neuropsycho-pharmacology: The Fifth Generation of Progress (eds Davies, K., Charney, D., Coyle, J. T. & Nemeroff, C.) 689-701 (Lippincott Williams & Wilkins, 2002).
65. Matsuoka, T. et al. Prostaglandin D2 as a mediator of allergic astma. Science 287, 2013-2017 (2000).
66. Arimura, A. et al. Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J. Pharmacol. Exp. Ther. 298, 411-419 (2001).
67. Shichijo, M. et al. A prostaglandin D2 receptor antagonist modifies experiemental asthma in sheep. Clin. Exp. Allergy 39, 1404-1414 (2009).
68. Lukacs, N. W. et al. CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L767-L779 (2008).
69. Gervais, F. G. et al. Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Mol. Pharmacol. 79, 69-76 (2011).
70. Barnes, N. et al. A randomized, double-blind, placebo-controlled strudy of the CRTH2 antagonist OC0000459 in moderate persistent asthma. Clin. Exp. Allergy. 42, 38-48 (2012).
71. Busse, W. W. et al. Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients. J. Allergy Clin. Immunol. 131, 339-345 (2013).