Atherosclerosis drug development in jeopardy: The need for predictive biomarkers of treatment response

Science Translational Medicine

Volumn 3, Issue 72, 2011, Pages

  Fryburg, David A ^a   Vassileva, Maria T ^b  

^a ROI BioPharma Consulting   (United States)

^b NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; C REACTIVE PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MONOCYTE CHEMOTACTIC PROTEIN 1; MYELOPEROXIDASE; NEOPTERIN; NEW DRUG; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST;

ATHEROSCLEROSIS; COMPUTER MODEL; DRUG DEVELOPMENT; DRUG INDUSTRY; DRUG RESPONSE; GOVERNMENT; HUMAN; IMAGING; MEDICAL EXPERT; NON PROFIT ORGANIZATION; NOTE; ORGANIZATION; OUTCOME ASSESSMENT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PREDICTION; PRIORITY JOURNAL; PUBLIC-PRIVATE PARTNERSHIP; ARTICLE; CLINICAL TRIAL (TOPIC); METABOLISM; TREATMENT OUTCOME;

ATHEROSCLEROSIS; BIOLOGICAL MARKERS; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; DRUG INDUSTRY; HUMANS; TREATMENT OUTCOME;

EID: 79952321373     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3002029     Document Type: Note

References (38)

1. C. Baigent, A. Keech, P. M. Kearney, L. Blackwell, G. Buck, C. Pollicino, A. Kirby, T. Sourjina, R. Peto, R. Collins, R. Simes; Cholesterol Treatment Trialists' (CTT) Collaborators, Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366, 1267-1278 (2005).
2. J. C. LaRosa, S. M. Grundy, D. D. Waters, C. Shear, P. Barter, J. C. Fruchart, A. M. Gotto, H. Greten, J. J. Kastelein, J. Shepherd, N. K. Wenger; Treating to New Targets (TNT) Investigators, Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425-1435 (2005).
3. W. Koenig, Cardiovascular biomarkers: Added value with an integrated approach? Circulation 116, 3-5 (2007).
4. U. N. Khot, M. B. Khot, C. T. Bajzer, S. K. Sapp, E. M. Ohman, S. J. Brener, S. G. Ellis, A. M. Lincoff, E. J. Topol, Prevalence of conventional risk factors in patients with coronary heart disease. J. Am. Med. Assoc. 290, 898-904 (2003).
5. T. H. Dent, Predicting the risk of coronary heart disease I. The use of conventional risk markers. Atherosclerosis 213, 345-351 (2010).
6. World Health Organization, Cardiovascular Diseases (http://www.who.int/ cardiovascular-diseases/en/).
7. P. Libby, The forgotten majority: Unfinished business in cardiovascular risk reduction. J. Am. Coll. Cardiol. 46, 1225-1228 (2005).
8. FDA Guidance on Cardiovascular Risk of Diabetes Drugs, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf.
9. A. Singh, J. H. Gilbert, P. Henske, Rebuilding big pharma's business model. In Vivo 21, 1-10 (2003).
10. D. A. Fryburg, Do technical and commercial biases contribute to the pharmaceutical industry's productivity problems? An analysis of how reordering priorities can improve productivity. Drug Discov. Today 15, 766-772 (2010).
11. "Pharmaprojects. Analysis of Reported Reasons for Drug Discontinuation, 2000-2008," in Parexel's Biol./Pharmaceutical R&D Statistical Sourcebook 2009/2010, M. P. Mathieu, Ed. (Parexel International Corporation, Waltham, MA, 2009), p. 226.
12. P. M. Ridker, J. Genest, S. M. Boekholdt, P. Libby, A. M. Gotto, B. G. Nordestgaard, S. Mora, J. G. MacFadyen, R. J. Glynn, J. J. Kastelein; JUPITER Trial Study Group, HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: An analysis from the JUPITER trial. Lancet 376, 333-339 (2010).
13. S. Wood, Pfizer to drop development of drugs for hyperlipidemia, atherosclerosis, and heart failure. Heartwire 2 October 2008 (http://www.theheart.org/article/908435.do).
14. T. Mazzone, P. M. Meyer, S. B. Feinstein, M. H. Davidson, G. T. Kondos, R. B. D'Agostino Sr., A. Perez, J. C. Provost, S. M. Haffner, Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: A randomized trial. J. Am. Med. Assoc. 296, 2572-2581 (2006).
15. S. E. Nissen, E. M. Tuzcu, P. Schoenhagen, B. G. Brown, P. Ganz, R. A. Vogel, T. Crowe, G. Howard, C. J. Cooper, B. Brodie, C. L. Grines, A. N. DeMaria; REVERSAL Investigators, Effect of intensive compared with moderate lipidlowering therapy on progression of coronary atherosclerosis: A randomized controlled trial. J. Am. Med. Assoc. 291, 1071-1080 (2004).
16. P. M. Ridker, E. Danielson, F. A. Fonseca, J. Genest, A. M. Gotto Jr., J. J. Kastelein, W. Koenig, P. Libby, A. J. Lorenzatti, J. G. MacFadyen, B. G. Nordestgaard, J. Shepherd, J. T. Willerson, R. J. Glynn; JUPITER Study Group, Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195-2207 (2008).
17. S. E. Nissen, J. C. Tardif, S. J. Nicholls, J. H. Revkin, C. L. Shear, W. T. Duggan, W. Ruzyllo, W. B. Bachinsky, G. P. Lasala, E. M. Tuzcu; ILLUSTRATE Investigators, Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304-1316 (2007).
18. J. J. Kastelein, S. I. van Leuven, L. Burgess, G. W. Evans, J. A. Kuivenhoven, P. J. Barter, J. H. Revkin, D. E. Grobbee, W. A. Riley, C. L. Shear, W. T. Duggan, M. L. Bots; RADIANCE 1 Investigators, Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N. Engl. J. Med. 356, 1620-1630 (2007).
19. H. R. Underhill, C. Yuan, X. Q. Zhao, L. W. Kraiss, D. L. Parker, T. Saam, B. Chu, N. Takaya, F. Liu, N. L. Polissar, B. Neradilek, J. S. Raichlen, V. A. Cain, J. C. Waterton, W. Hamar, T. S. Hatsukami, Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: A high-resolution magnetic resonance imaging trial. Am. Heart J. 155, 584.e1-e8 (2008).
20. A. J. Sinusas, F. Bengel, M. Nahrendorf, F. H. Epstein, J. C. Wu, F. S. Villanueva, Z. A. Fayad, R. J. Gropler, Multimodality cardiovascular molecular imaging, Part I. Circ. Cardiovasc. Imaging 1, 244-256 (2008).
21. P. W. Wilson; CDC; AHA, CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Ability of inflammatory markers to predict disease in asymptomatic patients: A background paper. Circulation 110, e568-e571 (2004).
22. A. C. Lindsay, R. P. Choudhury, Form to function: Current and future roles for atherosclerosis imaging in drug development. Nat. Rev. Drug Discov. 7, 517-529 (2008).
23. J. H. Revkin, C. L. Shear, H. G. Pouleur, S. W. Ryder, D. G. Orloff, Biomarkers in the prevention and treatment of atherosclerosis: Need, validation, and future. Pharmacol. Rev. 59, 40-53 (2007).
24. M. Nahrendorf, D. E. Sosnovik, B. A. French, F. K. Swirski, F. Bengel, M. M. Sadeghi, J. R. Lindner, J. C. Wu, D. L. Kraitchman, Z. A. Fayad, A. J. Sinusas, Multimodality cardiovascular molecular imaging, Part II. Circ. Cardiovasc. Imaging 2, 56-70 (2009).
25. J. Sanz, Z. A. Fayad, Imaging of atherosclerotic cardiovascular disease. Nature 451, 953-957 (2008).
26. H. Tomiyama, A. Yamashina, Non-invasive vascular function tests: Their pathophysiological background and clinical application. Circ. J. 74, 24-33 (2010).
27. T. J. Wang, P. Gona, M. G. Larson, G. H. Tofler, D. Levy, C. Newton-Cheh, P. F. Jacques, N. Rifai, J. Selhub, S. J. Robins, E. J. Benjamin, R. B. D'Agostino, R. S. Vasan, Multiple biomarkers for the prediction of first major cardiovascular events and death. N. Engl. J. Med. 355, 2631-2639 (2006).
28. J. Danesh, S. Lewington, S. G. Thompson, G. D. Lowe, R. Collins, J. B. Kostis, A. C. Wilson, A. R. Folsom, K. Wu, M. Benderly, U. Goldbourt, J. Willeit, S. Kiechl, J. W. Yarnell, P. M. Sweetnam, P. C. Elwood, M. Cushman, B. M. Psaty, R. P. Tracy, A. Tybjaerg-Hansen, F. Haverkate, M. P. de Maat, F. G. Fowkes, A. J. Lee, F. B. Smith, V. Salomaa, K. Harald, R. Rasi, E. Vahtera, P. Jousilahti, J. Pekkanen, R. D'Agostino, W. B. Kannel, P. W. Wilson, G. Tofler, C. L. Arocha-Piñango, A. Rodriguez-Larralde, E. Nagy, M. Mijares, R. Espinosa, E. Rodriquez-Roa, E. Ryder, M. P. Diez-Ewald, G. Campos, V. Fernandez, E. Torres, R. Marchioli, F. Valagussa, A. Rosengren, L. Wilhelmsen, G. Lappas, H. Eriksson, P. Cremer, D. Nagel, J. D. Curb, B. Rodriguez, K. Yano, J. T. Salonen, K. Nyyssönen, T. P. Tuomainen, B. Hedblad, P. Lind, H. Loewel, W. Koenig, T. W. Meade, J. A. Cooper, B. De Stavola, C. Knottenbelt, G. J. Miller, J. A. Cooper, K. A. Bauer, R. D. Rosenberg, S. Sato, A. Kitamura, Y. Naito, T. Palosuo, P. Ducimetiere, P. Amouyel, D. Arveiler, A. E. Evans, J. Ferrieres, I. Juhan-Vague, A. Bingham, H. Schulte, G. Assmann, B. Cantin, B. Lamarche, J. P. Després, G. R. Dagenais, H. Tunstall-Pedoe, M. Woodward, Y. Ben-Shlomo, G. Davey Smith, V. Palmieri, J. L. Yeh, A. Rudnicka, P. Ridker, F. Rodeghiero, A. Tosetto, J. Shepherd, I. Ford, M. Robertson, E. Brunner, M. Shipley, E. J. Feskens, D. Kromhout, A. Dickinson, B. Ireland, K. Juzwishin, S. Kaptoge, S. Lewington, A. Memon, N. Sarwar, M. Walker, J. Wheeler, I. White, A. Wood, A. White; Fibrinogen Studies Collaboration, Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: An individual participant meta-analysis. J. Am. Med. Assoc. 294, 1799-1809 (2005).
29. R. Temple, Are surrogate markers adequate to assess cardiovascular disease drugs? J. Am. Med. Assoc. 282, 790-795 (1999).
30. L. J. Lesko, A. J. Atkinson Jr., Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: Criteria, validation, strategies. Annu. Rev. Pharmacol. Toxicol. 41, 347-366 (2001).
31. The Biomarkers Consortium, http://www.biomarkersconsortium.org.
32. J. Tegnér, J. Skogsberg, J. Björkegren, Thematic review series: Systems biology approaches to metabolic and cardiovascular disorders. Multi-organ whole-genome measurements and reverse engineering to uncover gene networks underlying complex traits. J. Lipid Res. 48, 267-277 (2007).
33. D. Diez, A. M. Wheelock, S. Goto, J. Z. Haeggström, G. Paulsson-Berne, G. K. Hansson, U. Hedin, A. Gabrielsen, C. E. Wheelock, The use of network analyses for elucidating mechanisms in cardiovascular disease. Mol. Biosyst. 6, 289-304 (2010).
34. D. Eddy, L. Schlessinger, R. Kahn, B. Peskin, R. Schiebinger, Relationship of insulin resistance and related metabolic variables to coronary artery disease: A mathematical analysis. Diabetes Care 32, 361-366 (2009).
35. A. Kadambi, Integration of modeling approaches to capture multi-scale and temporal dynamics: The Entelos cardiovascular physiolab platform (22 April 2009) (http://www.epa.gov/ncct/virtual-tissues/files/ 28%20Kadambi%20Integration%20of%20Modeling%20VT.pdf ).
36. H. V. Joffe, M. H. Parks, R. Temple, Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus. Rev. Endocr. Metab. Disord. 11, 21-30 (2010).
37. "Cutting-Edge-Information. Average Per-Patient Clinical Trial Costs: A 2006 Assessment," in Parexel's BioPharmaceutical SourceBook 2007/2008, M. P. Mathieu, Ed. (Parexel International Corporation, Waltham, MA, 2006), p. 118.
38. Acknowledgments: As of August 2010, when this manuscript was written, the AWG membership included S. Allerheiligen, Merck Research Labs, Merck and Co.; D. Applebaum-Bowden, NIH/NHLBI; K. Azer, Merck Research Labs, Merck and Co; J. Backus, Ortho Clinical Diagnostics, a Johnson & Johnson Company; D. Berman, Cedars-Sinai Hospital; D. Buxton, NIH/NHLBI; A. Chatterjee, Pfizer; E. Colman, Center for Drug Evaluation and Research/FDA; J. Edelberg, BristolMyersSquibb; Z. Fayad, Mount Sinai School of Medicine; O. Francone, Pfizer; D. Fryburg, ROI BioPharma Consulting and AWG Chair; D. Gordon, NIH/NHLBI; M. Hellerstein, University of California, San Francisco; D. Herrington, Wake Forest University; C. Hughes, Quintiles; M. Klimas, Merck Research Labs, Merck and Co.; J. Kochan, Hoffmann-LaRoche; R. Krauss, Children's Hospital, Oakland Research Institute; D. Lee, Pfizer; P. Libby, Brigham and Women's Hospital and Harvard Medical School; R. Myers, BG Medicine; D. Polidori, Johnson & Johnson; J. Raichlen, AstraZeneca; J. Revkin, Boehringer-Ingelheim; G. Ruotolo, AstraZeneca; M. Sabatine, Harvard University; M. Sandstrom, Astra- Zeneca; A. Schechter, Novartis; H. Schilske, Eli Lilly & Co.; A. Soubret, Novartis; P. Srinivas, NIH/NHLBI; J. Swinton, AstraZeneca; A. Taylor, Washington Hospital Medical Center; J. E. Van Eyk, Johns Hopkins University; M. Vassileva, FNIH; T. Wang, Harvard University; and R. Wolk, Pfizer. The members of the AWG gratefully acknowledge the support and input of B. Carlsson, D. Kelley, and M. Staten, former and current co-chairs of the MDSC, as well as the members of the MDSC. The assistance and support of the BC staff members is also gratefully acknowledged. Competing interests: The authors declare that they have no competing interests. Disclaimer: The views expressed in this article are those of the authors and should not be construed as reflecting official policy of their respective organizations, including the FDA.