Abstract
Biomarkers are measurable properties that reflect the pathophysiology of disease, mechanism of action of a molecule or the interaction between the two. The early implementation of a biomarker strategy within drug development offers a great opportunity to enhance the efficiency of drug development. More specifically, biomarkers may be used to aid in lead compound selection, dose focusing, patient stratification and defining the mechanism of action of novel therapeutics. Validated biomarkers, especially surrogate endpoints, may have broader utility in both a regulatory context and in clinical practice. Biomarkers may be used to evaluate both the safety and efficacy of new drugs. Biomarker identification is enhanced with a clear understanding of the steps involved in a pathophysiology cascade.
Biomarkers discovered with the aid of molecular profiling may have particular utility in approaching complex diseases with poorly characterised pathophysiology, as in type 2 diabetes mellitus. For example, expression profiling experiments enabled the discovery of the 30kD protein adiponectin — a specific biomarker for in vivo activation of peroxisome proliferator-activator receptor gamma (PPARψ) activity. Adiponectin offers great utility in short-term clinical studies in healthy volunteers or patients with type 2 diabetes to assess whether new potential PPAR? agonists are efficacious in humans. In addition to enlightening key underlying pathophysiology, biomarkers such as adiponectin allow for improved decision-making earlier in development.
Ultimately biomarkers can be used to optimise development efficiency from discovery through to registration.
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References
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69: 89–95
Lesko LJ, Atkinson AJ. Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu Rev Pharmacol Toxicol 2001; 41: 347–66
Ackerman BL, Hale JE, Duffin KL. The role of mass spectrometry in biomarker discovery and measurement. Curr Drug Metab 2006; 7: 525–39
Aronson JK. Biomarkers and surrogate endpoints. Br J Clin Pharmacol 2005; 59: 491–4
Horig H, Marincola E, Marincola FM. Obstacles and opportunities in translational research. Nat Med 2005; 7 (11): 705–8
Wagner JA. Overview of biomarkers and surrogate endpoints in drug development. Dis Markers 2002; 18: 41–6
Lesko LJ, Woodcock J. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Disc 2004; 3: 763–9
Guidance for Industry. Pharmacogenomic data submissions. Mar 2005 [online]. Available from http://www.fda.gov [Accessed 2007 Jul 10]
FDA-NIH conference: biomarkers and surrogate endpoints: advancing clinical research and applications [abstracts]. Dis Markers 1998; 14 (4): 187–334
Lathia CD. Biomarkers and surrogate endpoints: how and when might they impact drug development? Dis Markers 2002; 18: 83–90
Srivastava S, Wagner JA. Surrogate endpoints in medicine. Dis Markers 2002; 18: 39–40
Mol MJTM, Erkelens DW, Gevers JA, et al. Effects of simvastatin (MK-733) on plasma lipids in familial hypercholesterolemia. Lancet 1986 Oct 25; 2 (8513): 936–9
Lipids Research Clinics Program. The relationship of reduction in incidence of coronary artery heart disease to cholesterol lowering. JAMA 1984; 251: 365–74
Exht DS, Liebon B, Mitchell RW, et al. Mortality and morbidity of patients receiving encainide, flecainide or placebo: the cardiac arrhythmia suppression trial. N Eng J Med 1991; 324: 781–8
Biomarkers Definitions Working Group. Biomarkers surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69 (3): 89–95
Marschner IC, Collier AC, Coombs RW, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 1998; 177: 40–7
Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 2005; 5: 845–56
Gutman S, Kessler LG. The US Food and Drug Administration perspective on cancer biomarker development. Nat Rev Cancer 2006; 6: 565–71
FDA clears genetic test that advances personalized medicine test helps determine safety of drug therapy. 2005 Aug 22 [press release; online]. Available from URL: http://www.fda.gov/bbs/topics/NEWS/2005/NEW01220.html [Accessed 2007 Jul 10]
Lewin DA, Weiner MP. Molecular biomarkers in drug development. Drug Disc Today 2004; 9 (22): 976–83
Combs TP, Wagner JA, Berger J, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPAR? agonists: a potential mechanism of insulin sensitization. Endocrinology 2002; 143 (3): 998–1007
Yang WS, Jeng CY, Wu TJ, et al. Synthetic peroxisome proliferator-activated receptor-ψ agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25 (2): 376–80
Nawrocki AR, Scherer PE. The adipocyte as a drug discovery target. Drug Disc Today 2005; 10 (18): 1219–30
Bloom S. Prominent investigator wins diabetes research award. J Clin Invest 2005; 115: 1678
Gimeno RE, Klaman LD. Adipose tissue as an active endocrine organ: recent advances. Curr Opin Pharmaocol 2005; 5: 122–8
Pajvani UB, Scherer PE. Adiponectin: systemic contributor to insulin sensitivity. Curr Diab Rep 2003; 2: 207–13
Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregu-lated in obesity. J Biol Chem 1996; 271: 10697–703
Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26746–9
Schapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 1998; 8: 335–8
Pajvani UB, Du X, Combs TP, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 2003; 278: 9073–85
Rajala MW, Scherer PE. Minireview: The adipocyte at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 2003; 5: 122–8
Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112: 91–100
Wang Y, Xu A, Knight C, et al. Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. J Biol Chem 2002; 277: 19521–9
Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003; 423: 762–9
Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001; 98: 2005–10
Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–6
Berg AH, Combatsiaris TC, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947–53
Wagner JA. Early clinical development of pharmaceuticals for type 2 diabetes mellitus: from preclinical models to human investigation. J Clin Endo Metab 2002, 6
Wagner JA, Larson PJ, Weiss S, et al. Individual and combined effects of peroxisome proliferator-activated receptor α and ψ agonists, fenofibrate and rosiglitazone, on biomarkers of lipid and glucose metabolism in healthy nondiabetic volunteers. J Clin Pharmacol 2005; 45: 504–13
Pajvani UB, Hawkins M, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004; 279 (13): 12152–62
Das K, Lin Y, Widen E, et al. Chromosomal localization, expression pattern and promoter analysis of the mouse gene encoding adipocyte-specific secretory protein Acrp30. Biochem Biophys Res Commun 2001; 280: 1120–9
Tontonoz P, Hu E, Spiegelman BM. Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor?. Curr Biol 1995; 5: 571–6
O’Connor-Semmes R, Mydlow P, Walker A, et al. G1262570, a PPAR? agonist, maintains metabolic improvements throughout 24 hour profiles in type 2 diabetic patients. Diabetes 2000; 49 Suppl. 1: A119
Fiedorek FT, Wilson GG, Frith L, et al. Monotherapy with G1262570, a tyrosine- based non-thiazolidinedione PPAR? agonist, improves metabolic control in type 2 diabetes patients. Diabetes 2000; 49 (Suppl. 1): A38
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The authors are both employees at Merck & Co. Inc. and own stock options in the company.
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Stoch, S.A., Wagner, J.A. Biomarker Analysis as a Decision-Making Tool in Drug Discovery and Development. Int J Pharm Med 21, 271–277 (2007). https://doi.org/10.2165/00124363-200721040-00003
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DOI: https://doi.org/10.2165/00124363-200721040-00003