Atherosclerosis Drug Development in Jeopardy: The Need for Predictive Biomarkers of Treatment Response

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Science Translational Medicine  02 Mar 2011:
Vol. 3, Issue 72, pp. 72cm6
DOI: 10.1126/scitranslmed.3002029


  • Fig. 1. Many options in biomarker selection.

    An illustration of the complexity of biomarker selection for testing the effects of a hypothetical, anti-inflammatory, investigational agent. (Top) An incomplete, noncomprehensive, and nonprioritized list of some biomarkers (and relevant imaging techniques) and their time-dependent application. The intent is to illustrate some of the possible choices that sponsors of atherosclerosis programs must decide among. Some measures could be deployed in either phase I or II. (Bottom) The augmented complexity of decision-making when clinically meaningful changes are included. In addition, it is possible that more than one biomarker could be assessed in phase I or II, further increasing complexity. Illustrated are a few different investigational paths, as symbolized by the differentially colored arrows. For example, in phase I with participants with a history of coronary artery disease (CAD) and increased Lp-PLA2, an investigator/sponsor could choose to measure a change in the uptake of labeled glucose [fluorodeoxyglucose (FDG)] by atherosclerotic plaques using positron emission tomography (PET) scanning as well as urinary (or plasma) levels of the inflammatory marker neopterin. In phase II, measurements of the necrotic core component of plaques by means of magnetic resonance imaging (MRI) or analysis of plaque volume through intravascular ultrasound (IVUS) and levels of monocyte chemoattractant protein-1 (MCP-1, a marker of inflammation) could be chosen. Associated with these variables are the degrees of change that would be considered meaningful. Taken together, there may be several paths that lead to a decision to initiate a phase III program. For any of these paths, however, the investigator/sponsor must have reason to believe that the markers will be predictive of a positive phase III outcome. If that is not achieved, the development of the new agent would be stopped. SPECT, single-photon-emission computed tomography; FMD, flow-mediated dilatation (a measure of endothelial cell function in blood vessels); IMT, intima-media thickness (in reference to the thickness of the carotid artery wall); MSCT, multislice computed tomography of the coronary circulation.



  • Table 1. Summary of participant numbers, cost per participant, and cost per phase for atherosclerosis drug development programs.

    Data are derived from recent drug development programs (1719) or publicly available data (37). The cost per phase was derived by multiplying subject number per phase and the corresponding cost per subject per phase. In order to show a reduction in clinical events (such as myocardial infarction), a large number of participants must be recruited, which also demands a large financial investment. Phase II biomarkers, therefore, must provide a high-quality and decisive assessment of whether to commit to phase III. Additional cost may be incurred depending on technologies used and other issues.

    VariablePreclinicalPhase IPhase IIPhase IIIRegulatoryTotal
    Subject numberN/A100500 to 100015,000N/A~16,000

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