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Jan 1, 2011 (Vol. 31, No. 1)

Solving the Antithrombotic Conundrum

Selective and Reversible Inhibition of Clotting Cascade Yields Safer, More Effective Therapies

  • Blueprint for Success

    While there is no single, universally applicable approach to navigating the path from drug discovery to the marketplace, translational medicine success stories do share common attributes. They begin with a clearly defined medical need, less-than-optimal standard-of-care treatment options, and a readily identifiable, dissatisfied patient and care provider population.

    The rapid and cost-efficient translation of a novel drug concept from the laboratory to the clinic comprises a series of fundamental characteristics. These include a solid theoretical, scientific, and medical foundation; a well-defined mechanism of action; and compelling preclinical data derived from carefully designed and meticulously executed experiments.

    Moving forward, the design of clinical trials should continue to follow a path of pragmatic drug development, in which highly relevant studies yield results that provide direct and increasingly strong evidence of a drug’s safety and efficacy, enabling rapid advancement through the sequential stages of clinical testing.

    The recipe for success should also include a strong intellectual property portfolio, an optimized and readily scalable manufacturing process, and the identification and quantification of pharmacoeconomic parameters that will favorably impact a cost/benefit analysis. A drug with a well-defined mechanism and activity profile is more likely to garner the attention of medical opinion leaders and principal investigators who are best positioned to shepherd a drug candidate through clinical testing. Likewise, an appealing cost/benefit appraisal, combined with robust safety and efficacy data, will go a long way toward convincing practitioners and payers to adopt the new therapy.

  • Translational Model

    In the acute care antithrombotic market, there is room and a need for improvement. Using the common treatment paradigm of standard heparin therapy will decrease a patient’s risk of ischemia; however, one in five recipients will experience bleeding complications. This risk profile can be reduced to one in fifteen by giving patients a lower dose of heparin or switching to another agent with a shorter half-life, but this then increases the risk of unwanted clot formation and ischemic complications.

    Improvement can be achieved through better target selection, better drug design with an active control element, and better overall safety and efficacy. Selection of an advantageous and “druggable target” is the first step. Thrombosis presents a well-understood yet complex array of potential drug targets that comprise the coagulation cascade.

    Antithrombotic agents act by disrupting one or more of the serine proteases, clotting factors, and protein co-factors that make up the cascade and trigger platelet aggregation and clot formation. Coagulation proceeds in a three-stage, escalating cascade, and individual clotting factors may have a role in one or more of these stages.

    Targeted inhibition of a clotting factor or co-factor farther upstream (i.e., earlier) in the cascade should more effectively and efficiently shut down the coagulation response, requiring less drug and reducing the risk of cross reactivity. Commonly used Factor Xa and direct thrombin inhibitors primarily exert their effects in the later stages of the cascade. Novel treatment paradigms should instead focus on targets active in the early stage of the cascade.

    While the ability to achieve complete anticoagulation during PCI is essential, an optimal inhibition strategy would enable partial or complete reversibility, allowing for a continuum of coagulation inhibition. By administering an antithrombotic drug that is paired to an active control agent, the clinician would be able to shift the therapeutic effect rapidly and predictably from complete to partial to no coagulation as needed during and post procedure.

    To achieve this, the drug would have to be highly selective and have a strong affinity for its target. Other factors, such as its half-life in the circulation, bioavailability, metabolic profile, potential immunogenicity, and mechanism of clearance from the body would all contribute to the drug’s safety and efficacy.

    In assessing the ideal characteristics of a new treatment paradigm, a broad scope of chemical entities should be considered. This would include looking beyond conventional drug classes.

    Aptamers, complemented by their active control agents, represent an ideal class of potential new therapeutic systems that encompass all the characteristics defined for optimized antithrombotic therapy. Data generated to date on reversible antithrombotic drug candidates reinforces the promise this class of compounds holds for patients and physicians seeking an optimal anticoagulant therapy for use in the acute and subacute care cardiovascular setting.

    Indeed, if development of these agents continues with similar success as that reported to date, a new benchmark in antithrombotic therapy will emerge, completing the translation of medical theory to practice.

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