January 1, 2011 (Vol. 31, No. 1)
David J. Mazzo, Ph.D.
Selective and Reversible Inhibition of Clotting Cascade Yields Safer, More Effective Therapies
The multibillion-dollar worldwide market for injectable antithrombotic drugs (including anticoagulants and antiplatelet agents) will continue to grow as minimally invasive surgical interventions to open blocked coronary vessels become increasingly commonplace.
Despite the agents available in the clinician’s antithrombotic toolbox today, control of clotting remains suboptimal. Clinicians performing intravascular interventions are still faced with achieving the delicate balance between preventing the formation of ischemia-producing clots while allowing healing clots to form and develop normally to prevent excessive bleeding.
Antithrombotic technology in the acute and subacute care cardiovascular setting is poised for a paradigm shift and is in need of therapeutic alternatives with improved safety profiles and enhanced effectiveness. New treatment strategies capable of more selective and actively controlled inhibition of critical targets in the coagulation cascade will reduce the risk of adverse events associated with revascularization procedures.
Novel approaches that give clinicians a greater degree of control over coagulation will concomitantly minimize the risk of ischemia and bleeding and allow for real-time adjustment of the therapeutic effect in individual patients. The result will be optimized safety and efficacy of anticoagulant therapy and a broadly applicable approach to antithrombosis that embraces the principles and advantages of personalized medicine.
Optimizing Antithrombotic Control
Patients with acute coronary syndromes routinely undergo coronary revascularization procedures such as percutaneous coronary interventions (PCI)—angioplasty with or without intracoronary stent placement—to unblock clogged arteries.
With the anticoagulant therapies available for use during PCI, patients are at risk of coagulation-related complications such as unwanted thrombus formation that can lead to myocardial infarction, stroke, and/or the need for vessel revascularization, or, at the other end of the spectrum, uncontrolled bleeding resulting in life-threatening exsanguination, the need for transfusion, and/or extensive medical treatment and a prolonged hospital stay.
Because existing anticoagulants are administered as IV infusions and the infusion is only stopped at the end of the PCI procedure, these drugs persist in the circulation and continue to exert their effects long after it would be desirable to reduce anticoagulation to a level that would minimize the risk of excessive bleeding and maintain homeostasis. The inability to reverse anticoagulant effects with an active control strategy adversely impacts both medical outcomes and the pharmacoeconomics of PCI.
While it is readily accepted that ischemic events lead to increased costs and grave medical consequences, it is not as well known that excessive bleeding carries a high cost in terms of both mortality and medical expenditures. Patients who experience a major bleed are at least two and a half times more likely to die in the hospital than those who do not.
The economic toll associated with bleeding complications has been estimated at $1,300 to more than $15,000 per patient. The treatment for bleeding may range from frequent monitoring of anticoagulation to extensive hands-on care, often requiring the use of compression or closure devices. In the instance of a major bleed, blood transfusions, with their associated costs and risks, are often necessary. Thus, the next generation of anticoagulants will need to address the issues of ischemia and bleeding equally well.
A pivotal characteristic of the optimized antithrombotic agent will be rapid, predictable, real-time control over coagulation. The ability of clinicians to adjust the antithrombotic effect in response to the specific patient and setting would allow them to minimize the risk of ischemia and of bleeding simultaneously without erring on the side of either clotting or anticoagulation. This is a realistic goal that is now within reach due to recent advances in the development of aptamer therapeutics paired with complementary active control agents.
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.
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.
David J. Mazzo, Ph.D. (firstname.lastname@example.org), is president and CEO at Regado Biosciences.