ARC1779 for Carotid EndarterectomyCarotid endarterectomy is a surgical procedure which removes an unwanted build-up of inflammatory cells, cholesterol and cellular debris known as plaque from the inner lining of the major arteries in the neck which supply blood to the brain. These vessels, known as the carotid arteries, can become narrowed by plaque, causing a reduction in blood flow to the brain. Blood clots can form on the surface of the plaque. Plaque or clots can then break loose and travel to the brain, blocking the blood flow to the brain and potentially causing permanent brain damage, stroke or death, if a large enough area of the brain is affected. If a clot or plaque blocks only a tiny artery in the brain, it may cause a transient ischemic attack, or TIA, also known as a ministroke. For patients experiencing a minor stroke or a TIA, a surgeon may recommend the surgical procedure known as carotid endarterectomy to remove plaque in the carotid arteries and help prevent a stroke. According to the AHRQ, more than 114,000 carotid endarterectomy procedures were performed in the United States in 2006. Role of vWF in Carotid EndarterectomyCarotid endarterectomy is performed in conjunction with the administration of anti-thrombotic drugs, including anti-platelet agents, to prevent the formation of additional blood clots during and after the procedure. During the procedure, the surgeon removes the plaque causing the arterial blockage. The removal of plaque leaves the internal lining of the artery injured and denuded. In response to this injury, vWF is activated and actively recruits platelets to the site of injury. These recruited platelets aggregate on the blood vessel wall and form the beginning of a blood clot. As the blood clot grows and shear force within the artery is further increased, more vWF is activated, enabling the formation of new and larger clots. Surgeons use anti-thrombotic drugs including anti-platelet agents during the carotid endarterectomy to minimize the growth of these clots and reduce the risk that these clots will break off and travel to the brain, which could block the blood flow to the brain and cause a stroke. Limitations of Current TherapiesWe believe that the anti-platelet agents currently used in patients undergoing a carotid endarterectomy have several limitations. These agents, which include aspirin, dipyridamole, and Clopidogrel®, suppress platelet function in the veins and arteries throughout the body beyond the region of the primary blood clot. Accordingly, there is an increased risk of significant bleeding in the systemic circulation in patients receiving these drugs. In addition, the efficacy of these existing agents for suppression of platelet function and reduction of stroke risk is limited and we believe that there is an unmet need for new drugs which are both safer and more effective. Potential Advantages of ARC1779Because only activated vWF plays a role in thrombus formation, we believe that using ARC1779 to inhibit activated vWF may lead to improved outcomes for patients undergoing carotid endarterectomy. We also believe that by targeting vWF, ARC1779 may reduce bleeding risk during carotid endarterectomy compared to other anti-platelet agents. Because ARC1779 targets and binds to only activated vWF, the anti-platelet effect of ARC1779 should only be present in regions subject to high physical shear forces. These shear forces are only present in the arteries, including those leading into and within the brain. Therefore, we believe that ARC1779 can locally suppress platelet function and thrombus formation in the carotid arteries, while not disrupting normal platelet function and blood clotting in the remainder of the body. Phase 2a Clinical DevelopmentWe submitted the request for a CTA in the United Kingdom for the Phase 2a trial in September 2008. Regulatory approval was received in November 2008, and we expect to dose the first patient in this trial as early as the first quarter of 2009. The Phase 2a trial will evaluate the safety and efficacy of ARC1779 in patients undergoing carotid endarterectomy. The primary objectives of the trial will be to measure the effectiveness of ARC1779 in reducing the number of small blood clots which form immediately following the operation and then flow to the brain, and assess the safety of ARC1779 by measuring the amount of bleeding that occurs at the site of surgery during the operation. This trial is expected to be a randomized, double-blind, placebo controlled single dose study in up to 100 patients undergoing elective carotid endarterectomy. Other secondary objectives expected to be assessed include the effect of ARC1779 administration on reducing the brain damage caused by the small blood clots which form immediately following the operation. The study will also assess the safety and tolerability and the pharmacokinetic and pharmacodynamic parameters of ARC1779. |
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