Project: Development of an improved anticoagulant therapy

Anticoagulant drugs (blood thinners) prevent the ability of blood to clot (coagulate). Anticoagulants are most commonly prescribed to treat or prevent thrombosis, which is the unwanted formation of blood clots in the circulation. Unwanted formation of blood clots can occur in the legs (known as deep venous thrombosis or DVT), in the lungs (pulmonary embolus), in the blood vessels that feed the heart leading to myocardial infarction, or within the heart during arrhythmia including atrial fibrillation (see Figure 1). In the latter situation parts of the blood clot, called emboli, in the heart can be released and dragged along with the bloodvessels to the brain where it plugs the blood vessel and lead to a stroke (infarction of brain tissue). Antithrombotic therapy with anticoagulant drugs is used to prevent the blood clots from forming and to lower the risk of stroke. However, in spite of their wide use serving a multibillion dollar market, the therapeutic window (which is the difference between the effective dose and the dose at which side effects occur) of these drugs is narrow, and therefore has significant drawbacks. The effective dose varies among patients and even changes over time in the same patient. Therefore careful monitoring of patients on anticoagulant therapy is required to ensure that they are not over- or under-dosed. Overdosing of anticoagulants may induce severe bleeding which is observed in up to 5% of the patients, resulting in severe complications and sometimes death. Anticoagulants are therefore often not used in conditions which have an increased risk for bleeding. On the other hand, under-dosing due to the concern for bleeding results in sub-optimal efficacy of the drug, and therefore many patients do not fully benefit from receiving anticoagulant drugs which might result in severe embolism such as stroke, to occur. Therefore, there is an urgent need for better anticoagulants with an improved benefit to risk ratio._x000D_The aim of this project is to develop a novel anticoagulant drug, which is as effective as current anticoagulants but is safer because of reduced bleeding risk. Clotting of blood is mediated by blood proteins that are known as clotting factors. The Ps are convinced that recent exciting discoveries of the role of one of these clotting factors, i.e. clotting factor XI (FXI), offer the opportunity to develop such a new generation anticoagulant. Key for the project is the concept that clotting FXI plays an unusual but very important role in the coagulation cascade (explained in chapter 2.2). FXI offers an attractive target for the development of novel clotting inhibitors. Prothix BV aims to translate this discovery on the unique role of FXI in normal hemostasis and pathologic thrombosis into new drug products for clinical application. To achieve this goal, Prothix will join forces with Bioceros BV (NL), Antitope Ltd (UK), and the University Medical Center Utrecht (NL). In this EUROSTARS project, these Ps will develop humanized monoclonal anti-FXI antibodies and perform pre-clinical testing to achieve Proof of Principle (PoP). The consortium will initially target the new drug at vascular access thrombosis which has a much lower incidence than e.g. atrial fibrillation. This “niche buster” strategy will allow to achieve rapid Proof of Principle (POP) in this orphan drug indication thereby providing quick access to the market, while demonstrating its potential for the blockbuster indications such as atrial fibrillation. _x000D_Vascular access thrombosis occurs in patients with kidney failure or end-stage renal disease (ESRD), which often is an outcome of common diseases such as diabetes mellitus, chronic glomerulonephritis, or hypertension. The majority of patients with ESRD are currently treated with at least twice weekly hemodialysis as renal replacement therapy. Hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water and electrolytes from the blood when the kidneys are failing. During hemodialysis an external access to the circulation, so called vascular access, is established (see Figure 2). Without an adequate vascular access, hemodialysis efficiency is reduced, which results in increased morbidity and mortality (1), and requires immediate medical intervention. Access-related problems are responsible for 50% of the hospitalizations of hemodialysis patients. The CO complication is vascular access thrombosis (2). This condition will occlude the vascular access due to the formation of blood clots and blood platelets at the access site, posing a major health issue. Currently, no effective method to prevent vascular access thrombosis is available (3). Conventional anticoagulants could potentially be administered to patients to treat this condition. However this therapy is associated with another major health issue, as hemodialysis patients have a higher risk of severe bleeding (~10%). Therefore, for this specific group of patie

Acronym ANTICO (Reference Number: 6938)
Duration 01/01/2012 - 31/12/2015
Project Topic The aim of this project is to develop a novel and improved anticoagulant drug for the treatment of blood clotting, using the niche indication vascular access thrombosis as a model for development. It will also offer great blockbuster potential
Network Eurostars
Call Eurostars Cut-Off 7

Project partner

Number Name Role Country
4 Antitope Ltd Partner United Kingdom
4 Bioceros B.V. Partner Netherlands
4 Prothix BV Coordinator Netherlands
4 University Medical Center Utrecht Partner Netherlands