Hookworm anticoagulant safe in humans

Abstract

Recombinant NAPc2 (rNAPc2), a novel anticoagulant product derived from hookworms, recently completed a Phase Ia clinical trial sponsored by Corvas International Inc. (San Diego, CA, USA). The trial, conducted at Guy's Drug Research Unit (London, UK), demonstrated no adverse effects following the single subcutaneous administration of rNAPc2 to healthy human male volunteers. A Phase Ib trial of patients with disseminated intravascular coagulation (DIC) also began in October 1997 at the Academic Medical Centre (Amsterdam, The Netherlands). DIC results from a systemic activation of the coagulation cascade, resulting in microthrombosis and multiple organ failure. On the basis of their animal studies, Corvas are proposing that rNAPc2 could also be used to treat arterial and venous thrombosis. In several experimental rat and pig models of arterial and venous thrombosis, rNAPc2 proved to be 1000–3000-fold more potent than a currently used anticoagulant, low-molecular-weight heparin (LMWH). rNAPc2 was effective after both intravenous and subcutaneous administration, and at doses that do not cause excessive bleeding. The hookworm from which rNAPc2 was isolated, Ancylostoma caninum, feeds on blood and has therefore evolved highly effective anticoagulant strategies. Scientists at Corvas used molecular cloning techniques to identify in the worm a family of specific and highly potent small proteins with antithrombotic action, the nematode anticoagulant proteins (NAPs). At the start of the blood clotting cascade in humans, factor VIIa, a protease, binds to tissue factor, forming an enzymic initiating complex. NAPc2 works by binding to the factor VIIa–tissue factor complex, inhibiting its enzymatic activity. George P. Vlasuk, Corvas' Executive Vice President of Research and Development, points out that rNAPc2 exerts its effect at the start of the cascade, when only a few molecules of factor VIIa/tissue factor are present, whereas LMWH primarily affects the bottom of the cascade, when there are millions of molecules of thrombin—the terminal protease in the cascade—present. It may be a more effective strategy to prevent thrombin from being formed in the first place by intervening at the top of the cascade than trying to inhibit thrombin once it's formed, says Vlasuk. Clearly, if you compare the inhibitor of the VIIa–tissue factor complex to inhibitors of thrombin there is a huge difference in overall efficacy of approach. Another advantage of rNAPc2 is its long half life (larger than 50 h), which might obviate the need for the multiple daily dosing regimens currently used for most LMWHs. Potentially, rNAPc2 could be used to treat a wide range of cardiovascular conditions where thrombosis plays a key role. These include deep vein thrombosis (DVT), pulmonary embolism, unstable angina, myocardial infarction and ischemic stroke. Early in 1998, Corvas plan to file an Investigational New Drug application with the US Food and Drug Agency to start Phase II studies (in the USA and/or Europe) looking at the prevention and treatment of DVT. It is thought that the drug will be given to patients with established DVT and to those undergoing knee replacement surgery, where an estimated 10-20% of patients develop DVT, even with optimal prophylaxis using LMWH. Another possible indication is for patients suffering from unstable angina. The material that composes an atherosclerotic plaque is separated from the bloodstream by a fibrous cap, which can rupture. If this occurs, platelets can adhere to the site of injury and initiate the process of clotting, causing episodic blockages of blood flow to a region of the heart (resulting in unstable angina) or complete blockage (resulting in myocardial infarction). In people with unstable angina, prophylactic rNAPc2 could be used to prevent the clot from growing, thereby allowing time for the fibrous cap to re-form. Dr Eric Topol, Chairman and Professor of Cardiology at The Cleveland Clinic Foundation (Cleveland, OH, USA), comments: `This agent (rNAPc2) has considerable mechanistic and experimental data promise. We hope it will build substantially on the positive results that we obtained in large-scale trials of direct thrombin inhibitors (eGUSTO 2). By blocking thrombin generation, rNAPc2 may achieve far greater clinical benefit.