EV-077 for Cardiovascular Disease

About Cardiovascular Diseases

Some 29% of deaths worldwide result from cardiovascular (“CV”) disease. Whilst many of these deaths can in principle be prevented by life-style changes (e.g., healthy diets, not smoking, exercise), there is a major and growing need for treatments that can reduce the risk of disability and death. One of the most common causes of cardiovascular morbidity and mortality is arterial thrombosis with approximately 13 million people dying every year from complications related to blood clots.

The formation of a blood clot is a normal vascular repair mechanism that can be harmful if it is excessively or abnormally activated. In these cases, it can partially or fully block blood vessels as the result of plaque formation on the vessel walls, rupture or tear of the plaque and appearance of a clot which cuts off the supply of blood and nutrients to the legs, lungs, brain or heart. Blood clots in veins can cause deep vein thrombosis and pulmonary embolism, which can result in acute heart failure and death. Blood clots occurring in arteries can cause strokes, peripheral vascular occlusion and heart attacks.

Current Treatments

The most widely used medications to prevent arterial thrombosis in at-risk individuals are “anti-platelet” drugs, which are compounds that prevent the platelets circulating in blood from sticking together and forming potentially dangerous clots. Two of the most frequently used compounds are aspirin (Bayer and others) and clopidogrel (Plavix™, BMS, Sanofi), which have emerged as mainstay therapies in the treatment of cardiovascular diseases. As of 2009, prasugrel (Effient™, Eli Lilly) has also become available in certain countries. Prasugrel has the same mechanism of action as clopidogrel.

How EV-077 May Benefit Patients

Patients at risk of arterial thrombosis typically receive aspirin, clopidogrel or similar drugs and these compounds are efficacious in a large percentage of individuals. However, a significant number of individuals (estimates vary, but between 10–30% of the at risk population) either cannot take these compounds or do not respond well to them. Most notably, many diabetics are not very effectively protected by current treatments as diabetes can lead to increased production of certain prostanoid metabolites. These metabolites in turn activate the thromboxane receptor, and this predisposes these individuals towards platelet aggregation and thrombosis (clotting). Neither aspirin nor clopidogrel (nor prasugrel) directly address this mechanism of platelet aggregation.

Studies by expert academic labs have shown that EV-077 prevents many of these prostanoid metabolites from activating the thromboxane receptor. This means that potentially EV-077 can offer individuals such as diabetics a new treatment option that may reduce their risk of thrombosis and of cardiovascular events compared to existing treatments.

The Phase I SAD study has shown that, compared to existing anti-platelet drugs, EV-077 has a very fast onset of action that might quickly provide protection from clotting. The Phase I SAD study has also shown that the action of EV-077 on the platelets is reversible (platelet function is restored when the compound is removed from the bloodstream), which may offer physicians a way to rapidly reverse its anti-clotting actions. This is important in case of emergency surgery, for instance, in coronary bypass surgery for coronary lesions non amenable to PCI (percutaneous coronary intervention). Additionally, as explained above, EV-077 does not need to be metabolised prior to becoming active, which could potentially reduce the variability in individual response to the compound and thus broaden the number of patients responding to treatment.

Current Development Status

EV-077 is in Phase I clinical trials. The Phase I SAD study was completed in 2009. This study was a singlecentre, double-blind, randomised, placebo-controlled study with ascending single oral doses of EV-077. A total of 55 subjects were included in the study, and seven doses of EV-077 were tested. The study showed EV-077 to be safe, well tolerated, a potent inhibitor of platelet aggregating and fast-acting and to have a reversible effect on the platelets. Evolva intends to perform a multiple ascending dose study in 2010, which will further access the safety and tolerability, pharmacokinetics and pharmacodynamics of EV-077.

Scientific Paper