EV-077 for Proteinuric Kidney Disease
About Proteinuric Kidney Disease
Healthy kidneys filter waste products out of the blood and leave in the elements the body needs, like albumin and other proteins.
However, if the kidney’s filtration system (the “glomeruli”) becomes damaged, then proteins from the blood can leak into the urine – leading to proteinuria, which is a condition in which the urine contains an abnormally high amount of proteins.
Damage to the glomeruli can result from many causes, for example, diabetes, high blood pressure, and diseases that cause inflammatory damage in the kidneys. Often, this inflammation is mediated via chronic activation of the thromboxane receptor. Unchecked, the damage is cumulative, eventually reducing kidney function to the point where dialysis or transplantation is required. The usual span of time between the onset of overt proteinuria in diabetics and kidney failure is about five to seven years.
Current Treatments
In diabetic nephropathy, drugs that inhibit the renin-angiotensin system, such as ACE (angiotensin-converting enzyme) inhibitors and the angiotensin receptor blockers are the current treatments but they typically lower proteinuria by only 35% which is not sufficient to bring it to manageable levels. This is reflected in a significant percentage of patients still progressing to end stage renal disease. Furthermore, none of these drugs significantly decreases mortality rates.
In ANS, symptoms are also mitigated with corticosteroids and immuno-suppressants but often patients do not respond to therapy. When patients reach end stage renal disease (ESRD), their cardiovascular morbidity and mortality is significantly increased to the point where 42.2% of all deaths are due to cardiovascular events.
How EV-077 May Benefit Patients
In-vitro studies carried out by Evolva SA and expert academic labs have shown that EV-077 inhibits the action of thromboxane and other arachidonic acid metabolites on the thromboxane receptor and hence has the potential to prevent and/or reduce “inflammatory” damage to the glomeruli and by so doing to preserve the intact structure of the kidney’s filtration system. This could lead to a reduction of the amount of protein eliminated in the urine in those individuals with impaired renal function and proteinuria.
EV-077 could thus help afflicted individuals slow the progression of their disease (or maybe even stabilise it) and hence reduce their need for dialysis or transplants. Because of its mechanism of action (which also reduces platelet aggregation – see “Cardiovascular Diseases” beginning on page 30), it also has the potential to reduce the elevated risk of cardiovascular events and mortality in these individuals.
In-vitro studies have also shown that EV-077 does not require to be metabolised prior to becoming active, potentially leading to a reduced risk of variability in individual responses to EV-077, thus broadening the number of patients actually covered by it.
Additionally, since a Phase I SAD study has shown EV-077 to be fast-acting and its action on platelets fully reversible, it might offer physicians a rapid way to reverse its anti-clotting action, enabling individuals to be put on and taken off medication quickly and invasive procedures and/or surgery to be performed as soon as required.
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.