Project: Drug development for maximal protection and prevention of remodelling after myocardial infarction.

Cardiovascular disease is the most common cause of morbidity and mortality in developed countries. Despite knowledge advancements as to causes, prevention and pharmacological treatment, cardiovascular disease continues to increase and to appear at earlier ages. This development is largely attributable to life style conditions such as smoking, sedentary life and stress. _x000D_Hypertension and diabetes represent the most important background factors to potential circulatory disasters like myocardial infarction, stroke and renal failure and these conditions hit more than one third of the populations in North America and Europe. Myocardial infarction typically hits people in middle age as a consequence of chronic arteriosclerosis which is strongly linked to hypertension. There are numerous effective anti-hypertensive pharmaceuticals, which in controlled studies have proven their efficacy in controlling blood pressure level. Anti-hypertensive drugs affecting the Renin-Angiotensin-System (RAS) belong to the best established and most frequently prescribed anti-hypertensive drugs. RAS is a phylogenetically well preserved hormone system controlling blood pressure and other fundamental bodily functions. In principle, it is dormant under homeostatic conditions, but reacts rapidly to physiological and psychological stress as an expression of readiness to expected dangers and trauma. In modern man the system is often permanently activated due to life style and hence the epidemic nature of cardiovascular disease. Certain organs such as vessels, kidney or myocardium are particular sensitive in reaction to hypertension or diabetes. _x000D__x000D_One of the most effective and modern classes of anti-hypertensive drugs are the so called Angiotensin AT1 Receptor Blockers (ARBs), which block the AT1-receptor (AT1R) that is responsible for blood pressure enhanced and which is, moreover, involved in the patho-mechanisms of various kinds of end-organ-damage (brain, heart, kidney). Consequently, ARBs have also proven to have beneficial effects on end-organ consequences (nephropathy and cardiac failure) of hypertension or diabetes, respectively. These effects have not been possible to explain solely by blood pressure decrease and control. It is assumed that some of these effects are "spill-over" stimulating effects on the so called Angiotensin AT2-Receptor (AT2R). As with the AT1R, the AT2R is well described and characterized. It appears in abundant quantities in fetal tissue. In adults it is re-expressed in damaged tissue as an expression of a need to stimulate regeneration and repair. It holds anti-inflammatory, anti-fibrotic and tissue-protective properties._x000D_AT2R research has up to recently been indirect through blockage of this receptor. Blockers of AT2R have been available for some time and the effects of treating experimental animals with these have been harmful to the cardiovascular system and to other central organ systems. There has up until now been a lack of substances with an ability to stimulate the AT2R. _x000D__x000D_Vicore Pharma have developed substances with an ability to directly and selectively stimulate AT2R. Together with the Center for Cardiovascular Research (CCR) at the Charité Hospital in Berlin, a candidate drug with high affinity for the AT2R have been tested pre-clinically. The candidate drug ("Compound 21" or "C21") has demonstrated highly impressive results in animal models of myocardial infarction, stroke and diabetic nephropathy. The same models have previously been used in the development of currently established RAS-blockers and such drugs have consequently been used as positive controls to C21. C21 has mediated better results than ARBs for myocardial infarction and heart failure treatment following coronary vessel occlusion and renal protection in diabetic and hypertensive rats. Please view the article: Kaschina et al, Circulation,2008; 118:2523-2532, AT-2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin-system in myocardial infarction._x000D_The results strongly support the development of a pharmaceutical drug for the treatment of myocardial infarction in the acute phase (intravenous administration) and in the recovery phase to prevent or delay the harmful remodelling of myocardium post-infarction and consequently prevent or delay the development of heart failure. _x000D__x000D_The consortium has elected the treatment of myocardial infarction as the first clinical indication for the drug compound since the benefits of the treatment, i.e. a lesser loss of cardiac function and lesser risk for relapse and development of heart failure are realistic to demonstrate within a relatively short period of time in controlled clinical trials. _x000D_The means sought in this application are consequently aimed at developing the candidate compound up until and including a phase I clinical trial. _x000D_The consortium holds all necessary competence and facilities to undertake this project as detailed in this application.

Acronym Heartsave (Reference Number: 5226)
Duration 01/08/2010 - 15/08/2012
Project Topic The project aims at developing a new pharmaceutical drug for oral and intravenous administration to restore heart function and heart muscle tissue integrity after myocardial infarction. The project also aims at demonstrating the compounds organ protective abilities in conjunction with hypertension.
Project Results
(after finalisation)
1. Effect of C21 on post-myocardial-infarction: _x000D_We found that C21 treatment results in a long term improvement of cardiac function after myocardial infarction (MI) in rats. Improved remodelling of the infarcted myocardium seems an important mechanism of action. Thus, one potential indication for C21 in humans may be treatment of post-MI chronic heart failure. Results of our study have been presented at international conferences and are currently being submitted to a high-impact international, cardiovascular journal._x000D__x000D_2. Effect of C21 hypertension-induced cardiac hypertrophy and renal disease:_x000D_We found no effect of C21 on cardiac hypertrophy, but a reduction of cardiac fibrosis and a significant reduction of hypertension-induced vascular remodeling resulting in a lowering of pulse-wave-velocity. The latter results have been presented at international conferences and published in a high-impact, international CV journal (Hypertension). Protection from vascular stiffening may be an interesting future indication for patients suffering from hypertension and/or diabetes.
Network Eurostars
Call Eurostars Cut-Off 3

Project partner

Number Name Role Country
2 Center for Cardiovascular Research (CCR), Charitè Universitätsmedizin Berlin Partner Germany
2 Vicore Pharma AB Coordinator Sweden