Synvista Initiates Phase 2 Study With Alagebrium For Chronic Heart Failure
Chronic Heart Failure
Synvista Therapeutics announced dosing of the first patient in BENEFICIAL, a 100-patient Phase 2 clinical trial of alagebrium (ALT-711), a novel compound designed to act as an Advanced Glycation End-product (AGE)-cross-link breaker, in patients with chronic heart failure (CHF). The BENEFICIAL study (Double- blind, placebo-controlled, randomized trial evaluating the efficacy and safety of alagebrium) is designed to measure the effect of alagebrium on exercise tolerance in patients with CHF. The Company plans to use the experience and results of this study to guide development of its Phase 3 program for alagebrium in CHF. The single-site Phase 2 trial is being conducted at the University Medical Centre Groningen, The Netherlands and the principal investigator is Adriaan A. Voors, M.D., Associate Professor of Cardiology.
The objective of the BENEFICIAL study is to improve maximal oxygen consumption (VO2max), which is highly correlated with an improvement in myocardial function in patients with CHF. Diastolic and systolic function will be measured by tissue velocity imaging with echocardiography. The ability of alagebrium to break down AGEs will also be measured by tracking levels of carboxy-methyllysine (an AGE) in the skin using an auto-fluorescence device.
"Alagebrium is the first orally active AGE-cross-link breaker that has been evaluated in preclinical and clinical studies, and studies using animal models of diabetes and aging have demonstrated its effect in reversing cardiac stiffening," said Dr. Voors. "We are encouraged by the potential that alagebrium has demonstrated in our preclinical models, and are aggressively pursuing clinical development in this indication."
"Initiating the BENEFICIAL study is an important milestone in the development of alagebrium as a treatment for CHF," said Noah Berkowitz, M.D., Ph.D., President and Chief Executive Officer of Synvista Therapeutics. "This study will involve 9 months of treatment and we hope to announce results in 2009."
Alagebrium has been studied in two human heart failure trials: the DIAMOND trial in patients with diastolic heart failure; and the PEDESTAL trial in patients with systolic heart failure. While both trials provided encouraging results, each had an open-label design and thus neither was able to draw definitive conclusions about the effectiveness of alagebrium in heart failure.
About Heart Failure
Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The primary manifestations of heart failure are dyspnea and fatigue, which may limit exercise tolerance, result in fluid retention, and lead to pulmonary congestion and peripheral edema. These abnormalities impair the functional capacity and quality of life of affected individuals.
Heart failure is a major and growing global public health problem. Approximately 5 million patients in the U.S. and about 10 million in Europe have heart failure, according to the American Heart Association. The number of heart failure deaths has increased steadily despite advances in treatment. Heart failure results in more than 1 million hospitalizations at a cost of more than $15 billion annually in the U.S. alone.
Most of the available treatments for heart failure are not aimed at the underlying pathophysiological processes that occur in the heart and blood vessels. In this respect, the Company believes that accumulation of AGEs might prove to be a promising, novel target for the treatment of heart failure. AGEs are proteins formed by oxidative or non-oxidative reactions. AGEs cause the formation of collagen cross-links, which result in increased myocardial stiffness whereby the stiff ventricle fails to relax adequately between beats and allow blood to fill the chamber. As a result, blood volume backs up into the lungs and makes patients short of breath. More than 50% of patients with symptoms of heart failure have evidence of a stiff non-compliant ventricle (heart chamber) by echocardiogram.