Alagebrium

Alagebrium is the first orally active cross-link breaker being investigated for the treatment of diastolic and systolic heart failure. Currently in Phase II clinical trials, alagebrium is designed to break glucose cross-links that develop as a result of both aging and diabetes and improve ventricular and arterial compliance and function. Alagebrium is the first of Synvista’s proprietary crosslink breakers. More than 900 people have received alagebrium treatment to date, including some patients enrolled in proof of concept studies for heart failure. The drug continues to exhibit a clean safety profile.

How It Works – Heart Failure

The process of aging naturally increases the presence of cross-linked collagen. Collagen is an important connective tissue protein found in the spaces between cells. It provides structure and contributes to the functionality of tissues. Cross-linked collagen is less compliant (flexible) than healthy collagen, which causes increased stiffness of tissue. This is of particular concern in the heart and vascular system, particularly in the aorta, which all function better when they are elastic and flexible, allowing them to increase or decrease their resistance to blood flow. Measures of stiffness in the vasculature can predict adverse cardiovascular outcomes, such as myocardial infarction (heart attack) and stroke.

Similar to vascular stiffness, ventricular stiffness (the rigidity of the muscular chamber responsible for ejecting blood from the heart) can have negative consequences on the cardiovascular health of patients. In fact, stiffness of the heart is an important characteristic of heart failure. A scarred heart that has recovered from a heart attack tends to develop stiffness which prevents the heart from relaxing properly in between contractions and filling with blood. As a consequence, not only will the scarred heart fail to squeeze adequately and eject blood, but the filling is also impaired. Patients with a long history of high blood pressure or a history of diabetes are known to have a higher tendency for ventricular stiffness. Their hearts do not adequately fill with blood , which requires that they maintain a higher blood volume, causing fluid overload and backup of fluid into the lungs with symptoms identical to those observed in patients with a scarred heart.

Currently approved heart failure medications tend to decrease blood pressure, improve the ejection of blood from the heart or reduce blood volume. We believe that alagebrium may provide an added benefit to existing therapy by focusing on an otherwise unaddressed mechanism. It also serves to reduce the stiffness of the heart and vessels that occurs as a result of the collagen buildup due to heart failure and/or diabetes, having demonstrated decreased mass of the heart in human clinical trials. We believe that alagebrium it prevents the undesired deposition of excessive stiffness-inducing collagen in the already damaged hypertensive or diabetic heart.

How It Works – A.G.E.s

Another way in which collagen is crosslinked, is through a pernicious process characteristic of aging but seen more profoundly in diabetes. Sugar in the bloodstream reacts with proteins, such as collagen, in our body forming structures called advanced glycation end products (A.G.E.s ). A.G.E.s have no known salutary purpose and are often viewed simply as byproducts of living. They are scavenged by specialized receptors (RAGE, or receptors for A.G.E.s) on the surface of many cells. RAGEs not only internalize these waste products, but they trigger an inflammatory response in the cell. The RAGE-activated cell is induced to secrete factors that trigger the production of more collagen and elastin and other “fresh” connective tissue. Yet, the secretion of those factors (cytokines) has two undesired effects. First, cytokines may also cause leakiness in neighboring tissue. Second, they might promote the deposition of more connective tissue than is otherwise warranted in a location causing dysfunction.

In the case of the kidney, RAGE activation leads to inflammation and leakiness. The functionality of the kidney can deteriorate. At first, the kidney allows more protein to spill into the urine. Over time, the ongoing deposition of new material in the kidney filtering apparatus, may lead to lost filtering capacity, or renal failure. Patients with diabetes are particularly prone to this disease. Alagebrium has also been shown to decrease RAGE expression in the kidney and retard protein leakage (proteinuria).

Application

In a variety of preclinical studies, alagebrium demonstrated significant reduction in stiffness in both the ventricle and blood vessels in a variety of both diabetic and non-diabetic and aged and non-aged subjects. In those subjects where blood pressure was already elevated (e.g., diabetic or aged subjects) there was also a reduction in blood pressure, but no change in blood pressure in subjects where blood pressure was already normal. (Click here for full published results of preclinical trials.)

In the DIAMOND study, a 16-week open-label Phase I study of alagebrium 210mg twice daily in 23 adults, mean age 71 years with stable diastolic heart failure, there was a significant decrease in left ventricular mass and improvements in improvements in left ventricular diastolic filling, as well as quality of life.

Another Phase I study, PEDESTAL, was a six-month open-label study of 22 adults (minimum age 30 years) with systolic heart failure and diastolic dysfunction who received alagebrium at doses of 35mg once-daily and 210mg twice daily. Treatment produced a trend toward decrease in left ventricular mass and early/late diastolic filling, increase in isovolumetric relaxation time and early mitral deceleration time. Decrease in left atrial pressure was also noted in both treatment groups. These results were compared with a matched “contemporary control group.” (Click here for full published results of Phase I trials.)

Ongoing Studies

Currently there are two ongoing Phase II studies of alagebrium. BENEFICIAL is a Phase II double-blind, placebo-controlled, randomized trial designed to measure the effect of alagebrium on exercise tolerance in patients with chronic systolic heart failure. The trial is being conducted on 100 patients at a single site in the Netherlands, and is expected to yield results in early 2009.

The BREAK study, a randomized, double-blind, placebo-controlled, multiple-dose Phase II study being conducted in 160 patients in 30 centers throughout the United States. The study will evaluate exercise tolerance using the six-minute walk test, as well as a host of other secondary and tertiary measures, including the presence of carbocymethyllesine (CML), a biomarker of A.G.E. activity (see CML assay).