Studies Examine Treatment of Acute Decompensated Heart Failure
November 18, 2009 — Results of preclinical studies with CXL-1020 demonstrate beneficial effects across the board on the treatment of acute decompensated heart failure (ADHF). All three major facets of the pathophysiology — contractability, relaxation and vascular load — showed improvements with no significant safety liabilities.
CXL-1020, a proprietary nitroxyl donor and lead clinical candidate, significantly improved both contractility and relaxation of failing isolated mouse cardiomyocytes (heart cells) and improved the left ventricular (LV) function of canines with advanced heart failure, without increasing heart rate or evoking ventricular arrhythmias.
These studies are complementary, in that they demonstrate both the cellular and systemic pharmacological effects of CXL-1020 in two well-established preclinical models.
The mouse cardiomyocyte data provide important insights into the cellular mechanism of action of nitroxyl donors while the canine model is a useful predictor of drug response in humans with ADHF.
Chris Kroeger, M.D., president and chief executive officer of Cardioxyl Pharmaceuticals Inc., the company that manufacturers CXL-1020, said the data provide “a firm foundation to support the advancement of CXL-1020 into the clinic.”
Cardioxyl is currently conducting a phase I/IIa dose-ranging study in patients with chronic stable heart failure to evaluate the safety and tolerability of CXL-1020, as well as the effects of this agent on non-invasive hemodynamic parameters and pharmacokinetics.”
“Current therapies for acute decompensated heart failure have not been able to produce improvements in contractability, relaxation and load without posing the risk of untoward effects on heart rate and rhythm,” said Dr. Kroeger. “We look forward to recapitulating the physiological effects demonstrated in these canine models in the ongoing phase I/IIa clinical trial.”
Reza Mazhari, Ph.D., vice president of research and pharmacology, co-founder of Cardioxyl, and an investigator in both studies, added, “The novel results from the isolated myocyte experiments are complementary to and consistent with canine studies in demonstrating direct load-independent effects of CXL-1020 on contractility and relaxation. More importantly, these studies illustrate that CXL-1020 is an effective therapy independent of the beta- adrenergic signaling pathway.”
Despite the severity of the condition, the treatment options available for patients with ADHF remain limited. Current first-line treatments target the removal of excess fluid (diuresis) and preload and afterload reduction (vasodilation). In order to improve the hemodynamic profile of the heart and increase cardiac contractility, a physician may also administer an intravenous inotropic agent such as dobutamine (beta-adrenergic agonist) or milrinone (PDE3- inhibitor), which requires close monitoring and poses serious safety risks.
For more information: www.cardioxyl.com