Cardioxyl Pharmaceuticals Announces Pre-Clinical Results on Lead Clinical Candidate, CXL-1020 at American Heart Association Scientific Sessions 2009
Pre-clinical Studies Demonstrate Physiological Activity of CXL-1020
Chapel Hill, NC and Orlando, FL – November 18, 2009 – Cardioxyl Pharmaceuticals, Inc., a clinical stage pharmaceutical company developing therapies for the treatment of cardiovascular disease, this week announced results of pre-clinical studies with CXL-1020 demonstrating beneficial effects on all three major facets (contractility, relaxation and vascular load) of the pathophysiology of acute decompensated heart failure (ADHF), with no significant safety liabilities. CXL-1020, a proprietary nitroxyl donor and Cardioxyl’s 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 pre-clinical 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, MD, President and Chief Executive Officer of Cardioxyl Pharmaceuticals, commented, “These data, combined with the results of prior studies, confirmed the effects of CXL-1020 in pre-clinical models of heart failure and provided 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.”
Kroeger continued, “Current therapies for acute decompensated heart failure have not been able to produce improvements in contractility, relaxation and load without posing the risk of untoward effects on heart rate and rhythm. 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 Research and Pharmacology, a cofounder of Cardioxyl and an investigator in both studies, commented, “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.”
About the Late-Breaker Session – “Nitroxyl Enhances Contractility in Failing Isolated Mouse Cardiomyocytes”
Prior to this study, CXL-1020 had been demonstrated to enhance contractility (inotropy) and accelerate relaxation (lusitropy) in normal mouse cardiomyocytes independent of beta-adrenergic receptor signaling. In this study, CXL-1020 directly enhanced contractility and accelerated relaxation in failing mouse cardiomyocytes with altered beta-adrenergic signaling. Unlike a beta-adrenergic agonist, the positive inotropic/lusitropic action of the HNO donor, CXL-1020, was fully preserved in failing mouse cardiomyocytes. The measure of contractility increased by 116 +/- 27 percent and relaxation time (return to baseline) improved by 16 +/- 3 percent (both statistically significant p<.001). This research was performed at Johns Hopkins University.
Oral Presentation – “Acute Intravenous Infusion of CXL-1020, a Nitroxyl Donor, Improves Left Ventricular Function in Dogs with Advanced Heart Failure”
In this pre-clinical canine model, CXL-1020 at two doses (3 and 10 µg/kg/min) significantly and dose-dependently improved LV function (both contractility and relaxation) as measured by a reduction in both LV end-diastolic and end-systolic volumes (EDV and ESV), as well as an increased ejection fraction (EF) and peak power index (PPI, load-independent index of contractility). At the highest CXL-1020 dose, the improvement in LV function was also associated with significantly reduced myocardial oxygen consumption (MVO2). CXL-1020 was not observed to evoke ventricular arrhythmias. At both doses, CXL-1020 significantly decreased load and stretch induced chronic heart failure (CHF) sensitive biomarkers: plasma Troponin-I (p<0.01), proANP (p<0.05) and NT-proBNP (p<0.05) levels all decreased compared to baseline values. This research was performed at Henry Ford Hospital.
CXL-1020, a proprietary nitroxyl donor, is the company’s lead compound for the intravenous treatment of acute decompensated heart failure (ADHF). Cardioxyl recently (June 2009) initiated the first Phase I/IIa safety and dose-escalation study of CXL-1020 in stable chronic heart failure patients. Based on all pre-clinical studies to date, CXL-1020 is anticipated to improve the symptoms, hemodynamics and clinical status of patients with ADHF. Further, CXL-1020, with its rapid onset of effect, may provide pharmacoeconomic benefits by shortening the length of hospital stay, reducing the severity of acute events and potentially decreasing the frequency of recurrences.
About CXL-1020 Phase I/IIa Study
The study is a multi-center trial that is being conducted in seven sites in the U.S. with affiliated heart failure specialty centers and academic medical centers. The Phase I/IIa study is enrolling subjects with chronic stable heart failure, who will receive escalating doses or a sustained intravenous infusion of CXL-1020 or placebo. The primary endpoints for this study are safety and tolerability, pharmacokinetics, and non-invasive hemodynamic measurements.
About Congestive Heart Failure (CHF)
Congestive heart failure is the inability of the heart to pump enough blood to supply the metabolic demands of the body. Heart failure may result either from the heart's inability to effectively contract (systolic heart failure), or from the heart's inability to relax and fill with blood (diastolic heart failure). There are more than 5.7 million people in the U.S. and more than 22 million people world-wide with congestive heart failure (CHF), with over 650,000 new CHF diagnoses each year in the U.S. The prognosis for patients with CHF remains poor, with a 5-year mortality rate of 50 percent, following diagnosis. The expected economic impact of the medical care for CHF is substantial, with over $37 billion spent in the U.S. in 2009 for the medical care of heart failure patients.
About Acute Decompensated Heart Failure (ADHF)
ADHF is an acute exacerbation of congestive heart failure and the leading diagnosis at the time of discharge from U.S. hospitals and the most common cause of hospitalization for patients over 65 years of age. ADHF is a life threatening condition, with in-hospital mortality rates of 2-6 percent and six month readmission rates as high as 30-60 percent. Episodes of ADHF are marked by a severe diminution of cardiac function that typically result in fluid accumulation in the lungs (pulmonary edema) and consequent severe shortness of breath, as well as worsening renal function. There were 1.1 million hospitalizations for acute heart failure in the U.S. in 2006. Among patients hospitalized with ADHF, the thirty day mortality rate is approximately 11 percent and the one year mortality rate is 34 percent. These poor outcomes indicate the clear need for better therapies to treat this patient population.
Current Treatments for ADHF
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). Administration of dobutamine or milrinone often requires very close monitoring in the hospital’s cardiac or intensive care unit setting due to the life-threatening safety risks associated with these drugs, including ventricular/atrial arrhythmias, hypotension, sudden cardiac death, and other potential adverse long term outcomes.
About Cardioxyl Pharmaceuticals
Cardioxyl Pharmaceuticals is a clinical-stage pharmaceutical company focused on the discovery and development of new classes of safe and effective therapeutic agents for the treatment of cardiovascular disease. Cardioxyl has developed industry-leading expertise in the chemistry, biology and clinical applications of nitroxyl (HNO) technology. The company's core HNO platform has generated several pre-clinical and clinical candidates, including the company's lead compound, CXL-1020, currently in clinical development for ADHF. Cardioxyl is a privately held company financed by life science venture investors, including the Aurora Funds and New Enterprise Associates.