CHAPEL HILL, NC and ORLANDO, FL--(Marketwire - 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
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
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.