May 1, 2010 (Vol. 30, No. 9)
Nitric-Oxide-Like Therapeutic Designed for Range of Cardiovascular Indications
Nitric oxide’s beneficial biological effects are well known and form the foundation of drugs used to treat heart disease and erectile dysfunction. A chemical relative, nitroxyl, is emerging as a promising new option for cardiovascular disorders, according to researchers at Cardioxyl Pharmaceuticals. The company is designing drugs based on nitroxyl chemistry and is building a pipeline of intravenous and oral treatments.
For 100 years, researchers have generated nitroxyl from Angeli’s salt, a prodrug of nitroxyl named after the Italian chemist Angelo Angeli, without appreciating its physiological effects. Once generated, however, nitroxyl rapidly decomposes and is highly unstable. Moreover, a side product of Angeli’s salt is nitrite, which is known to have toxic side effects.
The medicinal chemists at Cardioxyl are identifying different scaffolds and nitroxyl donors with benign chemical groups and better stability and solubility features than Angeli’s salt. The company’s lead compound, CXL-1020, is a nontoxic, small molecule nitroxyl donor therapeutic drug. CXL-1020 “is not simply a modification of Angeli’s salt but a new chemical entity that generates nitroxyl through a completely different mechanism,” says Chris Kroeger, M.D., president and CEO.
David Kass, M.D., a cardiologist at Johns Hopkins University School of Medicine, co-founded Cardioxyl in 2006 after he and colleagues observed that nitroxyl enhances cardiac contractility, accelerates cardiac relaxation, and reduces vascular stiffness in canine models of heart failure. Impairment of these functions underlies the pathophysiology of heart disease. Cardioxyl’s lead compound addresses these disorders.
CXL-1020 produces a set of positive effects, according to Dr. Kroeger, including improving the heart’s ability to contract and its ability to relax and refill, while also acting on the peripheral vasculature to cause dilation and reduce loads on the heart. Unlike other heart drugs, CXL-1020, reportedly does not negatively impact the heart rate or rhythm. “This broad and ideal suite of effects that we can target and control has not been demonstrated for any other drug,” says Dr. Kroeger.
Last year, Cardioxyl began enrolling patients with chronic stable heart failure in a multicenter Phase I/IIa dose-escalation trial of CXL-1020. The experimental drug is ultimately aimed at patients with acute decompensated heart failure, the most common cause of hospitalization for patients older than 65 years of age. The safety and tolerability of CXL-1020 are first being assessed in people with chronic stable heart failure.
Many stable patients eventually become decompensated due to arrhythmias, heart attacks, or failure of drug or dietary regimens. In cases of acute decompensation, patients are pushed out of their baseline equilibrium into a state where their hearts cannot pump enough blood to meet the body’s needs, leading to excess fluid accumulation, lung edema, and shortness of breath. “When patients fall into a state of acute decompensation, they often end up hospitalized,” Dr. Kroeger says. Cardioxyl plans to treat hospitalized decompensated patients with intravenous infusions of CXL-1020 to bring their heart and vascular function back into equilibrium.
Physicians have few treatment options for acute decompensated heart failure. Current heart drugs tend to address just one aspect of heart failure. Some vasodilators have side effects of renal toxicity and most do not act directly on the heart.
Inotropes, another class of drugs, are more effective in the clinic than diuretics and vasodilators because they stimulate the heart to contract. However, inotropes can cause calcium overload, resulting in ventricular arrhythmias and sometimes death. CXL-1020 works differently than current drugs by producing a spectrum of encompassing positive effects, while avoiding calcium overload and side effects like arrhythmias, Dr. Kroeger explains.
Oral Formulations in Pipeline
Although the lead program at Cardioxyl is aimed at acute decompensated heart failure, nitroxyl-based drugs could also benefit patients with chronic congestive heart failure or other cardiovascular disorders. As an intravenous drug, CXL-1020 could prove ideal for treating hospitalized patients suffering from acute decompensated heart failure.
An oral drug, however, is needed to address the larger population of patients with chronic congestive heart failure and other disorders. Oral formulations of nitroxyl-based drugs for other chronic cardiovascular disorders are in preclinical testing.
Just how CXL-1020 works has not been fully defined, but researchers have shown that heart contractility and relaxation are related to calcium ion channels in cardiomyocytes, which need calcium to contract. Nitroxyl interacts with the ryanodine receptor and SERCa2a pump, both of which are involved in calcium cycling.
This calcium cycling is enhanced by nitroxyl without dramatically affecting the overall calcium load or the influx of calcium from the extracellular space, leading to more effective myocardial contraction and relaxation, Dr. Kroeger notes.
Nitroxyl also enhances calcium sensitivity of myofilaments, thereby increasing the amount of force generated. How CXL-1020 improves peripheral vascular dilation is less clear, but likely operates through different mechanisms since peripheral smooth muscle cells lack calcium channels.