Iroxanadine is an orally available small molecule compound that CytRx believes represents a potentially powerful breakthrough in the treatment of vascular diseases that are caused in part by damage to "vascular endothelium" that lines the inside of blood vessels. Vascular endothelium is believed to regulate blood flow by modulating the elastic properties of blood vessels and to control cellular proliferation as well as inflammatory and immune mechanisms in the blood vessel wall. Normal vascular endothelium maintains the non-adhesive internal surface of blood vessels and has anticoagulant, fibrinolytic, and antithrombotic properties. Injury to the endothelial cells that comprise the endothelium ("endothelial dysfunction") is thought to disrupt the normal regulatory properties of blood vessels. It is believed that endothelial dysfunction plays a key role in the development of various vascular diseases including atherosclerosis, thrombosis, proliferative retinopathy, ischemia/reperfusion injury, diabetic ulcers and angiopathies, congestive heart failure, angina, and peripheral artery disease. Preclinical and clinical studies with iroxanadine indicate that it has therapeutic potential for the treatment of cardiovascular atherosclerosis. According to the National Heart, Lung & Blood Institute, atherosclerosis is a leading cause of illness and death in the U.S. and affects approximately 4.6 million people annually.

Similarly to arimoclomol, iroxanadine is believed to function by amplifying "molecular chaperone" proteins, normally found in all cells of the body and thought to enhance the cell's natural ability to mend damaged, misfolded proteins. Iroxanadine may thus protect endothelial cells from misfolded, toxic proteins, repairing those that are believed to cause many diseases, including ALS. Iroxanadine has been shown in tissue culture to stimulate the migration of endothelial cells and to protect them from oxidative damage caused by variations in oxygen levels ("ischemia/reperfusion).

One line of evidence which suggests that iroxanadine may prove to be an effective treatment for cardiovascular disease is through its experimental inhibition of a process known as coronary restenosis, the undesirable re-closing of the coronary artery following balloon angioplasty for atherosclerosis. It is generally believed that coronary restenosis occurs as a result of physical damage to the endothelial layer of the blood vessel. Because of this damage, the vessel tries to repair itself by activating the proliferation of smooth muscle cells, another cell type prevalent in blood vessels. These cells do not effectively control their own growth and proliferate so extensively that they ultimately block proper blood flow. It is believed that repairing the damage to endothelial cells would allow efficient repair of the damage, without the excessive proliferation of smooth muscle cells that results in restenosis.  

To test the ability of iroxanadine to improve endothelial cell damage and migration during coronary restenosis, researchers performed balloon angioplasty in the coronary arteries of pigs, whose cardiovascular system is thought to be very close to that of humans. Some of the animals received no further treatment; others were given iroxanadine. After five weeks, the resulting blockage of the coronary artery at the site of angioplasty was measured. The animals treated with iroxanadine showed significantly reduced coronary restenosis compared to the animals that did not receive drug treatment.

Iroxanadine was also effective in treating cardiovascular disease in an experimental mouse model for atherosclerosis.  The experiments demonstrated that iroxanadine significantly reduced plaque formation and arterial thickening in mice, both of which are symptoms that lead to serious cardiovascular disease. The experiments were performed in a strain of mouse ("ApoE") which is genetically engineered to have deficient cholesterol metabolism, resulting in acceleration of the generation of cardiovascular disease. Iroxanadine significantly reduced the progression of cardiovascular disease in these animals. Treatment with iroxanadine significantly decreased plaque formation and reduced arterial thickening. This is consistent with its proposed mechanism of action, namely restoring the normal function of the endothelial cells lining the blood vessels.

Additional experimental animal models suggest that iroxanadine may be useful in the treatment of otherdiseases of poor blood circulation, such as diabetic foot ulcers. In these experiments, iroxanadine was tested for its ability to improve the function of endothelial cells in the capillaries of the legs of rats with spontaneously high blood pressure. Rats with high blood pressure, like humans, tend to suffer damage to their blood vessels over an extended period of time. In the study, capillaries in the hind limbs of rats with high blood pressure were further damaged by oxygen deprivation after blocking the large artery that normally provides the blood supply. After 60 minutes of blockage, blood flow was restored and the average flow of blood through the leg tissues was measured by a process called Laser Doppler Flowmetry. The test demonstrated that iroxanadine significantly improved the flow of blood to the tissues of the leg of the rats by protecting endothelial cells from damage. CytRx believes that restoring proper circulation to the extremities of diabetic patients, who often have damaged capillaries, may accelerate the abnormally slow healing of wounds characteristic of diabetes.

Iroxanadine has been shown to be well tolerated in two previous Phase I clinical trials with healthy human subjects. It was also tested in patients being treated for high blood pressure in a Phase II clinical trial designed to assess the effect of the drug on endothelial cell function in the arteries. Patients with high blood pressure are often thought to be at risk for diseases of blood vessel endothelial cell damage, including cardiovascular disease. A generally accepted method of determining blood vessel endothelial cell function is measured by the increase in diameter of a blood vessel that occurs when its endothelial cells are stimulated with a chemical known as acetylcholine (Flow Mediated Vasodilitation, or FMD). Decreased FMD is believed to correlate to increased tendency toward cardiovascular disease. In healthy individuals, FMD results in approximately a 10% increase in the diameter of the brachial artery, which is the artery in the arm from which blood is often drawn for tests. In the tested hypertensive patients, the average FMD was only approximately 4%, indicating damage to their blood vessel endothelial cells. In the patients treated for 12 weeks with iroxanadine, the average FMD increased significantly to over 6%. These data suggest that iroxanadine may help repair damage to endothelial cells lining the blood vessels of patients at risk for cardiovascular disease.

Although CytRx believes that iroxanadine may ultimately be useful in the prevention of cardiovascular disease, we initially intend to develop iroxanadine to improve endothelial dysfunction in other indications that we believe will have clinical end-points that can be demonstrated more quickly, such as diabetic wound healing.  CytRx believes that demonstrating efficacy in these smaller market indications will not only build value for that indication, but will also prove the principle of endothelial improvement as part of a strategy to potentially out-license iroxanadine to a larger pharmaceutical company for the major market cardiovascular indications.