Overview

Lack of oxygen to tissue (hypoxia) is a common underlying factor in morbidity and mortality for numerous medical conditions. The ability to get more oxygen to oxygen-starved tissue provides new treatment opportunities in patients with life-threatening conditions including:

• treatment of solid cancerous tumors in conjunction with radiation therapy
• cardiovascular diseases such as peripheral arterial disease, heart attack and congestive heart failure
• stroke
• respiratory disorders
• other hypoxia-related conditions

The Company’s lead drug, trans sodium crocetinate (TSC), has been shown in animal models to significantly increase the delivery of oxygen selectively to hypoxic tissue, providing a powerful therapeutic effect.

Studies in animal models also indicate that TSC can be administered with good bioavailability intravenously, by intramuscular injection, inhalation, orally, and transdermally, allowing the drug to be adapted to a variety of therapeutic modes targeted at numerous clinical indications.

Current Approaches

Despite the urgent medical needs, previous attempts using other approaches to treat hypoxia have a history of failure. Many of the current approaches to increase the rate at which oxygen moves through its pathway from the lungs to the cells are based on increasing oxygen concentration within the blood. Treatments that have been tried are:

• Breathing enriched oxygen gas
• Increasing oxygen solubility in blood plasma through the use of artificial hemoglobins or perflurocarbons
• Facilitating oxygen dissociation from hemoglobin

However, current approaches are unable to safely and consistently move more oxygen to the intended destination in hypoxic tissue. Some of the issues with the previously studied treatments include:

• Oxygen toxicity at higher concentrations
• Toxicity from modified hemoglobins or perflurocarbons
• History of clinical failures with the above approaches

TSC’s Mechanism of Action: A New Approach

TSC, a small molecule (MW=372), uses a novel diffusion-enhancement approach to treating tissue hypoxia, rather than one of the other approaches that have previously failed in clinical trials. TSC has been shown to increase oxygen levels in hypoxic tissue. Thus, it prevents or mitigates the underlying hypoxia, whereas those treatment approaches that are based on interrupting the subsequent effects of oxygen deprivation do not address the source of the problem. TSC’s novel approach to increase the rate of oxygen diffusion through plasma and then selectively delivery that oxygen to oxygen-starved tissue offers a new paradigm for the treatment of many conditions.

In this diagram, black circles represent oxygen moving from the lungs into a blood vessel. Oxygen moves to the red blood cells once inside the vessel by the process of diffusion. Then the oxygen is picked up and carried by red blood cells through the body to the tissues where it is needed. When it nears its destination, oxygen leaves the red blood cells and moves, again by diffusion, through the plasma and membrane walls and eventually into the tissue cells.

Plasma, which is comprised of 91% water, is the major resistance to oxygen movement.

“…up to 95% of the resistance resides in the diffusion (plasma) boundary layer.” Huxley, V. H. and Kutchal, H., J. Physiol., 1981

Diffusion through plasma can be increased by decreasing the density of the water:

• Water’s structure is determined by hydrogen bonds among water molecules
• Each molecule is theoretically capable of forming four hydrogen bonds with neighboring water molecules (see diagram)
• Each water molecule actually form on average two to three and a half bonds each

TSC decreases density by promoting more hydrogen bonding among water molecules:

• TSC increases the number of hydrogen bonds among water molecules
• More hydrogen bonds creates a less dense liquid

By imparting more structure to water, TSC reduces blood plasma’s resistance to oxygen diffusion. The enhanced hydrogen bonding creates a more ordered water structure.

The reduced resistance, or enhanced hydrogen bonding, enhances the rate of diffusion of small molecules such as oxygen and glucose.

Preclinical and clinical testing of TSC have yielded positive results.

• Preclinical trials in animal models of radiation oncology, ischemic stroke, hemorrhagic shock and acute lung injury have demonstrated therapeutically significant results with increased survival
• A completed Phase I trial has demonstrated that the drug is well-tolerated in humans at doses significantly higher than the estimated efficacious dose 
• Positive data from a Phase I/II clinical trial, which were presented by oral abstract at the American Heart Association Annual Meeting Scientifc Sessions 15-Nov, 2010, are clinically meaningful, suggesting that TSC could benefit PAD patients’ daily functioning, such as walking ability, onset of leg pain and overall quality of life. 
• Further studies will continue to assess TSC’s potential in this and other serious hypoxia-related conditions.
• TSC is the subject of numerous peer-reviewed articles in the scientific and medical literature.