of heart attack, stroke, and death when the drug is used at high doses.
Other studies of substitutes for hemoglobin, the protein in a red blood cell that carries oxygen molecules, also have shown a higher risk of heart attack and death, NormOxys says. One drug candidate from Boulder, CO-based Allos Therapeutics, efaproxiral, failed because it didn’t last long enough inside red blood cells to help them deliver enough oxygen where it needs to go, Tolar says.
What NormOxys has developed is a different kind of drug, which doesn’t try to produce more hemoglobin. Instead, it crosses inside red blood cells and works to ensure the hemoglobin can release more oxygen molecules to oxygen-deprived tissues, Tolar says.
NormOxys likes this approach partly because it shouldn’t cause tissues to get too much oxygen, he says. Other scientists that have tried to enrich the amount of oxygen in the blood have found it can increase the rate of free radicals, which can damage tissues.
The big finding so far in mice is that NormOxys’ lead drug candidate, OXY111A, was able to increase exercise capacity by about 70 percent, Tolar says. The standard beta-blockers and ACE inhibitors that people take have a much more limited effect on that measure, improving exercise capacity by 5 to 10 percent, he says. If all goes according to plan, people with congestive heart failure, whose hearts aren’t pumping very well, ought to at least get more oxygen from the blood that is flowing in their system, which should translate into making them feel better, Tolar says.
NormOxys is also getting primed for a more complex idea of using these drugs to treat cancer. This is because about three-fourths of tumors are in a stressed, low-oxygen state, which prompts them to do crafty things like produce new blood vessels to nourish them, and to switch off normal cell suicide pathways.
At first glance, when NormOxys proposed using drugs to deliver more oxygen to tumors, it didn’t go over very well. “Oncologists we talked to said this is crazy, it will never work,” Tolar says.
Still, NormOxys has been encouraged by what it has seen in animal tests. The idea is that by delivering more oxygen to the tumor, it switches off the active formation of new blood vessels, and allows the body to keep on the self-destruct switches that will essentially kill off the tumor, like other cell types.
NormOxys plans to test its concept initially in healthy volunteers in early 2010, and then move into a study of congestive heart failure patients in the second or third quarter of the year, Tolar says. The first cancer trial is on the docket for next year as well, he says.
The goal will be to develop the molecules until the concept can be proven. Then it will be time to call on Big Pharma to help out with the expensive Phase III clinical trials and commercialization, Tolar says.
That’s all a long way down the road, but to hear Tolar tell the story, he doesn’t have much doubt this will work. “It’s paradigm-changing,” he says. “I’ve never seen anything close to this.”
