NormOxys Emerges from Stealth with New Class of Oxygen Drugs for Cancer, Heart Failure

Everyone needs oxygen, and major health problems can pop up when certain tissues get too little or too much. Now a small biotech company based in Wellesley, MA, co-founded by a Nobel Laureate, says it has discovered a new class of drugs that delivers targeted oxygen to tissues that are starving for it, without going overboard.

The company, NormOxys, is starting to talk publicly for the first time today about what it is trying to accomplish. I heard about it yesterday from the company’s CEO, Martin Tolar. He was a professor of neurology at Yale University before taking on a series of jobs in clinical development and business development at Pfizer (NYSE: PFE), and then in executive roles at South San Francisco-based CoMentis.

The big idea at NormOxys is like the name suggests—to normalize the amount of oxygen in deprived tissues. The technology comes from a combination of biology research from Claude Nicolau, a visiting professor at Tufts University in Medford, MA, and chemistry research from Jean-Marie Lehn, a Nobel Laureate at the College de France in Paris. The company, founded in 2004, has now built up a portfolio of small-molecule compounds that it says can get tiny oxygen-carrying red blood cells to release a controlled amount of oxygen into tissues that desperately need more—such as heart muscle laboring under the stress of congestive heart failure, unable to pump enough blood to give people the energy they need.

The company doesn’t have any proof that it can do this efficiently in humans, but it is poised to enter its first clinical trials this year to see if it can do that. If this early test shows promise, it could open up a new way of treating heart failure, anemia, and even cancer, Tolar says.

“We’re not talking about a few percentage points of incremental improvement,” Tolar says. “The reason I joined the company is that it has such a profound effect.”

Martin Tolar

Martin Tolar

Those are pretty bullish words for a company that’s still not yet in the clinic. But NormOxys has some prominent people backing it up. Nicolau and Lehn have collaborated before on a pair of biotech companies, including Cambridge, MA-based Alantos, which sold to Amgen two years ago for $300 million. Former GlaxoSmithKline CEO Jean-Pierre Garnier is the chairman of the board at NormOxys, and Switzerland’s Index Ventures has participated in the company’s first two venture rounds, along with several wealthy individuals, Tolar says. About $15 million in venture capital has gone to the company so far, he says. The startup’s ability to recruit Tolar is “a testament to the innovative and exciting science we are pursuing,” Garnier says in a company statement.

The best-known example of a drug that treats oxygen deficiency is Amgen’s erythropoietin (Epogen) and darbepoeitin (Aranesp), a couple of billion-dollar molecules. They are both hormones that stimulate the body to produce more oxygen-carrying red blood cells, and it has been used by millions of people over the past two decades to treat anemia associated with kidney disease, or as a side effect of cancer. But the FDA has warned physicians repeatedly about studies that show an increasing risk 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.”

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