By Karen Pihl-Carey
For years, scientists have known nitric oxide (NO) as a pollutant, found in cigarette smoke, car exhaust and city smog.
It wasn't until 1987 that three scientists, who later won the Nobel Prize for their work, discovered humans produced the molecule in small puffs. NO is needed for neurotransmission, blood pressure regulation and immune defense. Their discovery sparked the interest of thousands of researchers, including Monte Lai, who was then a biophysics professor at the Medical College of Wisconsin in Milwaukee and who is now the CEO of Medinox Inc., a company developing treatments for diseases associated with the overproduction of NO.
The researchers soon uncovered a list of physiological conditions - tissue damage, organ failures and even death - influenced by the overproduction of NO.
What they didn't know was how to stop the overproduction, which can result in a number of health problems, such as intradialytic hypotension (IH) and hemorrhagic shock.
That's where privately held Medinox, of San Diego, came in. The four-year-old company is seeing positive results of its NO neutralizing technology, exclusively licensed from the Medical College of Wisconsin. Medinox recently began a Phase I/II trial of NOX-100 for IH.
While scientists studied inhibitors designed to shut down the enzymes that overproduce nitric oxide, Lai discovered Medinox's core neutralizing technology while a professor at Wisconsin. Studies of the inhibitors found they caused a number of side effects because the enzyme that produces NO, the one being inhibited, is important in memory process, blood pressure regulation and immune defense.
"When I was still at the medical school, I thought there may be some other way," said Lai who is also founder, president and chairman of Medinox. "And I thought why not neutralize the nitric oxide directly, not having to worry about enzymes."
So after 15 years in Wisconsin, Lai took a sabbatical leave in San Diego. Three months later, in spring 1995, he had formed Medinox, a name that stands for medical nitric oxide, and resigned his position as a professor of biophysics.
In its four years, the company has raised more than $13 million, starting with $1 million in seed money from San Diego-based BD PharMingen. In 1997, it raised another $5 million through a venture capital financing. And in June, it raised $7.4 million in private equity financing to fund the Phase I/II trial of NOX-100 for IH. The amount should last the company at least two years, Lai said.
"Compared to other biotech companies, I think we've accomplished quite a bit with a very low burn rate," he said.
Medinox's nitric oxide neutralizers bind excessive NO without removing the low levels needed in the body. The compounds can be administered intravenously, subcutaneously or orally. They enter the circulation and are distributed to tissues and organs where they bind NO. The kidneys remove the resulting complex, which is excreted through urine.
Preclinical studies of NOX-100 were conducted in a rat model of hemorrhagic shock, in which hemorrhage caused a sudden drop in blood pressure, stimulating an immune response. The response resulted in excessive NO production and the subsequent destruction of tissues by free radicals, as well as damage to vital organ functions. University of Pittsburgh researchers found that NOX-100 stabilized blood pressure, reduced excessive levels of NO, reduced free radical damage to tissue and reduced organ injury, increasing the survival rate of the animals.
"We found that it is pretty effective in controlling the nitric oxide level," Lai said. "We found very little side effects compared to the inhibitory approach."
Medinox officials met with the FDA in March to discuss bringing NOX-100 to the clinic.
"They basically suggested that we skip the Phase I studies and go directly into Phase I/II," Lai said.
The Phase I/II trial is being conducted at the University of California, San Diego, focusing on IH, which is the episode of low blood pressure associated with the production of excessive NO during hemodialysis. It is a double-blind, placebo-controlled study that should be completed by March, Lai said.
Lai plans to take Medinox public when market conditions are favorable. The company has 20 employees.
"The market is not exactly good for a small company at the present time," he said. "So in one or two years we, hopefully, will be able to go to the public [market] to support the company's activities."
In the meantime, it will continue to focus on its clinical and preclinical studies of NOX-100. The company plans to initiate a clinical trial for an oral dose of NOX-100 for allograft rejection in the first quarter of 2000, and a clinical trial for an injectable dose of the compound for septic shock. Preclinical studies of the neutralizing agents will continue in other indications, such as neurodegenerative diseases and hemorrhagic shock.
Medinox has several collaborations with academic institutions, including Harvard Medical School and Stanford University, in areas ranging from neurodegenerative diseases to cardiovascular disorders. The company has been issued 10 U.S. patents and several more are pending worldwide.