By Mary Welch

Apex Bioscience Inc. was acquired by VitaResc Biotech AG, a move that will allow the struggling company to get back on its feet and proceed to Phase III trials with its lead product, pyridoxalated hemoglobin polyoxyethylene (PHP).

A year ago the Research Triangle, N.C.-based company was forced to close down part of its operations, slash staff and put itself up for sale.

"We had to close our research and development efforts and take other cost-cutting measures in order to conserve our resources so we could continue developing PHP," said Vipin Garg, chief operating officer at Apex. "We had to do what we did to buy time so that we could convince investors that our technology was valid. It just took longer than we thought it would."

Apex came together with VitaResc through the efforts of A.M. Pappas & Associates, of Durham, N.C., which was brought on to assist in Apex's restructuring efforts. The acquisition itself was led by Techno Venture Management (TVM), a venture capital firm headquartered in Munich, Germany. Apex will become a wholly owned subsidiary of Munich-based VitaResc. Financial terms were not disclosed.

"TVM has been pretty active in the U.S. biotechnology world," Garg said. "They've invested in about 10 to 15 companies."

Nitric Oxide Is Target In Shock Patients

Apex is developing proprietary products that selectively modulate in vivo nitric oxide levels. One of Apex's founder, Joseph DeAngelo, now chief scientific officer, initially was developing blood substitute applications of hemoglobin when he switched to using hemoglobin as a way to prevent and treat shock-induced hypotension by reducing nitric oxide.

"He discovered this unique application that occurs when a person goes in shock. There is an acute drop in blood pressure that takes place and we believe it's due to excess nitric oxide," Garg said. "We believe that treatment with PHP to scavenge excess nitric oxide and restore blood pressure has the potential to complement and enhance current shock therapy, which uses fluids and vasopressor drugs. Patents were filed on the use of hemoglobins as a natural scavenger of excessive nitric oxide and we shifted the focus of the company to this application."

PHP is a human-derived and chemically modified hemoglobin preparation originally developed by Ajinomoto Co., of Tokyo, as a blood substitute. In 1995, Apex obtained exclusive rights to PHP for all indications and for all geographies except Japan. PHP is prepared from hemoglobin purified from outdated human red blood cells obtained from the American Red Cross.

Hemoglobin is the most potent natural scavenger of nitric oxide. Nitric oxide is an important mediator of blood pressure, platelet function, neurotransmission and cellular immunity.

Nitric oxide-induced shock occurs in more than 700,000 patients in the U.S. each year. In proinflammatory states, it can be the result of infection or other etiologies such as burns, pancreatitis, hemodialysis and cytokine therapies. Collectively, the proinflammatory disorders are referred to as systemic inflammatory response syndrome (SIRS). The most common form of this syndrome is called septic shock.

During shock, cytokine levels increase dramatically, causing an overproduction of nitric oxide, which leads to uncontrolled blood vessel dilation, which in turn leads to clinical hypotension (severe low blood pressure).

"We were able to demonstrate in in vivo models that administration of low-dose cell-free hemoglobin scavenges nitric oxide and reverses hypotension," Garg said. "We had done a Phase I in mid-1996, a Phase I/II in 1996-97 and a Phase II in 1998. We were awaiting the results from Phase II before going to the FDA and trying to raise money at the same time. The trouble was the company couldn't last long enough for the Phase II results to be released. It became a survival game."

The company cut 10 employees and sought to sell or license its core technology as well as its 17,500-square-foot manufacturing facility. It stopped research and development efforts. The company earned money by lining up manufacturing contracts with pharmaceutical and biotech companies.

Further crippling the company's efforts to raise $10 million was the stream of companies that failed in their efforts to treat acute hypotension, which has been estimated to be a $1 billion market.

"Not only did we face a bad financial market, but so many companies had failed. There were a lot of skeptics," Garg said. "No one wanted to believe. It hurt us. Investors would ask how could we succeed when everyone else didn't. We had no Phase II data to show them."

Phase II Results Show Promise

The Phase I/II study involved 18 shock patients with presumed infection who were refractory to standard intravenous fluid therapy. PHP demonstrated the potential to restore normal hemodynamic effects and reduced the need for vasopressor drugs, such as dopamine or norepinephrine. The FDA granted Apex an amendment to extend the Phase I/II trial to include a protocol of continuous infusion and dose escalation in 22 more septic shock patients.

"The Phase II data showed that PHP has the expected activity of reversing vasopressor-dependent shock, "DeAngelo said. "It does what we believe it should have in this specific patient population. Now we need to show efficacy."

The data showed PHP increased systemic vascular resistance and decreased heart rate. In addition, it indicated PHP infusion brought about a decrease in vasopressor use while maintaining or increasing mean arterial pressure.

The company, which will operate as a wholly owned subsidiary of VitaResc, will meet with the FDA and start a Phase III trial as soon as possible. While the original Apex leadership will remain, the company will be headed by Ulrich Delvos, who will serve as CEO and president. Delvos, a physician, co-founded and headed Pathogenex, which spun out VitaResc into a separate company this year. Pathogenex, like VitaResc, is backed by Techno Ventures.

Apex is now hiring staff and expects to bring employee levels to around 30. Although VitaResc is pumping money into Apex, long-term plans for the company are to seek a corporate partner and be listed on the German stock market and eventually in the U.S.

"We knew our strategy was valid," Garg said. "It was just a matter of waiting for things to work out. And, now we're on the road to Phase III and filing a new drug application. There is value in the technology."