By Chris Delporte

Apex Bioscience Inc. initiated a Phase III clinical study of VTR-PHP for the treatment of nitric oxide-induced shock.

The multinational trial, which is designed to support a new drug application filing, will enroll 1,000 patients in more than 100 centers throughout the United States and Europe. Enrollment is expected to take a little more than 24 months, and the company will be prepared to present its findings three months later.

¿We¿re trying to resolve cardiovascular dysfunction to stabilize patients so that they can survive long enough to be treated for their underlying disease and co-morbidities,¿ said Joseph De Angelo, Apex¿s chief scientific officer.

The Durham, N.C., company ¿ a wholly owned subsidiary of VitaResc Biotech AG, of Martinsried, Germany ¿ is actively looking for partners, but is waiting for the right deal, De Angelo said.

Nitric oxide (NO) is an important mediator of blood pressure, platelet function, neurotransmission and cellular immunity. In pro-inflammatory states, however, such as infection, burn, trauma and pancreatitis, toxic levels of NO are produced that can send the patient into shock.

Hemoglobin is the most potent natural scavenger of nitric oxide. VTR-PHP, or pyridoxalated hemoglobin polyoxyethylene conjugate, is a hemoglobin-based therapy that is designed to selectively reduce toxic levels of NO, while allowing critical beneficial levels to persist. According to the company, NO-induced shock affects approximately 700,000 people annually in the Unites States and roughly the same number in Europe.

Failure of the cardiovascular system, or NO-induced shock, results in death in more than 50 percent of cases. De Angelo said that the current standard of care, vasopressors such as norepinephrine, is inadequate to treat shock patients and may even make their condition worse.

Apex¿s Phase II data showed that VTR-PHP had the expected hemodynamic activity of an NO scavenger and reduced the need for vasopressors in shock patients. Using this data, the company was able to design its Phase III study to target the most accurate patient population, De Angelo said. Since toxic levels of NO always lead to shock, the company can be sure that virtually 100 percent of the target population of shock victims has excess nitric oxide.

The trial is a two-arm, placebo-controlled study. Two equally sized groups will be tested. One group will receive the current standard of care and placebo, while the other will be treated with VTR-PHP and standard care. The drug is administered using continuous intravenous infusion over four days. The trial endpoints are reduction of 28-day all-cause mortality or reduced functional morbidity.

In addition to VTR-PHP, VitaResc has two other products in preclinical development, both of which have applications in the intensive care arena. The company is developing VTR-4, a humanized monoclonal anti-endotoxin antibody, for the prophylactic treatment of Gram-negative sepsis in high-risk patients. VitaResc also is working on a pegylated synthetic thrombin inhibitor (TI) called VTR-TI. It is being evaluated for multiple applications as an antithrombotic and as a coating for devices such as blood dialysis cartridges, stents and tubings. The pegylation of the TI is, De Angelo said, what gives it its unique properties and makes it useful for device coatings to prevent coagulation. The company also is looking for partnerships with these two products and expects to file investigational new drug applications to begin clinical trials in the first quarter of next year.

Apex was purchased by VitaResc in July 1999 in a move that allowed it to continue development of VTR-PHP. (See BioWorld Today, July 19, 1999.)