West Coast Editor

Arginox Pharmaceuticals Inc. started patient enrollment in a pivotal Phase III trial of its lead drug candidate, tilarginine acetate, an injected small-molecule inhibitor of nitric oxide, for cardiogenic shock.

The specialty pharmaceutical firm is taking aim at CS - which afflicts as many as 100,000 heart attack victims who reach the hospital alive in the U.S. every year - by interrupting the circulatory shutdown that can lead to death.

"It doesn't involve a large number of deaths every year, maybe as many as 70,000 or so, but it's the major cause of death in patients who have an acute myocardial infarction and make it to the hospital," said David Hathaway, chief medical officer for Menlo Park, Calif.-based Arginox.

Figures show that if patients with CS can survive the first 30 days, they often are able to live much longer. On the other hand, about half die from CS, despite having an open coronary artery. Patients may get catheter-based intervention such as placement of a stent, or they may go for bypass grafting, but mortality still is about 50 percent.

The randomized, double-blind, placebo-controlled trial called TRIUMPH will enroll 658 patients at more than 120 sites in the U.S., Canada and Europe, with subjects getting either tilarginine acetate as a bolus and as five-hour infusion, or placebo. Enrollment is expected to finish by the end of the third quarter of next year.

TRIUMPH follows a Phase II dose-ranging study of the drug that showed it was well tolerated in the full cohort of patients tested, including those more than 75 years old.

"CS patients are very unstable, and there aren't a huge number of them, so getting access to them was a little complicated, but we managed to do that," Hathaway said. "We did not power the study to look specifically at mortality, but we did see a small trend in improvement at the higher doses of the drug."

TRIUMPH was put together "based on the safety profile [from the Phase II study], which looked good, and pharmacokinetics, which looked very good," he added.

First in its class, tilarginine acetate has orphan drug designation by the FDA for CS.

The "good" and "bad" faces of nitric oxide have made news in health care.

"On the good side, it plays a role in maintaining blood vessel tone," Hathaway noted. "The bad side is in these acute and more chronic inflammatory conditions, [where] the overproduction in the heart and blood vessels can result in deleterious effects."

The FDA last week approved BiDil, Cambridge, Mass.-based NitroMed Inc.'s heart failure treatment for black patients. BiDil enhances nitric oxide instead of inhibiting it, like Arginox's drug. (See BioWorld Today, June 27, 2005.)

Hathaway said tilarginine acetate snared his firm's interest as a result of two small studies in Israel, one involving 11 patients and one enrolling about 30.

"In patients who got tilarginine acetate or a drug closely related to it, there was an unusually high survival," he said. "Two-thirds or more were able to leave the hospital alive and do well. It caught our attention," since CS is a relatively small but important area of medical need.

"If you look at the patients who are being transferred to major centers, it's 25,000 or so, maybe a little larger or smaller, but this represents only about half of the total patients with CS who might merit therapy with the drug," Hathaway said. In cardiac care, he said, "this is one of those mountains that need to be climbed."

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