By Lisa Seachrist

Washington Editor

Succumbing to the fourth clinical failure in as many indications for LeukArrest, ICOS Corp. has stopped development of the drug and decided to move forward with other clinical programs.

Fortunately for the Bothell, Wash.-based company, the bad news comes with the good: Phase II clinical results of Pafase have the company looking to move the drug into Phase III trials by the end of this year as a means of preventing acute respiratory distress syndrome (ARDS) in severe sepsis and severe trauma.

The Phase III clinical trial of LeukArrest for the treatment of ischemic stroke was stopped midstream when an independent monitoring panel said an interim analysis of the study showed the drug wouldn't be able to show a clinical benefit over placebo. There never were any safety issues identified with LeukArrest administration.

"It's important to recognize the whole model of drug development recognizes that not all drugs are going to make it - some are going to fail," said Tom St. John, vice president of therapeutic development at ICOS. "It's disappointing [LeukArrest] has fallen by the wayside, but what's important is we're a company that has numerous drugs in development in numerous indications, and that's a very healthy thing."

The past year has been a rough one for LeukArrest. In June 1999, the drug failed in a Phase II hemorrhagic shock trial. In September, it failed in a Phase II study as a treatment for multiple sclerosis. In November, the company announced the drug had failed in a study testing it as a means of preventing damage during a heart attack. (See BioWorld Today, June 16, 1999, p. 1; and Nov. 4, 1999, p. 1.)

LeukArrest is designed to block movement of leukocytes from the bloodstream into inflamed tissue. The humanized monoclonal antibody is designed to inhibit cell adhesion by blocking the CD14 receptor. When cells experience a loss of blood supply, they are susceptible to injury as blood flow is restored and pro-inflammatory cells overreact to the damage caused by the lack of oxygen. At least that's the concept that has been driving research into reperfusion injury for the past 10 years. ICOS' experience with LeukArrest puts that hypothesis on shaky ground.

"[LeukArrest's failure] is going to be met with some measure of surprise in the academic community," St. John said. "We tried three times with a potent immunosuppressant agent to combat these conditions. You'd have to conclude reperfusion injury is not a major contributor to these diseases."

With the end of the LeukArrest program, ICOS is focusing on developing Pafase as a means to prevent ARDS in patients with severe sepsis. The rationale for that decision is bolstered by robust Phase II results.

Sepsis has been an historically tricky indication for the biotechnology industry. In the early 1990s a number of Phase III failures in sepsis sent the whole biotech sector into a tailspin. In fact, John Pribble, assistant director for clinical research at ICOS, was involved with the development of Antril, an IL-1 receptor antagonist, at Boulder, Colo.-based Synergen Inc. That drug failed in a Phase III trial in 1993. (See BioWorld Today, April 2, 1993, p. 1.)

"What we intend to do is learn from this history and take that knowledge into how we develop Pafase," Pribble said.

Pafase is a recombinant human serum enzyme that cleaves platelet-activating factor and completely inactivates it. Platelet-activating factor is a pro-inflammatory mediator that has been found in excess amounts in the blood and lungs of patients with severe sepsis and severe trauma. The company decided to proceed with Pafase to prevent ARDS because excess platelet-activating factor is found in the lung fluid of patients with the condition.

The Phase II trial tested two doses of Pafase in 240 patients with severe sepsis or severe traumatic injuries. For one of the dosages of Pafase, the company found a statistically significant reduction in death from all causes compared to placebo: a 14 percent death rate with Pafase compared with a 28.4 percent rate in placebo. In addition, only 23.8 percent of Pafase-treated patients developed ARDS compared with 37 percent of placebo patients. This result, too, was statistically significant.

The company also looked at measures of multiple organ failure dysfunction, number of days in the intensive care unit and number of days on a ventilator. All of these measures strongly favored Pafase over placebo.

"All of these endpoints were consistent and positive with respect to Pafase," Pribble said. "In addition, we did a very conservative analysis, an intent-to-treat analysis, and still found it favored Pafase."

An intent-to-treat analysis typically is required by FDA in pivotal Phase III studies and offers the most conservative estimate of a drug's efficacy. Pribble noted no other sepsis drug stood up to such intense scrutiny at the Phase II level. As a result, ICOS is confident enough to move ahead to a Phase III study of Pafase in severe sepsis by the end of this year.

"We are going to work very closely with our counterparts at FDA to develop the best program for Pafase in severe sepsis," said Gary Peterman, ICOS' senior director of therapeutic development of Pafase.

In addition to moving into a Phase III study of Pafase, ICOS is suspending a Pafase program in severe acute pancreatitis, another condition that can lead to ARDS. Peterman said, "We're still a small, growing company. If you look at sepsis and trauma it's about 650,000 patients annually; pancreatitis afflicts fewer than 50,000 per year. It's the best way for us to focus our resources."

ICOS reported this news on Thursday after the markets had closed for the long Easter weekend. The company's stock (NASDAQ:ICOS) closed on Thursday at $30.062.

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