Preparing to tackle one of the more difficult diseases to treat, Eisai Co. Ltd. plans to move its drug eritoran (E5564) into a Phase III severe sepsis trial.

The decision was made based on positive Phase II results that showed a reduction in mortality in eritoran-treated patients vs. placebo. Tokyo-based Eisai now is talking about the Phase III program with regulatory authorities in the U.S., Canada and the European Union. A pivotal trial could start in early 2006.

The Phase II trial involved 293 patients in North America who were randomized to one of three groups: the eritoran high-dose group (105 mg/six days), the eritoran low-dose group (45 mg/six days) and placebo. Patients received eritoran twice daily intravenously to see if the drug could reduce the 28-day all-cause mortality by at least 5 percent compared to placebo.

It did. While the study was not sized to find statistical significance, it showed a 6.4 percent reduction (p=0.34) in mortality in the high-dose group compared to placebo. Mortality was 33.3 percent in placebo, 32 percent in the low-dose group and 26.9 percent in the high-dose group.

"This is pretty gratifying," said Melvin Lynn, senior director and head of the sepsis and anti-infective therapeutics area at Eisai Medical Research Inc., of Ridgefield Park, N.J. "These studies take a long time to do. It's difficult to enroll patients."

Most of the Phase II patients - 80 percent in all - followed the protocol. The mortality rate in those patients was reduced by 12.2 percent (p=0.09) in the high-dose group compared to placebo. The mortality was 34.6 percent in placebo, 32.5 percent in the low-dose group and 22.4 percent in the high-dose group.

The results got even better when Eisai broke out the population of patients who had the highest risk of mortality. Among those patients, mortality in the placebo group was 50.9 percent, compared with 37.9 percent in the low-dose group (a 13 percent reduction; p=0.17), and 33.3 percent in the high-dose group (a 17.6 percent reduction; p=0.07).

Eritoran appeared to be well tolerated, but phlebitis was seen in 6.7 percent of patients dosed with the drug through a peripheral vein.

Severe sepsis is characterized by infection and an inflammation that leads to life-threatening organ failure.

"When people who have other serious diseases develop these infections, their bodies over-respond to it for some reason," Lynn told BioWorld Today. "You have an overproduction of cytokines and that is why the organ begins to fail."

The disease is the leading cause of death in hospital intensive care units. Up to half of those who get it die from it. About 750,000 people in the U.S. develop the disease each year.

Severe sepsis can result in a rapid decrease in blood pressure to cause septic shock, it can affect respiratory function to cause acute lung injury, and it can affect the kidneys and other organs, as well.

Indianapolis-based Eli Lilly and Co. has the only marketed severe sepsis product - Xigris - which was approved in 2001 and had sales of $57.7 million worldwide in the second quarter.

"Up until the time that Xigris was approved in 2001, there was really nothing out there that was specifically approved for severe sepsis," Lynn said.

Before Xigris, patients received antibiotics for their infection, and supportive care, such as a mechanical ventilator for respiratory problems, or acute dialysis following kidney shut-down.

A number of biotech companies have tried to develop drugs for severe sepsis, but their products failed in Phase II and Phase III studies. Those who have worked in the space, unsuccessfully, include Centocor Inc., of Malvern, Pa.; Immunex Corp., of Seattle; XOMA Corp., of Berkeley, Calif.; and ICOS Corp., of Bothel, Wash., to name a few. ICOS dropped development in December 2002 of Pafase after the drug did not reduce 28-day all-cause mortality. A year before that, Emeryville, Calif.-based Chiron Corp.'s drug Tifacogin failed to show significance in the same endpoint. Since then, very few biotech companies have tried to develop anything for sepsis, and only one other company besides Eisai has announced a Phase III program for the indication.

Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, announced in July its plans to start a pivotal Phase III trial this month of TAK-242 to treat severe sepsis. The Phase III trial of Eisai's product is slated to begin in the first quarter of 2006.

Similar to eritoran, TAK-242 suppresses production of inflammatory mediators by inhibiting the signal transduction through Toll-like receptor 4. TLR4 is linked to the immune system and is thought to play a role in the course of severe sepsis. It can be activated by endotoxin and can trigger the inflammatory cascade. Eritoran is believed to block endotoxin's activation of TLR4. In a Phase I study, the product blocked the signs and symptoms - fever and rapid heart rate - and the production of inflammatory cytokines induced by endotoxin infusion.

In addition to conducting seven Phase I studies, and enrolling more patients than is typical for a Phase II study, Eisai worked hard to get a positive outcome that would lead eritoran to a Phase III program. It limited enrollment in the Phase II, for instance, to those who could be treated within 12 hours of a severe sepsis diagnosis, giving eritoran the highest probability of success.

"We tried to listen pretty carefully to people who had done other sepsis studies," Lynn said. "We like to think that we managed to design a study that was more state-of-the-art."

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