BioWorld Today Contributing Writer

The failure of Eisai Inc.'s eritoran (E5564) to meet its primary Phase III endpoint of reducing 28-day all-cause mortality in patients with severe sepsis may have relegated yet another candidate to the graveyard of failures for this indication.

Based on preliminary findings from its ACCESS (A Controlled Comparison of Eritoran and Placebo in Patients with Severe Sepsis) trial, the Woodcliff Lake, N.J.-based firm indicated it will not submit applications to regulatory agencies in the U.S., European Union and Japan by the end of its fiscal year on March 31 as previously planned.

Although the company reiterated its commitment to address areas of unmet medical need, including sepsis, the future for eritoran appeared cloudy.

"These are preliminary findings, so we'll continue to evaluate the data from the ACCESS trial," company spokeswoman Judee Shuler told BioWorld Today, "but it's really too early to talk about future development plans for eritoran, and that includes timelines."

Eritoran is a Toll-like receptor 4 antagonist that had been well tolerated in Eisai's Phase II trial, which involved 293 patients in North America who were randomized to one of three groups: an eritoran high-dose group (105 mg/six days), an eritoran low-dose group (45 mg/six days) and placebo.

Although not sized to statistical significance, the Phase II trial showed a 6.4 percent reduction (p = 0.34) in mortality in the high-dose group compared to placebo.

At the time, Melvin Lynn, the company's senior director and head of the sepsis and anti-infective therapeutics area at Eisai Medical Research Inc., of Ridgefield Park, N.J., called the results "gratifying," adding that Eisai had worked hard to "design a study that was more state of the art." (See BioWorld Today, Aug. 30, 2005.)

The Phase III ACCESS study was a global, randomized, double-blind, placebo-controlled trial designed to evaluate eritoran's efficacy and safety in treating severe sepsis. The population studied had a moderate-to-high risk of mortality as determined by baseline APACHE II severity-of-illness scores ranging from 21 to 37.

In March 2010, Eisai Europe Ltd., of London, reported that it was continuing to enroll a planned 2,000 patients in ACCESS following an independent data monitoring committee's evaluation of the first 1,500 subjects to complete the 28-day follow-up.

Should Eisai decide to abandon eritoran, it would by no means be the first to succumb to sepsis – an indication that has been notoriously difficult to defeat.

Other biotech companies that have tried to advance investigational compounds – and failed during Phase II or Phase III studies – include Centocor Inc., now Centocor Ortho Biotech, of Horsham, Pa.; Immunex Corp., of Seattle, which later was acquired by Amgen Inc.; XOMA Ltd., of Berkeley, Calif.; and ICOS Corp., which subsequently was acquired by development partner Eli Lilly and Co.

Certainly, the need for effective sepsis treatment is compelling. Each year, severe sepsis causes approximately 215,000 deaths in the U.S. – as many as heart attacks, and nearly as many as lung, colorectal and breast cancers combined – with a mortality rate of approximately 30 percent, according to Eisai's data.

The incidence of severe sepsis in the European Union has been estimated at 90.4 cases per 100,000 population, with a mortality of 36 percent. The incidence of severe sepsis in Japan is estimated at more than 380,000 cases per year. Worldwide, sepsis affects 18 million people a year.

If Eisai decides to push forward with eritoran, it will still have company in the sepsis space. The recent merger between BTG plc, of London, and Biocompatibles plc came with a significant partnership with London-based AstraZeneca plc for AZD9773 (CytoFab), an anti-TNF-alpha polyclonal antibody fragment for treating sepsis.

Last fall, AstraZeneca began dosing patients in a global Phase IIb study to compare the efficacy and safety of AZD9773 with placebo in adult patients with severe sepsis and/or septic shock. (See BioWorld Today, Nov. 22, 2010.)

Planegg, Germany-based Agennix AG also is preparing for a Phase III trial of its lead compound, talactoferrin, in sepsis. In a Phase II trial, the recombinant version of lactoferrin – an iron-binding glucoprotein found in human breast milk – nearly halved the sepsis mortality rate at 28 days, compared to placebo. (See BioWorld Today, Oct. 4, 2010.)

In addition, LPath Inc., of San Diego, has discovery stage programs targeting bioactive lipids for sepsis and other indications. (See BioWorld Today, Dec. 21, 2010.)

Atox Bio, Inc., of Rehovot, Israel, is studying AB103, an immunomodulator, for the treatment of sepsis, and Spectral Diagnostics Inc., of Toronto, is seeking to advance its sepsis drug toraymyxin into trials.

Meanwhile, Artisan Pharma Inc., of Waltham, Mass., has a Phase IIb study of ART-123 (Recomodulin, recombinant human thrombomodulin) under way in sepsis patients with disseminated intravascular coagulation.

Eisai Inc., is the U.S. pharmaceutical arm of Tokyo-based Eisai Co. Ltd.