Eritoran, a novel agent that blocks inflammatory reactions to the major endotoxin from gram-negative bacteria, doesn't help save lives in severe sepsis, the ACCESS trial showed.
The 28-day mortality was 28% among patients who got at least a dose of the drug compared with 27% in the placebo group (P=0.59), Steven M. Opal, MD, of Memorial Hospital of Rhode Island in Pawtucket, and colleagues found.
Nor were there any benefits to the investigational infusion for 1-year all-cause mortality or any other endpoint, the researchers reported in the March 20 issue of the Journal of the American Medical Association.
"Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients," they wrote.
The drug is a synthetic lipid A antagonist that blocks lipopolysaccharide on the surface of gram-negative bacteria from binding to cells, which sparks a strong inflammatory response.
The downfall of eritoran might have been that so many other drugs already used for sepsis in the ICU -- including glucocorticoids, statins, catecholamines, macrolides, anesthetics, and proton pump inhibitors -- alter the response to signaling in this same pathway in one way or another, Opal's group noted.
"Other common intermediary steps in the inflammatory cascade may be better targets for intervention," they concluded.
Other reasons may have been lack of statistical power due to the lower than expected mortality rate in the placebo group or giving the drug too late to provide benefit, they suggested.
Whatever the reason, drug developer Eisai announced it wouldn't seek regulatory approval for eritoran in severe sepsis treatment when it released top-line results earlier this year, although the company didn't say whether it would abandon development entirely.
The multinational phase III ACCESS trial included 1,961 patients with severe sepsis randomized within 12 hours of first organ dysfunction to double-blind treatment with a 6-day course of eritoran (105 mg total) or placebo.
The majority of these participants (80%) had septic shock at enrollment; all were at moderate-to-high risk of dying based on baseline APACHE II scores of 21 to 37.
Infection most commonly was in the lungs (in about half of patients) and documented to be from gram-negative bacteria in 35%, gram-positive bacteria in 27%, and a mixed infection in 11%.
Baseline risk scores and supportive care were similar between groups.
After excluding the few patients who didn't get at least one dose of their assigned drug for the primary modified-intent-to-treat analysis, the eritoran group had a 28-day all-cause mortality risk 5% higher than the placebo group, which was not statistically significant.
The key secondary endpoint showed a similar lack of significant impact from eritoran, with a hazard ratio of 0.98 versus placebo for 1-year all-cause mortality (P=0.79).
No advantage emerged in subgroups by septic shock status, type or location of infection, or baseline predicted mortality risk.
Patients with gram-positive bacterial infections or with skin and soft tissue infections actually seemed to do worse with the sepsis drug, although this might have been due to chance from analyzing differences in small subgroups, the researchers cautioned.
But there was an apparent benefit to the drug among patients without elevated endotoxin activity assay levels at baseline (mortality 12% versus 32% with placebo).
Treatment-emergent adverse effects didn't differ between treatment groups.
The study was funded by Eisai, which also provided study medications.
Opal reported receiving grant or research support from Sirtris Pharmaceuticals; consulting for Kenta Biotech, Arsanis, Agennix, and AstraZeneca; and serving on the clinical coordinating center and the clinical evaluation committee in support of this study.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Journal of the American Medical AssociationSource Reference: Opal SM, et al "Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial" JAMA 2013; 309: 1154-1162.