Eritoran, a promising first-in-class agent for combating Gram-negative sepsis, failed its Phase 3 clinical trial, according to the results of the ACCESS trial published in the March 20th issue of JAMA.
Eritoran is synthetic lipid A antagonist that blocks lipopolysaccharide (LPS or endotoxin) from binding the cell surface MD2-TLR4 toll-like receptor. Endotoxins are found on the surface of Gram-negative bacteria and are responsible for triggering the immune response and the overwhelming cytokine storm that occurs in Gram-negative sepsis.
ACCESS was an international, randomized, double-blind, placebo-controlled phase 3 clinical trial sponsored by Eisai, the developer of eritoran. The trial compared eritoran with placebo in 1,961 patients with severe sepsis enrolled at 197 intensive care units, with a primary endpoint of all-cause mortality at 28 days. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011.
The hope was that by blocking the endotoxin effect on human cells, investigators would be able to arrest the septic response. Eritoran had shown great promise in animal trials and was found to be a potent endotoxin inhibitor in early human trials. However, when administered in patients with established severe sepsis, the drug showed no efficacy vs. placebo (p=0.59, HR=1.05, 95% CI 0.88-12.6).
This disappointing result may be related to rapid cellular tolerance to endotoxin that develops quickly after initial exposure. In effect, human cells reprogram themselves to be less susceptible to endotoxin through a protective mechanism designed to prevent cellular death, a process that previous studies have shown can occur in as little as 1 minute. By the time sepsis is detected, this tolerance may have already occurred, making the blocking of endotoxin action not as relevant to stopping the septic response.
Future studies may look at other toll-like receptors (TLRs) that play a role in the triggering of the immune response. There are 10 TLRs in humans, and there is a possibility that blocking the action of endotoxin on other TLR receptors or a combination of these receptors, including TLR4, may show better results in established septic shock.
The complete JAMA article reporting the results of the ACCESS trial may be found here.
More information on ACCESS may be accessed on its ClinicalTrials.gov page available here.
Daniel Nichita, MD
The Escavo Team