Eisai Announces Successful Results in a Phase II Study of E5564 (eritoran) for Treatment of Severe Sepsis
Eisai Co., Ltd. (Headquarters: Tokyo, President: Haruo Naito) has announced today that it has observed a reduction in mortality in a recently completed phase II study of E5564 (generic name: eritoran) for treatment of severe sepsis. The study was conducted in North America. Eisai plans to initiate a Phase III clinical program after consulting with regulatory authorities in the U.S. and EU. A fast track designation was granted by the U.S. FDA in July 1999.
The study enrolled 293 patients randomized to three groups, E5564 high dose (105mg/6days), E5564 low dose (45mg/6days) and placebo. The 28-day all-cause mortality in the high dose group was reduced by 6.4% (p=0.34) compared to placebo in the intent-to-treat analysis (mortality was 33.3% in placebo, 32.0% in low dose and 26.9% in high-dose group) and achieved the targeted mortality reduction rate, greater than 5%. The mortality rate in per protocol evaluable patients was reduced by 12.2% (p=0.09§) in high dose group compared to placebo (mortality was 34.6% in placebo, 32.5% in low dose and 22.4% in high dose group). The greatest mortality benefit occurred in the population at the highest risk of mortality as assessed by PROM score. In this subgroup, mortality among placebo patients was 50.9%, 37.9% in low dose patients and 33.3% in high dose patients, and the reduction of mortality in low and high dose patients compared to placebo was 13.0% (p=0.17§) and 17.6% (p=0.07§), respectively. (Note §: p-values are of exploratory nature only, no multiplicity adjustment was made)
This study was not designed to produce a statistically significant difference but to test if E5564 could reduce the 28-day all-cause mortality by greater than or equal to 5 percent compared to placebo. Based on these results, Eisai concluded that the study has achieved the targeted efficacy.
The drug appeared to be well tolerated. Phlebitis, or inflammation of the vein, was observed in 6.7% of patients dosed with E5564 through a peripheral vein. It showed a tendency to recover with time.
Sepsis is a serious condition associated with systemic inflammatory response syndrome (SIRS). In severe cases, septic shock, disseminated intravascular coagulation (DIC) and multi-organ failure lead to high mortality. TLR4 plays an important role in the course of developing sepsis. It can be activated by endotoxin, which is associated with the outer membranes of certain gram-negative bacteria, and can then trigger the inflammatory cascade.
E5564 is a totally synthetic Lipid A analog discovered by scientists at the Eisai Research Institute of Boston, Inc. E5564 blocks binding of endotoxin to TLR4. E5564 was designed as a specific TLR4 antagonist aimed to exhibit a selective therapeutic effect. In a Phase I study conducted in the U.S., E5564 was demonstrated to potently block clinical symptoms (fever and tachycardia); and the production of inflammatory cytokines induced by endotoxin infusion in healthy volunteers.
Eisai strives to discover new treatments of various diseases that involve significant unmet medical needs. The success of Phase II study in patients with severe sepsis will take Eisai closer to the treatment of sepsis.