LONDON, December 21 /PRNewswire/ -- The investigational compound, eritoran tetrasodium (eritoran, also known as E5564) appeared to be well tolerated in patients with severe sepsis in a Phase II trial published in the January issue of Critical Care Medicine, the official journal of the Society of Critical Care Medicine, the largest multiprofessional organization dedicated to ensuring excellence and consistency in the practice of critical care.
The trial evaluated two doses of eritoran, low-dose (45mg given every 12 hours for six days) and high-dose (105mg given every 12 hours for six days), along with a placebo group. Additionally, the trial, although not powered for statistical significance, evaluated the efficacy (reduction in 28-day all-cause mortality) of eritoran versus placebo.
Currently, limited treatment options exist for severe sepsis. In this Phase II study, eritoran was well tolerated, and the adverse events were not surprising, given the significant co-morbidities commonly seen in patients with severe sepsis, said lead investigator Mark Tidswell, MD, Director, ICU Research, Baystate Medical Center, Adult Critical Care Division, in Springfield, Massachusetts. Although this Phase II trial was not sized to demonstrate a reduction in mortality and the observed 26.6% mortality rate for high-dose eritoran versus 33.3% for placebo (p=0.34) was not statistically significant, the data warrant further investigation of eritoran.
About the Phase II Trial
This trial of eritoran tetrasodium (E5564) was a Phase II, randomized, double-blind, placebo-controlled, multi-center, ascending-dose trial evaluating the safety and efficacy of eritoran in patients with severe sepsis. The trial, conducted in intensive care units (ICUs) in the United States and Canada, involved 300 patients randomized to three groups: 96 received placebo, 103 received eritoran low-dose (45mg given every 12 hours for six days) and 94 patients received eritoran high-dose (105mg given every 12 hours for six days). Seven patients did not receive any trial drug and were not included in the modified intent to treat population for analysis. Eritoran or placebo doses were administered via intravenous infusion within 12 hours of recognition of severe sepsis and repeated every 12 hours for six days.
In this Phase II trial, eritoran was well tolerated, and the following adverse events were found:
Anemia, diarrhea, insomnia, acute renal failure and rash were observed more frequently in the group receiving eritoran compared to the group receiving placebo, although not statistically significant.
Serious adverse events that occurred in greater than 5% of patients(1) in both the eritoran and placebo treated groups included cardiac arrest, multiorgan failure, sepsis, respiratory failure and deep vein thrombosis.
Four patients in the group receiving eritoran experienced a hepatobiliary serious adverse event compared with none in the group receiving placebo. Three of these four subjects had pre-existing liver disease.
A higher incidence of atrial fibrillation seen in the eritoran high-dose group (12.8%) compared to placebo (7.3%) was not statistically significant. Instances were mild or moderate in severity and it was unclear if the increased incidence is related to eritoran administration.
Phlebitis (inflammation of the vein) was observed in 6.7% of patients dosed with eritoran high-dose through a peripheral vein (versus 1.6% through central line); affected subjects recovered. No patient in the group receiving placebo experienced phlebitis.
The occurrence of infectious complications reported as adverse events by trial investigators did not differ notably among the three groups.
The mortality in the placebo, low-dose and high-dose groups was 33.3%, 32% and 26.6% respectively. Although not statistically significant (p=0.34), the difference in mortality between the high-dose group and placebo was 6.7%.
The greatest benefit was observed in the population at the highest risk of mortality as assessed by APACHE II Predicted Risk of Mortality (PROM). In patients who were considered at higher risk of death, mortality among placebo patients was 56.3% versus 33.3% in high-dose patients (p=0.105).
Based on the trial results, Eisai is now conducting a global Phase III clinical trial program, called ACCESS (A Controlled Comparison of Eritoran tetrasodium and Placebo in Patients with Severe Sepsis). The trial will further evaluate eritoran as a potential treatment for severe sepsis, the second most frequent cause of death in intensive care patients in the U.S., surpassed only by cardiovascular events.(2) In the European Union (EU), sepsis is the most common cause of death in the ICU.(3)
The ACCESS trial population will enroll substantially more patients than the Phase II trial and has been sized (n=2,000) to determine the efficacy (reduction in 28-day all-cause mortality) of eritoran and targets a population with severe sepsis that has a moderate-to-high risk of mortality as determined by baseline APACHE II (Acute Physiology and Chronic Health Evaluation II) scores from 21 to 37.(4) APACHE II is a severity of illness scoring system commonly used in sepsis research and ICUs.
About Eritoran, TLR4 and Severe Sepsis
Sepsis is a condition involving infection and inflammation. The body's normal response to an infection is to initiate an immunological chain reaction of inflammation.(5) In severe sepsis, systemic inflammation may be an overreaction leading to injury and failure of one or more organ systems that may become life-threatening.(6) The toll-like receptor 4 (TLR4) is part of the innate immune system and, when it is activated, TLR4 may play an important role in the course of severe sepsis.(7) Discovered and developed by Eisai scientists, eritoran is believed to block activation of TLR4.(8)
More than 750,000 individuals develop severe sepsis in North America each year, with a high mortality risk of 30-35% (depending on population studied).(9) Incidence figures in Japan are believed to be similar to those reported for North America.(10) The incidence of severe sepsis in the European Union has been estimated at 90.4 cases per 100,000 population,(11) with a mortality of 36%. (12)
Eisai's research and development efforts regarding eritoran and severe sepsis exemplify the company's human health care mission, which is to address unmet medical needs and increase benefits to patients and their families.
Eisai is one of the worlds leading research-based pharmaceutical companies, that has defined its corporate mission as giving first thought to patients and their families and to increasing the benefits health care provides, which we call human health care (hhc).
Eisai concentrates its research activities in three key areas
- Integrative Neuroscience, including: Alzheimer's disease, multiple sclerosis, neuropathic pain, epilepsy, depression - Integrative Oncology including: anticancer therapies; tumour regression, tumour suppression, antibodies, etc and supportive cancer therapies; pain relief, nausea - Vascular/Immunological reaction including: acute coronary syndrome, atherothrombotic disease, sepsis, rheumatoid arthritis, psoriasis, Crohn's disease
With operations in the U.S., Asia, Europe and its domestic home market of Japan, we employ more than 11,000 people worldwide.
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(1) Initial Review of Clinical Study E5564-A001-201 Eritoran in Severe Sepsis. Alec E. Wittek, Melvyn Lynn, Richard Kao, Jamila Clauzel, Leonard Oppenheimer, Antonia Lopresti-Solis. August 2, 2005. Page 14. Table 16.
(2) Polderman KH, Girbes ARJ. Drug Intervention trials in sepsis: divergent results. The Lancet. 2004;363:1721-23. Page 1721 (Column 2/Paragraph 1/Lines 1-3).
(3) Guideline on Clinical Investigation of Medicinal Products for the Treatment of Sepsis. European Medicines Agency. London, England. June 1, 2006; Page 3. http://www.emea.europa.eu/pdfs/human/ewp/471303en.pdf.
(4) ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis. Alec Wittek, MD (sponsor). July 11, 2007; Pages 6, 29. http://clinicaltrials.gov/ct2/show/NCT00334828.
(5) Rivers EP, McIntyre L, Morro DC, Rivers KK. Early and Innovative Interventions for Severe Sepsis and Septic Shock: Taking Advantage of a Window of Opportunity. Canadian Medical Association Journal 2005; 173 (9): 1054-65. Page 1055 (Column 1/Paragraph 1/Line 2).
(6) Bone RC, et al. Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis. ACCP/SCCM Consensus Conference. Chest. 1992:101(6):1644-1655. Page 1644 (Column 2/Paragraph 2/Lines 1-4); Page 1646 (Column 1/Paragraph 2/Lines 1-3); Page 1647 (Column 1/Paragraph 4/Line 4).
(7) Mullarkey M et al. Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist. J Pharmacol Exp Ther. 2003;304:1093-1102. Page 1093 (Paragraph 1/Line 1 and 5).
(8) Mullarkey M et al. Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist. J Pharmacol Exp Ther. 2003;304:1093-1102. Page 1100 (Column 2/Paragraph 4/Line 3).
(9) International Sepsis Forum. Promoting a Better Understanding of Sepsis. November 2003. Page 4 (Paragraph 1-2).
(10) DataMonitor: Stakeholder Opinions: Sepsis - Under reaction to an overreaction. March 2006 (reference code DMHC2172). Page 22.
(11) R. Daniels. Incidence, mortality and economic burden of sepsis. National Health Service Web site. http://www.library.nhs.uk/emergency/ViewResource.aspx?resID=269230tabID=290 catID=1870. November 2009. (Page 1/Line 2).
(12) Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine 2006; 34(2):344-53. September 2007. (Table 1).
CONTACT: Cressida Robson, Eisai Europe Ltd., +44 (0)845-676-5318 or +44(0)7739-183323; or Andrew Day, Eisai Europe Ltd., +44 (0)208-600-1400 or+44 (0)7973-411419