As described in our recently featured report, the anti-infectives market is poised to experience considerable growth in the next few years, with a forecast market value that is expected to double in size to more than $44 billion by 2010. One major problem related to infectious diseases is that of sepsis.

Sepsis represents a particularly troubling problem accounting for high levels of mortality. This condition occurs in 1-2% of hospital admissions and is secondary to the appearance of bacterial toxins in the circulation. Sepsis is caused by a number of LPS producing gram-negative organisms including E. coli, or meningococci and by gram-positive pathogens such as staphylococci and streptococci. The frequent progression of sepsis to septic shock results in hypotension and inadequate tissue perfusion. Septic shock carries a 45% risk of mortality making it the most common cause of death in intensive care units. Consequently over 30 pharmaceutical products are in development for this condition although few have reached the market yet. Many of these target specific inflammatory mediators and have thus been, in general, unsuccessful since the process of sepsis involves multiple mediators. More successful strategies include the targeting of the end stage of sepsis, altered coagulation, and Eli Lilly's Xigris, which is effective in this respect, has the potential to become a blockbuster product. Alternatively therapies that prevent the binding of LPS to host cells Toll receptors are also of benefit. These therapies can include LPS neutralizing agents or Toll receptor antagonists.

Eisai’s E5564 is an example of a Toll receptor antagonist. This molecule is a second-generation synthetic lipodisaccharide that dose dependently inhibited LPS-mediated activation of primary cultures of human myeloid cells and mouse tissue culture macrophage cell lines as well as human or animal whole blood as measured by production of tumor necrosis factor-alpha and other cytokines. E5564 also blocked the ability of Gram negative bacteria to stimulate human cytokine production in whole blood. E5564 blocked induction of LPS-induced cytokines and LPS or bacterial-induced lethality in primed mice. E5564 was devoid of agonistic activity In a mouse macrophage cell line, activity of E5564 was independent of serum, suggesting that E5564 exerts its activity through the cell surface receptor(s) for LPS, without the need for serum LPS transfer proteins. Phase I data was reported in February, 2003. E-5564 dose-dependently reduced elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6) in human volunteers injected with LPS. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia. These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis. Consequently E5564 has now entered phase II evaluation.

Entry date March, 2003

Adapted from Lynn et al, J Infect Dis 2003 Feb 15;187(4):631-9.

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