Septic shock - E-5564
Septic shock is a common cause of death in intensive care units, where it can develop in response to severe infections, is linked to hypotension, and can lead to multiple organ failure. It remains difficult to treat, and kills as many as half a million people every year. It is thought that the primary mediator in the development of sepsis is lipopolysaccharide, the endotoxin fragment of Gram-negative cell membrane that is released during normal bacterial cell metabolism. It sets off an inflammatory response in the body, and binds to a number of different receptors, stimulating lymphocytes, neutrophils and macrophages into producing tumour necrosis factor alpha and the inflammatory cytokines interleukins 1, 6 and 8. Eisai is now developing the drug E-5564 as a potential treatment for septic shock, which binds to the lipid portion of lipopolysaccharide, and inactivates it.
A randomised Phase I trial has been carried out in 24 healthy male volunteers.1 The subjects were given a single dose of the drug or placebo, with 50, 100 or 250µg given by intravenous infusion over half an hour, and then given a dose of lipopolysaccharide as a bolus injection to induce a mild septic syndrome. All doses were effective at reducing the sepsis, and the higher two doses inhibited the production of TNF-a and IL-6. The active also reduced the incidence of chills, fever, myalgia, tachycardia and headache.
Several further Phase I trials have been reported.2 Healthy volunteers were given continuous infusions of 0.5-3.5mg of E-5564 over 30 mins or 72 hours, or the same amount dosed twice daily. An escalating dose trial showed that a continuous infusion of 252mg of the active over 72 hours was sufficient to stop the effects of lipopolysaccharide completely.
Phase II trials are now under way. The initial results from Phase I trials on E-5564 show that it has great potential as a treatment for this significant problem, for which no effective therapy currently exists.