General Information

Xigris is a recombinant version of naturally occurring activated protein C. This medication has been approved for the reduction of mortality in adults with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. It is available in 5 and 20mg vials, and it is administered by intravenous infusion.

Eli Lilly voluntarily removed Xigris from all markets in 2011 following results from a study in which Xigris failed to show a survival benefit for patients with severe sepsis and septic shock.

Clinical Results

The approval of Xigris was based on results from a double-blind, placebo-controlled phase III trial known as PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis), which included 1,690 subjects from 11 countries. Results showed that Xigris reduced the relative risk of death from sepsis with associated acute organ dysfunction by 19.4%. Xigris was administered as a continuous infusion of 24 micrograms/kilogram/hour for 96 hours. The mortality rates were 24.7% among Xigris-treated subjects versus 30.8% among subjects treated with placebo. The response to Xigris was consistent across almost all subject subgroups in the trial, and Xigris increased the odds of survival by 38.1%.

Eli Lilly voluntary withdrew Xigris from all markets in 2011. This decision was made following results of the PROWESS-SHOCK study, which showed the study did not meet the primary endpoint of a statistically significant reduction in 28-day all-cause mortality in patients with septic shock.

Side Effects

Bleeding is the most common adverse reaction associated with Xigris. In the PROWESS trial, serious bleeding events occurred during the 28-day study period in 3.5% of Xigris-treated subjects and 2.0% of placebo-treated subjects. The incidence of intracranial hemorrhage (ICH) was 0.2% for subjects treated with Xigris and 0.1% for subjects receiving placebo. In non-placebo controlled trials, ICH has been reported in Xigris-treated subjects with an incidence of approximately 1% during infusion. ICH may be more likely to occur in patients with risk factors for bleeding, including severe coagulopathy and severe thrombocytopenia.

Mechanism of Action

Xigris is a recombinant form of human Activated Protein C. Activated Protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that Activated Protein C has indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and limiting generation of activated thrombin-activatable-fibrinolysis-inhibitor. Additionally, in vitro data indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium. (from Xigris Prescribing Information)