October 25, 2011 — Eli Lilly is withdrawing activated drotrecogin alfa (Xigris), a drug intended to treat severe sepsis in high-risk patients, from all markets including the United States in the wake of a new study showing that the agent did no better than a placebo in reducing mortality.

The European Medicines Agency (EMA), the European equivalent of the US Food and Drug Administration (FDA), announced today that the manufacturer had informed it of the decision to pull activated drotrecogin alfa from the market worldwide, as well as discontinue all ongoing clinical trials involving the drug.

The EMA stated that physicians should stop ongoing treatment of patients with activated drotrecogin alfa and should no longer start new patients on the agent — a warning repeated by the FDA today.

Activated drotrecogin alfa is a recombinant form of human activated protein C. The drug`s efficacy has been questioned ever since the FDA authorized it for use here almost 10 years ago after a 20 to 20 vote by an agency advisory panel to recommend approval.

In a press release today, the EMA stated that its Committee for Medicinal Products for Human Use had concluded in 2007 that ongoing studies could not reproduce the initial efficacy results reported by a pivotal clinical trial called the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. The committee asked the manufacturer to conduct a new test to confirm that "the benefits of Xigris outweigh its risks to patients with septic shock."

The new study, called PROWESS-SHOCK, reported a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study, according to the EMA, which did not deem the difference statistically significant. The risk for severe bleeding events, the main risk of the drug, was 1.2% and 1.0% for the activated drotrecogin alfa and placebo groups, respectively, "suggesting there is no increased harm." In contrast, a study published in 2009 had reported an increased risk for serious bleeding events and death in patients with sepsis who were treated with the drug.

More information about the withdrawal of activated drotrecogin alfa is available on the Web sites of the EMA and FDA.

To report adverse events related to activated drotrecogin alfa, contact MedWatch, the FDA`s safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.