The pharmaceutical agent drotrecogin alfa activated, marketed under the trade name Xigris, represents a significant historical chapter in the search for a targeted treatment for severe sepsis. Sepsis is a life-threatening condition defined as the body’s overwhelming and dysfunctional response to an infection, which can rapidly lead to acute organ damage and failure. The drug was the first biologic therapy approved for this devastating syndrome, but it is no longer available, having been voluntarily withdrawn from the global market by its manufacturer, Eli Lilly and Company, in 2011. This decision followed the publication of definitive clinical trial data that failed to confirm the drug’s effectiveness in improving patient survival.
Treating Severe Sepsis
The development of Xigris addressed the urgent medical need for effective interventions, as severe sepsis carried an extremely high mortality rate. Sepsis creates a complex, systemic reaction involving inflammation and a pro-coagulant environment, leading to widespread microvascular clotting and subsequent organ dysfunction. Patients with severe sepsis, characterized by infection accompanied by acute organ failure or hypotension, were the intended population for this drug. Xigris offered hope that a targeted biological intervention could interrupt the pathological cascade driving organ failure, supplementing the standard care of antibiotics and supportive measures.
Mechanism of Action
Xigris was a recombinant form of human Activated Protein C (APC), a natural serine protease involved in regulating blood clotting and inflammation within the body. When activated, APC functions as a potent anticoagulant by inhibiting key clotting factors, specifically Factor Va and Factor VIIIa. In addition to its anticoagulant properties, APC exhibits anti-inflammatory effects by blocking the adhesion of white blood cells to the inner lining of blood vessels and limiting the production of pro-inflammatory signaling molecules. APC also possesses profibrinolytic activity, promoting the breakdown of fibrin clots by inhibiting Plasminogen Activator Inhibitor-1 (PAI-1). Xigris was intended to supplement the body’s naturally depleted APC levels during sepsis, restoring balance to the dysregulated coagulation and inflammatory pathways.
Clinical Trials, Approval, and Controversy
The drug’s regulatory journey began with the PROWESS trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis). This Phase III, randomized, placebo-controlled trial involved over 1,690 patients with severe sepsis and a high risk of death. The trial was halted prematurely in 2001 after an interim analysis indicated a significant benefit, showing a 28-day all-cause mortality rate of 24.7% in the Xigris group compared to 30.8% in the placebo group.
Based on these results, Xigris received accelerated approval from the U.S. Food and Drug Administration (FDA) in late 2001 and was authorized in the European Union (EU) the following year. However, the initial approval was met with controversy due to concerns about the trial’s early termination and a change in the manufacturing process that occurred mid-study. Regulators also noted a narrow therapeutic window and a significant safety risk, as the drug’s anticoagulant effects increased the incidence of serious bleeding events (3.5% in the Xigris group compared to 2% of the placebo group).
Due to the lingering safety concerns and the narrow therapeutic benefit, the European Medicines Agency (EMA) requested a confirmatory trial in 2007. Eli Lilly initiated the PROWESS-SHOCK trial, a large, randomized study designed to confirm the benefit-risk profile of the drug specifically in patients with septic shock. This confirmatory trial was a regulatory condition for continued market authorization in Europe.
Market Withdrawal and Legacy
The fate of Xigris was sealed by the definitive results of the PROWESS-SHOCK trial, which failed to meet its primary endpoint of reducing 28-day all-cause mortality. The study, which included over 1,600 patients, showed no survival advantage for the Xigris group, with a mortality rate of 26.4% compared to 24.2% in the placebo group. The lack of efficacy, combined with the known risk of bleeding, led to a worldwide voluntary market withdrawal of Xigris on October 25, 2011.
The failure of the confirmatory trial highlighted a significant shift in critical care medicine that had occurred in the decade since Xigris’s initial approval. Aggressive early resuscitation strategies, including timely antibiotic administration and fluid management, had become the standard of care, significantly lowering the background mortality rate of sepsis patients. This improvement in supportive care likely reduced the therapeutic window for Xigris, masking any modest benefit that may have been present in the sicker patient populations of the earlier trial. The saga of Xigris serves as a lasting lesson in drug development for complex critical illnesses, underscoring the necessity for robust clinical evidence.