Xigris, also known by its generic name drotrecogin alfa, was a medication once used to treat severe sepsis. This drug had a unique trajectory, initially receiving approval from regulatory bodies for its potential to reduce mortality in high-risk patients. However, its journey concluded with a voluntary withdrawal from the global market years later, stemming from subsequent studies that questioned its effectiveness and highlighted safety concerns.
Understanding Sepsis
Sepsis is a grave condition arising from the body’s overwhelming and life-threatening response to an infection. It occurs when the immune system, designed to fight off invaders, instead turns on the body’s own tissues and organs. This uncontrolled response can lead to widespread inflammation and damage throughout the body.
The condition can begin with any type of infection, such as pneumonia or a urinary tract infection, and rapidly progress. As sepsis intensifies, it can cause organs like the kidneys, liver, and lungs to malfunction. Symptoms can include changes in mental status, rapid breathing, a fast heartbeat, and extremely low blood pressure, which, if severe, can lead to septic shock. Septic shock is a particularly dangerous stage where blood pressure drops to dangerously low levels, preventing oxygen from reaching the body’s organs and significantly increasing the risk of death.
Xigris and Its Initial Promise
Xigris (drotrecogin alfa) was a manufactured version of human activated protein C, a naturally occurring substance. It was believed to have a triple action: acting as an anticoagulant to prevent excessive blood clotting, possessing anti-inflammatory properties to reduce the body’s harmful inflammatory response, and profibrinolytic properties to help break down existing clots.
The U.S. Food and Drug Administration (FDA) initially approved Xigris in November 2001, based on the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial. This large, multi-center study involved 1,690 patients with severe sepsis. The PROWESS trial indicated a 6.1% absolute reduction in 28-day mortality in the Xigris-treated group compared to placebo, leading to initial optimism about its potential to improve outcomes for high-risk patients.
Reasons for Withdrawal
Despite the initial positive findings from the PROWESS study, subsequent clinical trials raised questions about the broader efficacy and safety of Xigris. The ADDRESS (Administration of Drotrecogin Alfa [Activated] in Early Septic Shock) study, designed for patients with severe sepsis but a lower risk of death, was terminated early and did not show a significant difference in mortality between the Xigris and placebo groups. Similarly, the RESOLVE (Researching Severe Sepsis and Organ Failure in Children) study, conducted in children, also failed to demonstrate a benefit in mortality and showed a numerically higher rate of central nervous system bleeding in the Xigris group.
The pivotal study that ultimately led to the drug’s withdrawal was PROWESS-SHOCK (Recombinant Human Activated Protein C Worldwide Evaluation in Septic Shock). This study, initiated in March 2008, aimed to confirm the benefit-risk profile of Xigris in patients with septic shock. However, the PROWESS-SHOCK study did not meet its primary goal of a statistically significant reduction in 28-day all-cause mortality in patients treated with Xigris compared to placebo. The 28-day mortality rates were similar, with 26.4% in the Xigris arm versus 24.2% in the placebo arm, a difference that was not statistically significant.
Beyond the lack of demonstrated benefit, ongoing concerns about the drug’s safety profile, particularly the increased risk of serious bleeding complications, also contributed to the decision to withdraw it. In the PROWESS study, serious bleeding events were observed in 3.5% of Xigris-treated patients compared to 2.0% in the placebo group. The incidence of intracranial hemorrhage, a severe type of bleeding, was also a concern. Consequently, Eli Lilly and Company voluntarily withdrew Xigris from the global market on October 25, 2011, citing the lack of demonstrated patient survival benefit and continued safety concerns.
Important Considerations
Due to the heightened risk of bleeding, Xigris was not suitable for all patients with severe sepsis. Contraindications included:
Active internal bleeding
A recent hemorrhagic stroke (within 3 months)
Recent intracranial or intraspinal surgery or severe head trauma (within 2 months)
Trauma with an increased risk of life-threatening bleeding
The presence of an epidural catheter
An intracranial neoplasm or mass lesion
Children under 18 years of age
The experience with Xigris underscored the complexities of developing treatments for conditions like sepsis, which involve intricate biological responses. It highlighted the importance of rigorous and well-designed clinical trials to thoroughly evaluate both the effectiveness and safety of new medications, even after initial promising results. The withdrawal of Xigris served as a significant lesson in pharmaceutical development and the ongoing need for robust scientific evidence.