By: Khilna Patel, Pharm.D. Candidate c/o 2012
On October 25 of this year, Eli Lilly and Company announced a worldwide market withdrawal of Xigris (drotrecogin alfa), a drug previously indicated to treat severe sepsis in high-risk patients. Drotrecogin alfa is a recombinant form of human activated protein C. The efficacy of drotrecogin alfa was questionable, ever since its FDA approval from almost 10 years ago, in November 2001.
In 2001, the initial efficacy results reported by the PROtein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial were not reproducible. The PROWESS trial was a large, randomized, multi-center, double blind, placebo-controlled trial that aimed to assess whether treatment with drotrecogin alfa reduced the rate of death from any cause among patients with severe sepsis.
Exactly 1,690 randomized patients split into the placebo group (840 people) and the activated drotrecogin alfa experimental group (850 people). Patients reasonably matched with an average APACHE II score of 25, and had clinical evidence of sepsis and organ dysfunction within 24 hours of randomization. Exclusion criteria included an age less than 18, platelet counts less than 30,000/mm3, a known hypercoagulable states, a moribund state, HIV infection, a history of organ transplantation, chronic renal failure requiring dialysis, severe chronic liver disease, acute pancreatitis, or in need of full dose anticoagulation. Patients received an intravenous infusion of either placebo or 24 μg/kg of activated drotrecogin alfa per hour for a total duration of 96 hours. The primary endpoint was death from any cause, assessed 28 days after the start of the infusion.
The results of this trial showed that the 28-day all-cause mortality was 30.8% for placebo vs.24.7% for patients treated with drotrecogin alfa, thus showing a 6.1% absolute reduction in risk of death (p = 0.005). The FDA approved the drug despite the advisory committee’s split vote (10 to 10), due to concerns about the validity of the claimed efficacy and safety findings based on a single trial. As a result, the FDA requested two additional trials: a trial in pediatric severe sepsis patients (RESOLVE trial: REsearching severe Sepsis and Organ dysfunction in children) and a trial in adults with less severe sepsis (ADDRESS trial: Administration of Drotrecogin alfa in early stage Severe Sepsis).
In 2002, the European Medicines Evaluation Agency (EMEA) approved the use of drotrecogin alfa for patients with severe sepsis and multi-organ failure. The EMEA later requested that the manufacturer conduct an additional multi-center, placebo-controlled, phase III trial (PROWESS-SHOCK) in severe sepsis patients at high risk of death. This study reported a 28-day all-cause mortality rate of 26.4% in patients treated with drotrecogin alfa compared with 24.2% in the placebo group, which was not considered to be statistically or clinically significant (RR 1.09 [0.92, 1.28]).
Since the PROWESS-SHOCK trial found no significant reduction in mortality in patients treated with Xigris compared with placebo, Eli Lilly decided to take action. The company discontinued all other ongoing clinical trials, and announced a voluntary withdrawal of Xigris from the market. Patients should not receive Xigris, and all remaining Xigris products should be returned to wholesalers / drug suppliers.