Xigris: The drug that cured sepsis… but then actually didn’t

This anti-inflammatory, pro-fibrinolytic, anti-thrombotic agent is actually an activated Protein C. In the 1990s, experimental use in animal models of sepsis showed enough promise to prompt its trial in humans. To state the obvious, any major breakthrough in the care of septic patients should receive a warm welcome from the emergency medicine and critical care communities. We see enormous numbers of patients with sepsis. It can be either deadly or completely cured, largely depending on the care we provide.

Accordingly, Eli Lilly & Co. funded the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) trial¹ that enrolled 1,690 patients. The results of this Phase 3 RCT were exciting: the group that received Xigris had a RRR of 19.4% and a NNT of 16 to prevent one death by 28 days. It was published in the New England Journal of Medicine and became the foundation for the FDA approval of Xigris in 2001. The FDA advisory panel were tasked with reviewing the evidence behind this drug’s efficacy and risk, especially given it had a known interaction with the coagulation cascade. The members’ votes were split (ten to ten) whether to approve the drug. In subsequent weeks, the FDA did approve Xigris for use in severe sepsis under the condition there would be further research in areas including patients with an APACHE II score <25 and pediatric patients.

A treatment for sepsis! This seemed like a miracle to many scientists, doctors, and patients. It was perhaps most exciting for Eli Lilly & Co. who had just watched one of its most lucrative drugs, fluoxetine, lose its patent and undergo production as a generic (this change cost about 22% of Eli Lilly & Co’s first quarter profits^[1]). In 2002, Eli Lilly hired a public relations firm, Belsito & Co., to help market Xigris, which costs around $8,000 per patient.

Belsito & Co. employed some interesting techniques in their public relations strategy beyond the usual swag and ads in “medical trade media.” While retaining Belsito & Co, Eli Lilly also funded (with $1.8 million) the Values, Ethics, & Rationing in Critical Care (VERICC) Task Force in 2003. This group was made up of largely academic professionals from institutions including Harvard Medical School, Johns Hopkins School of Medicine, the National Institutes of Health, the People’s Medical Society, the University of California San Francisco, the University of Pittsburgh, and Brown Medical School/Rhode Island Hospital. In publications and panels, the task force opined that there was now an ethical dilemma in critical care: providers were forced to ration costly resources like Xigris. This must have attracted a lot of attention to Xigris and its real value, I would think.

The other impressive technique that Belsito used was to facilitate Xigris’ acceptance into mainstream treatment recommendations. Eli Lilly & Co. funded 90% of a meeting of Surviving Sepsis Campaign. The resultant 2004 guidelines^[2] endorsed the use of activated protein C in adults with severe sepsis, assigning a Grade B quality of evidence rating (modified Delphi rating system with A being the strongest rating). As a comparison, the same guidelines² assigned lower grades to the administration of intravenous fluid therapy (Grade C) and intravenous antibiotics within an hour of septic shock recognition (Grade E). Eli Lilly & Co. also decided it would not reduce the price of Xigris because of the expensive research and development and the drug’s impact on patient care. Following this endorsement of the drug, Xigris became bundled into many hospitals standard care for severe sepsis. In fact, in 2002, the Centers for Medicare & Medicaid Services (CMS) granted Xigris new technology status, deserving of a special reimbursement for its appropriate use.^[3]

Bear Sterns, Lehman Brothers, and Salomon, Smith & Barney projected Xigris’ annual sales to be upwards of $400 million. Other financial institutions estimated near $1 billion. After 2004, however, revenue was not as robust as anticipated. I suspect this is at least in part because doctors are not quite that gullible. In the Wall Street Journal, September 2003, journalist Antonio Regalado called attention to Eli Lilly & Co and Belsito & Co.’s practices. In 2006, three NIH physicians, Drs. Eichacker, Natanson, and Denner, published an editorial^[4] in the New England Journal of Medicine further unveiling both the public relations techniques of Eli Lilly & Co. and major flaws in the PROWESS study. They and other critics underscored flaws in the study including the reliance on a subgroup analysis, inappropriate use of the APACHE II score, and lack of standardization in ventilation management, vasopressor use, and selection of antibiotics. The PROWESS study also changed the eligibility and exclusion criteria after the first 12 months of data collection. Perhaps, most obviously, was that this was a single study and had not yet been validated or reproduced.

By 2005, the ADDRESS trial^[5] was published, dampening the evidence base in support of Xigris. In 2012, PROWESS SHOCK^[6] was published and compelled Eli Lilly & Co. to remove the drug from the market with FDA encouragement. While never accomplishing the projected $400 million in sales, Xigris continued to make money throughout its life on the market.

So what should we learn about the story of Xigris and its 10 years on the market? In the end, it could have been worse. I think sales were flat because physicians did not take the bait quite as readily as Eli Lilly & Co and Belsito & Co had hoped. I think physicians recognized that a single study does not constitute a sufficient evidence base. The recommendation of a treatment through the Surviving Sepsis Campaign and promotion of some higher CMS reimbursements are not sufficient to change standard of care.

While I think the FDA, a large pharmaceutical company, and a public relations firm failed us, emergency and critical care physicians on the whole did not. We were not duped. So for us young doctors, we should continue to learn about the exciting new therapies but never stop recognizing conflicts of interest or questioning why we do things, old or new.