They said it couldn’t be done.
Despite decades of research, scientists had been unable to find a treatment for severe sepsis, a life-threatening complication of bacterial infection, usually of the bloodstream, that kills at least 250,000 adults in the United States each year. During the previous 25 years, more than 30 compounds had been tested to treat severe sepsis. All of them had failed.
“Researchers were getting discouraged. They were saying that this disease is too severe and too complex,” says Gordon R. Bernard, M.D., an internationally known sepsis researcher and assistant vice chancellor for Research at Vanderbilt University Medical Center.
Frustrated, some scientists argued that the U.S. Food and Drug Administration had set impossibly high standards for treating near-death patients in the intensive care unit. The FDA deemed an ICU drug efficacious only if the patient was still alive after 28 days. Despite the criticism, the agency stuck to its “28-day, all-cause mortality endpoint” required for approval.
Then in 1994, Bernard received a phone call from investigators at Eli Lilly & Co. in Indianapolis. They had patented a recombinant human activated protein C (APC) as a potential heart drug, but had decided not to pursue if for that use.
APC has anti-coagulant and anti-inflammatory properties. It can become depleted during an infection and as a result, clots can form indiscriminately throughout the body, cutting off the blood supply to vital organs. In this way, the initial infection can set off a chain of reactions, leading to multi-organ system failure and death.
Searching for another use for their compound, Lilly scientists noticed that in previous studies in baboons, APC had shown some efficacy in severe sepsis. They asked Bernard, chief of the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt, to design a small study of about 100 to 150 people to see if their protein could produce effects in severe sepsis in humans sufficient to warrant further investigation.
After treating 131 patients, Bernard reported back to Lilly in 1996 that their compound, later named Xigris, may have saved the lives of some critically ill patients. Also, it clearly replenished the body’s supply of protein C that had been sapped by infection and improved the coagulopathy, or coagulation disorders, caused by sepsis.
Lilly opted to continue development. Bernard was appointed principal investigator of a large-scale multi-centered, international, Phase III trial, known as PROWESS. The trial tested Xigris against a placebo in 1,690 patients worldwide who were in imminent danger of dying from severe sepsis.
Beginning in 1998, Bernard’s team of investigators fielded calls from critical care physicians in 160 centers around the globe to determine, in split-second decisions, if a patient could be included in the trial. To qualify, all of the patients had to be dying of sepsis and not from a primary disease such as cancer or heart disease.
Within two years, it became apparent that Xigris was having a significant impact on survival: among the sickest patients the mortality rate for those who took the drug was 13 percent lower than the rate among those on placebo. An independent board of advisors stopped the PROWESS trial in 2000, because it was no longer ethical to give the placebo.
“It was a huge day,” says William Macias, M.D., Ph.D., medical director of the Xigris Product Team at Lilly. “First there was a brief moment of disbelief. We knew it was a long shot for the overall trial to be successful, but to stop early was even bigger. This was a once-in-a-lifetime experience.”
The PROWESS team had met what had been considered an unattainable benchmark—for every eight patients treated with Xigris, one life was saved. “There are very few drugs for which such a sweeping statement can be made,” says Bernard.
“The company realized the risk of creating and testing biological products,” Macias says. “You have to invest very heavily before you ever know if you have a drug that will be worth the investment.”
Vanderbilt’s involvement was crucial, adds Mark Williams, M.D., medical director for Xigris. “One of the main reasons that PROWESS was successful was because Vanderbilt served as the coordinating center… a triage center under very difficult circumstances,” he says.
Williams estimates that more than 7,500 lives have been saved since 2001, when the FDA approved Xigris. With increasing use, as many as 40,000 lives could be saved each year, he says. Because it can cause bleeding, however, not all severe sepsis patients are candidates for the drug.
“The mortality rate (from severe sepsis) is still too high,” says Bernard. “But to make inroads into something this horrific is wonderful. It says we need to keep plugging away at scientific intervention and drug development.”
Which is exactly what is happening. Williams is currently running a large clinical trial in 110 sites around the world, testing the efficacy of Xigris in critically ill children. He also is examining the drug’s effectiveness in certain cancer patients, with the cautious expectation that treating severe sepsis in this patient cohort may lead to a drop in the overall cancer mortality rate.
The success of Xigris, says Williams, demonstrates how a partnership between university scientists, industry and the FDA can bring a life-saving product to fruition. “Each party has different expertise and strengths,” he says, “and when they work together for the common good, we all see the benefit.”