Once in a lifetime
Finding a way to short-circuit sepsis
They said it couldn’t be done.
“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.
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