Sepsis killing thousands in the absence of drugs to help

Rory, a 12-year-old New Yorker, cut himself when he dove for a basketball at his school gym in late March, according to the New York Times. Two days later, he was vomiting, feverish and had a pain in his leg. A few days later, on April 1, Rory died at NYU-Langone Medical Center of a kind of blood poisoning known as sepsis.

His death, and others, point to a major problem in treating sepsis -- there are currently no drugs approved to fight it. The only drug developed for it, called Xigris, was withdrawn from the market in 2011, when the drug failed rigorous testing required to maintain regulatory approval. The drug's fall from grace highlights just how difficult fighting sepsis is, and leaves doctors wondering whether developing a drug will ever be possible.

Bleak Prognosis, Then Brief Promise

About 750,000 people in the U.S. each year get sepsis, and about 225,000 of them die from it. The condition is an infection of the bloodstream, and it can arise from any number of infectious bugs that attack the body, such as meningitis, pneumonia and infections of the skin or bladder, to name a few. The blood poisoning is caused not by the germs themselves, but by the body's hyper-response to those germs, when it releases a barrage of chemicals that can lead to organ failure.

Those chemicals cause the body to go into shock, and patients have symptoms such as chills, fever, confusion, rapid heartbeat, headache and skin rashes.
The best shot patients have is for doctors to treat them early, ideally giving a patient antibiotics and fluids within the first hour that they show symptoms. Dr. Andre Kalil, an associate professor of medicine at the University of Nebraska Medical Center, said even in the best-case scenario, antibiotics don't always help.
"Unfortunately even with the best antibiotics and supportive care, a third of these patients will die," Kalil said. "We don't have other drugs that actually can act in the body in response to the infection. We just don't."

That wasn't always in the case. In 2001 when the U.S. Food and Drug Administration approved Xigris, made by the pharmaceutical company Eli Lilly, hopes were high that it would keep thousands of patients from dying. The company's initial clinical trials of the drug showed that it reduced the chances of dying by 20 percent in patients at risk of developing sepsis.

But the drug's initial performance was somewhat disappointing. Some patients benefited from the drug, others did not, and doctors had trouble defining which type of patient would benefit the most. The drug was also very expensive, so many hospitals put protocols in place that strictly limited when the drug could be given -- usually when all other methods had failed.

Dr. Jonathan Janes, medical director of acute care for Eli Lilly, said the company was encouraged by studies of the drug in real-life clinical settings, which showed that it kept many patients alive.

"We felt encouraged by those results, they seemed to support that the drug worked," Janes said. "Obviously, you need your clinical trial data, but these results were nice to have."

But questions about the drug's effectiveness and safety began to surface. Patients getting Xigris had a slightly increased risk of bleeding. Increasingly skeptical that the expensive drug was actually effective, European regulators asked Eli Lilly to conduct a second clinical trial. The results were the nail in Xigris' coffin -- the trial showed that the drug was little better than placebo. Based on those results, Eli Lilly voluntarily pulled the drug from the market in October 2011.

"This was the first drug specifically licensed for sepsis, which leaves us essentially with nothing now," said Dr. Greg Martin, director of the medical and coronary intensive care units at Emory University.

Drug's Withdrawal A Premature Decision, Some Say

But a new analysis, published Monday in the journal Lancet Infectious Diseases, throws into question whether or not Xigris should have been withdrawn at all. In it, Nebraska's Kalil analyzed the results of more than two dozen studies of Xigris, most performed in the "real-world" of clinics and hospitals, trying to save patients with sepsis.
The results suggest that Xigris is effective after all. The study found that Xigris reduced patients' risk of dying by 18 percent, similar to the results Eli Lilly had reported in its first study of the drug.
"I was expecting to see a very small effect, close to no effect. I was surprised when we saw these kinds of results," Kalil said.
So should the drug be put back on the market? The answer is uncertain and, as far as Eli Lilly is concerned, unfeasible. Putting the drug back on the market would mean conducting another long, expensive clinical trial to clear regulatory hurdles. Janes said the company has no plans to do that, even in the face of evidence suggesting the drug's effectiveness.
"We have to live with the results of our clinical trials," Janes said. "It goes back to the point of deciding what the company is going to invest in."
Although the drug would likely help hundreds of thousands of patients, it will likely never be as profitable as drugs that can help millions of patients with more common conditions, such as high blood pressure, diabetes or cancer.
And questions remain about whether the drug was ever truly helpful for patients. Doctors never really identified the type of patient who would benefit the most from Xigris. The new study suggests that perhaps only the sickest patients really improve after taking the drug. Trials of the drug in pediatric patients like Rory never succeeded.
Dr. Cliff Deutschman, a professor of anesthesiology and critical care at the University of Pennsylvania, said he was never really convinced that the drug was better than treating patients with antibiotics and fluids.
"Ultimately, it's pretty hard to know what to make of the results of these studies," he said.
Since Xigris was introduced and withdrawn, doctors and hospitals also seem to have gotten a little better at screening and stopping sepsis in its early stages. Programs like the Stop Sepsis campaign, a program started by the Greater New York Hospital Association, emphasize promoting awareness of the condition and the critical importance of getting care to patients in the first hours of their symptoms.
But many doctors say a drug like Xigris would be invaluable in saving the lives of hundreds of thousands of patients. Martin said he still believes Xigris could be that drug.

"There's real potential that this drug has the ability to treat and cure people. But we don't know who the drug works best in, and that's probably where the interest was lost," Martin said.

And for now, it seems that doctors will never know. Since Eli Lilly withdrew the drug from the market, it is no longer available even for research purposes.

Deutschman said the biggest blow is that given the Xigris's failure and Eli Lilly's experience, other pharmaceutical companies will be reluctant to spend the money to pursue any treatment for sepsis. For now, the scientific and regulatory bar for a drug is very high.

"There still may be groups of people that it [Xigris] does work on, but because the drug is no longer available we'll never know. And that's discouraging," he said.