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Drug expected to cure sepsis fails phase three trial

The failure of a promising drug, Eritoran, disproves the most recent hypothesis for the cause of sepsis

A clinical trial led by Steven Opal, professor of medicine at Alpert Medical School, found that the drug Eritoran was no more effective in treating sepsis than a placebo. The study was published in the Journal of the American Medical Association earlier this week.

The study involved close to 2,000 patients with severe cases of sepsis, an infection that often arises when people are being treated for other illnesses, according to a University press release.

Results from the study disprove the hypothesis that the release of toxins inside bacteria causes inflammation leading to death in sepsis patients, Opal wrote in an email to The Herald.

Opal wrote that researchers were testing a strategy to treat inflammation due to sepsis by inhibiting a specific receptor­ in the human immune system — the “toll-like” receptor. “There was high hope that this strategy would work where others had failed. Unfortunately, this was not true,” Opal added.

Alfred Ayala, a professor of surgery at the Med School who was not involved in the study, pointed to a central difficulty in sepsis research — defining the disease itself. He compared defining sepsis today to defining cancer a few decades ago, since there are many types of cancer with varying pathologies and treatments. Patients can develop sepsis in intensive care units or in long-term care facilities, resulting in different forms of the disease, he said.

“Maybe we have used a simplistic idea of sepsis. The definition historically is a combination of inflammatory response and a source of infection. Sometimes it’s well-diagnosed. Sometimes it’s not,” Ayala said. “The definition you use to recruit patients may affect results.”

Eritoran was designed to treat sepsis based on the theory that inflammation drives the disease, Ayala said. He questioned this assumption and said there may be a need to rethink the pathology underlying sepsis. From the perspective of sepsis as the failure of the immune system, stimulating a patient’s immune system might treat the disease, he said.

The unsuccessful phase three trial occurred after a promising phase two human trial and a successful treatment trial in mice.

A Feb. 11 New York Times article reported that researchers found mouse models are “misleading” for treatment of certain human diseases like sepsis due to significant genetic differences between the two species.

“Mice had been known to be a poor predictor of response to therapy for septic shock for over 25 years,” Opal wrote in his email.

But Opal noted that the mouse model proves useful for studying toxicity, action mechanisms and dosage, which cannot be examined in cell cultures. Larger animals would be better models for human disease, but they are too expensive to use in research, he wrote.

“It’s a very important study. It’s a little surprising given that the phase two study looked promising,” said Richard Hotchkiss, professor of anesthesiology, medicine and surgery at Washington University School of Medicine in St. Louis. He added that Opal is a leader in the field of sepsis research.

The limited sample size of the phase two trial and changes in treatment of sepsis may explain the success of that earlier human trial, Hotchkiss said. Patients now receive antibiotics to treat sepsis at an earlier stage of the disease, resulting in a lower mortality rate, he added. “Sepsis is being treated more effectively, so some of the drugs that were effective in phase two may not work anymore,” he said.

Opal said in the press release that it is not worth doing more trials of drugs that work to inhibit the same receptor that Eritoran targets. “We proved pretty convincingly that it’s not going to work in established septic shock, at least as a single agent,” he said in the release.



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