November 3, 2006

New treatment for sepsis shows early promise

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Thousands took part in last Saturday’s American Heart Association Heart Walk, held on the Vanderbilt campus.
Photo by Susan Urmy

New treatment for sepsis shows early promise

A new first-line therapy to treat severe sepsis has shown promise in early trials to better treat the life-threatening condition which affects 750,000 patients and kills an estimated 200,000 each year in the United States.

Eighty-one patients took part in the nearly 10-year, Phase II study, which was conducted at 19 centers including Vanderbilt University Medical Center, which served as the principal site for the clinical trials.

Results showed that patients receiving the drug CytoFab spent more time off the ventilator and spent five fewer days in the Intensive Care Unit than those receiving existing treatments. The study was published recently in the journal Critical Care Medicine.

To date, there is only one drug currently approved to combat sepsis, activated Protein C (aPC). Gordon Bernard, M.D., director of Allergy, Pulmonary Critical Care and assistant vice-chancellor for Research, and a lead investigator in the study, was interested in developing another approach to combating the deadly disease because mortality rates were still in the 25 percent range.

“We will still lose one in four patients,” he said. “The sepsis population is still significantly underserved because that drug, Xigris, is only used in about 6 percent of cases.”

Art Wheeler, M.D., another Vanderbilt investigator in both the Phase I and Phase II trials, said he is encouraged by the findings.

“CytoFab is a unique drug with special properties,” said Wheeler, associate professor of Medicine.

“It is our hope that this drug will improve the outcomes beyond the existing treatments. Despite modern medical advances, severe sepsis and septic shock are responsible for 200,000 deaths at a cost of $17 billion annually. This Phase II study recently published is encouraging, but only forms the basis for a larger, Phase III study designed to prove increased survival.”

CytoFab is comprised of polyclonal ovine (sheep) anti-TNF Fab fragments designed to neutralize tumor necrosis factor, thereby decreasing the production of interlukin-6 and interlukin-8. Investigators hoped that by controlling these chemical mediators there would be fewer days on a ventilator, without shock.

It works to bind and neutralize the tumor necrosis factor in the tissue and circulation of severe sepsis patients. Essentially, the polyclonal properties of the drug attach to multiple sites on the target molecules (TNF) that cause inflammation of sepsis. By clinging to or coating these antigens, sepsis development is controlled, creating better outcomes.

“We are very excited about this because we had always felt that this was a logical and rational approach to developing a potent drug against severe sepsis,” he said.

The recently published study is the latest chapter in drug's development. Renewed interest in CytoFab was sparked after a 2005 licensing agreement between Protherics and AstraZeneca to manufacture the anti-sepsis drug for the Phase III study expected to enroll 3,000 patients worldwide.

Although both companies involved in the global production of CytoFab are British owned, the history of the drug's creation is local.

When the trial first began in 1995, Vanderbilt worked with the British company Therapeutic Antibodies (TAb) in Brentwood, Tenn. In 1999 it became Protherics following the merger of TAb and Proteus, another British firm.

During the two consolidations, Phase I and II clinical trials were completed. Vanderbilt's Bernard served as the principal investigator of the preclinical testing as well as both clinical trials.

Bernard also accompanied the company to pre-investigational new drug application meetings with the FDA.