Experimental Therapy May Reduce Death From Sepsis

An experimental therapy that combines an antibiotic with a synthetic anti-inflammatory drug, designed at the University of Virginia Health System, has shown early promise in dramatically reducing death from sepsis, a life-threatening infection that kills 210,000 Americans each year.

"This anti-inflammatory drug, called ATL 146e, may prove to be an effective new therapy application for the treatment of sepsis, a very serious disease for which there aren't very good treatments today," said Joel Linden, professor of internal medicine at U.Va. and co-author of a study on sepsis and ATL 146e found in the April 28, 2004 issue of the Journal of Infectious Diseases.

For decades, antibiotics have been the standard treatment for sepsis, an inflammatory response to infection that can lead to a severe drop in blood pressure, cardiovascular collapse and death. But antibiotics have not been effective in treating infections once they have spread throughout the body, a condition that occurs in patients whose natural immune systems aren't working properly.

"Patients often die from sepsis even after the underlying bacterial infection has been controlled by antibiotics," said study co-author Dr. W. Michael Scheld, professor of infectious diseases at U.Va. and an authority on sepsis. Scheld believes that complications from the body's inflammatory response to the infection, rather than the infection itself, could be contributing to patient deaths.

The study, funded by two grants from the National Institutes of Health, demonstrated that ATL 146e used in combination with an antibiotic had a dramatic effect in improving survival in mice. In the experiment, mice with sepsis were treated with the antibiotic ceftriaxone alone, with ATL 146e alone and with both ceftriaxone and ATL 146e. Nearly 80 percent treated with just ATL 146e died within 30 hours, and 60 percent of the mice treated with ceftriaxone alone died within 96 hours. But none of the mice treated with both drugs died. "In discussing this, we developed the idea that we could kill bacteria with an antibiotic and protect patients by reducing the body's inflammatory response," Linden said. "We used ATL 146e, and it worked surprisingly well."

ATL 146e already has been subject to Phase I human safety trials. The U.Va. research team hopes to complete a Phase II clinical trial for the treatment of sepsis within 18 months, and, if successful, a larger Phase III trial one a year after that. "If the clinical trials are successful, ATL 146e or a similar compound could be clinically available to help treat sepsis within three to four years," Linden said.

Adenosine is a naturally occurring substance found in the body. Its role is to activate receptors that suppress inflammatory responses. But adenosine is degraded rapidly after being released from tissue. ATL 146e is a form of synthetic adenosine that produces more profound and prolonged immunosuppression than regular adenosine due to its specific action on adenosine receptors.

ATL 146e is owned by Adenosine Therapeutics, LLC, a Charlottesville-based start-up company co-owned by the University of Virginia Alumni Patent Foundation, U.Va. scientists, including Linden and Scheld, and other investors.

Source: University of Virginia Health System