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March 7, 2005
Medication shown to limit post-transplant side effects

BY lisa newbern

Emory physician-researchers have demonstrated that an investigational medication, known as LEA29Y (belatacept), is effective in preserving transplanted kidney function while at the same time avoiding the toxic side effects common to the currently used long-term, immunosuppressive transplant medications.

The pre-clinical research, conducted with nonhuman primates at the Yerkes National Primate Research Center, was an important step in establishing human clinical trials to develop an effective alternative to current anti-rejection therapies. Findings from one of the nonhuman primate studies appear in the March issue of the American Journal of Transplantation.

More than 23,000 organ transplants are performed each year in the United States. While current immunosuppressant medications have reduced the incidence of early organ failure following transplant, measures to prevent late failure and to halt other diseases that result from toxic side effects of current treatments have been limited.

Cyclosporine, the current standard of care following organ transplantation, prevents initial organ rejection by effectively blocking certain immune system pathways that are activated when the body detects foreign cells.
However, cyclosporine also indiscriminately targets and blocks other cellular signal pathways, causing serious side effects such as high blood pressure and cholesterol (which may lead to cardiovascular disease) and high kidney toxicity, which ultimately leads to long-term renal failure. Finally, long-term cyclosporine use damages the body’s immune system and prevents it from fighting off other infections.

“For the past 20 years, transplant patients have been treated with cyclosporine-like medications that effectively suppressed the immune system to prevent the body from rejecting the new organ,” said Christian Larsen, Carlos and Marguerite Mason Professor of Surgery in Transplantation Biology and director of the Emory Transplant Center. “The problem is the medication not only shuts down the immune system, but it has side effects that increase the risk of heart attacks and can damage the kidney. We need to develop a medication as effective as cyclosporine in preventing initial rejection, while at the same time preserving the kidney and providing better patient outcomes.”

Larsen and Thomas Pearson, Livingston Professor of Surgery, together with colleagues at Bristol-Myers Squibb Pharmaceutical Research Institute, developed LEA29Y to selectively block the second of two cellular signals (co-stimulatory signals) that trigger the body’s immune response. Blocking this co-stimulatory signal prevents organ rejection while allowing the body to continue fighting other infections.

Following in vitro studies, during which the researchers observed the drug was 10 times more effective than cyclosporine in blocking the co-stimulatory immune signal, Larsen and Pearson tested LEA29Y in nonhuman primates and found that it significantly prolonged survival of transplanted kidneys.

“The studies with nonhuman primates were critical because, while we knew the co-stimulatory blocker was effective in vitro, we needed to study it in a living organism,” Larsen said. “It allowed us to take a bold step toward studying this medication in humans to determine if it is a better choice than the current standard of care. Working with nonhuman primates enabled us to expedite the research process by four or five years.”

The research team recently completed a phase II clinical study comparing the new drug to cyclosporine in human kidney transplant patients. On behalf of investigators from 22 transplant centers worldwide. Larsen will present results from the phase II study at the annual American Transplant Congress, May 20–25 in Seattle. Multiple phase III studies currently are being planned.

 

 

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