Physician-researchers at Emory University in Atlanta have shown an investigational medication, known as LEA29Y (belatacept), is effective in preserving transplanted kidney function while at the same time avoiding the toxic side effects that are common in 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, which currently is online and will be available in print on February 21.
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 transplants, 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. At the same time, though, cyclosporine 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 that ultimately leads to long-term renal failure. In addition, long-term cyclosporine use damages the body's immune system and prevents it from fighting off other infections following transplant.
"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, MD, DPhil, director of the Emory Transplant Center. "The problem is, the medication not only shuts down the immune system, but 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."
Dr. Larsen and Thomas Pearson, MD, DPhil, with colleagues at Bristol-Myers Squibb Pharmaceutical Research Institute, developed LEA29Y to selectively block the second of two cellular signals (co-stimulatory signals) the body needs to trigger an 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 LEA29Y was 10 times more effective than cyclosporine in blocking the co-stimulatory immune signal, Drs. Larsen and Pearson tested the drug 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," said Dr. Larsen. "The nonhuman primate studies 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 LEA29Y to cyclosporine in human kidney transplant patients. On behalf of investigators from 22 transplant centers worldwide. Dr. 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.