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Experimental immunusuppressant drug preserves transplanted kidneys, avoids toxic side effects

25.08.2005


An international team of transplant physicians has shown that the investigational drug belatacept (LEA29Y) preserves transplanted kidney function as effectively as cyclosporine, the drug most commonly used to prevent the immune system from rejecting transplanted organs. At the same time, belatacept avoids many of the toxic side effects that adversely affect kidney function, blood pressure and cholesterol levels of patients undergoing long-term anti-rejection therapy with immunosuppressant drugs.

The findings from a Phase II clinical trial of belatacept, conducted in 218 patients at 22 centers in the U.S., Canada and Europe between March 2001 and December 2003, are published in the August 25 issue of the New England Journal of Medicine. Christian P. Larsen, MD, PhD, director of the Emory Transplant Center and professor of surgery at Emory University School of Medicine, and Flavio Vincenti, MD, of the University of California, San Francisco, are co-lead authors of the article.

"The results of this study on the safety and effectiveness of belatacept were as good as we could hope for from the first trial of this new class of drugs in human transplant recipients," Dr. Larsen said. "This arguably is among the most important new classes of immunosuppressive drugs to be evaluated since cyclosporine was introduced more than 20 years ago."



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.

Study participants were randomly assigned to receive an intensive or less intensive regimen of belatacept or cyclosporine, in addition to several other drugs that are part of standard immunosuppressive therapy. At six months following transplant the incidence of clinically suspected and biopsy proven acute rejection of transplanted kidneys was similar and not statistically significant among the groups: 6-7 percent of belatacept patients had acute rejection compared to 8 percent of patients receiving cyclosporine. The function of the transplanted kidneys of both groups of patients receiving belatacept was significantly better than in patients receiving cyclosporine. Lipid levels and blood pressure were similar or slightly lower in the belatacept groups, despite greater use of lipid-lowering and antihypertensive medications in the cyclosporine group.

Although kidney transplants are the current standard of care for patients with end-stage renal disease, the immune system’s hostile response to a foreign organ sets off a chain of events that can damage and cause rejection of the transplanted organ. Cyclosporine, the current standard of care following organ transplantation, has shown excellent results in preventing rejection over the short term. Cyclosporine prevents initial organ rejection by effectively blocking certain immune system pathways that are activated when the body detects foreign cells. At the same time, however, cyclosporine indiscriminately blocks other cellular signal pathways, causing serious side effects such as high blood pressure and high cholesterol, which may lead to cardiovascular disease and kidney toxicity that ultimately leads to renal failure. In addition, long-term cyclosporine use damages the body’s immune system and prevents it from fighting off other infections following transplant.

Belatacept, on the other hand, prevents T-cell activation by selectively blocking one of two signals needed for T-cells to become fully activated and to initiate an immune response against a transplanted organ. Selectively blocking this co-stimulatory signal prevents organ rejection while allowing the body to continue fighting other infections.

Preclinical research conducted with nonhuman primates at the Yerkes National Primate Research Center at Emory University also showed belatacept was equally as effective as cyclosporine in preventing rejection of kidney transplants while avoiding toxic side effects. The primate research was an important step in establishing human clinical trials to develop an effective alternative to current anti-rejection therapies.

The data from the primate studies and the current clinical trial have formed the basis of a similar international Phase III study of belatacept and kidney transplants as well as exploratory studies using belatacept that avoids both cyclosporine and steroids and a study of islet transplants using belatacept in place of cyclosporine.

Holly Korschun | EurekAlert!
Further information:
http://www.emory.edu

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