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New type of rejection blocker protects kidneys after transplant

In an international clinical trial, a new drug that selectively blocks immune responses has proved as effective in preventing acute kidney transplant rejection as cyclosporine, the standard anti-rejection treatment.

Patients who took the experimental drug, a co-stimulatory blocker called belatacept (LEA29Y), also had better kidney function and experienced less of the toxic side effects associated with standard anti-rejection drugs, including kidney damage, high blood pressure and high cholesterol.

In the August 25 issue of The New England Journal of Medicine, researchers report on the safety and efficacy of belatacept during a randomized phase II clinical study of 218 patients, conducted at 22 centers in the United States, Canada and seven European countries. Flavio Vincenti, MD, of the University of California, San Francisco, and Christian Larsen, MD, of Emory University in Atlanta, were co-principal authors of the study.

The results mark an important step toward proving the value of a new type of treatment based on blocking the immune system's reaction to a transplanted organ without hampering the body's ability to fight diseases and infections, according to Vincenti, clinical professor of medicine and surgery at UCSF and a kidney transplant specialist at UCSF Medical Center.

"This is the first clinical trial of a treatment for transplant recipients based on this new principle of inducing immune tolerance of the transplanted organ. If belatacept and similar drugs live up to their promise, they will usher in a new paradigm for organ transplantation," Vincenti said. Instead of sending patients home with a collection of medications that must be taken daily to prevent rejection by suppressing the immune system's hostile response to a transplanted organ, Vincenti said he expects his patients to receive an injected immune tolerance treatment a few times a year -- and perhaps to be able to stop taking anti-rejection drugs altogether.

UCSF enrolled the first patient to receive belatacept in the trial early in 2001. Twenty UCSF patients have been taking the drug for more than three years. "So far, results are excellent for long-term recipients of the treatment," Vincenti said.

A UCSF immunologist whose research has led to the development of immune tolerance drugs, Jeffrey Bluestone, PhD, put the study in context. "This work underscores the enormous potential of co-stimulatory blockade as a strategy for inducing immune tolerance, not only in transplantation, but in autoimmune diseases as well," Bluestone said. He is UCSF professor of medicine and director of the Immune Tolerance Network (ITN), an NIH-funded international network of more than 80 researchers coordinating clinical testing of new therapies to induce immune tolerance.

"Additionally, this phase II study provides a solid foundation for Dr. Vincenti's upcoming ITN-sponsored study of belatacept in kidney transplant recipients, in which we will test whether true immune tolerance can be achieved," Bluestone said. That new trial, to begin this fall enrolling patients who receive kidney transplants from living donors at UCSF, will test whether transplant patients can be treated with belatacept and can gradually withdraw from all immunosuppressants -- including belatacept itself.

In addition, Bristol-Myers Squibb Company, the pharmaceutical company that developed belatacept, is conducting phase III clinical trials of the drug for kidney transplants. UCSF also is participating in that trial.

RESEARCH RESULTS

Belatacept is an injectable protein, one of a group of experimental drugs called co-stimulatory blockers. The immune system's normal response to a transplant is to recognize the new organ as foreign and to signal production of T-cells poised to destroy it. A second, co-stimulatory signal is required before the T-cells attack the kidney. By blocking this second signal, belatacept prevents de struction of the kidney without suppressing the immune system's response to viruses and other pathogens.

Belatacept is based on research into the molecular basis of immune tolerance. Its precursor, CTLA4Ig, was first shown to induce transplant tolerance in research conducted by Bluestone. Animal studies at Emory University by Larsen and preliminary clinical studies by Vincenti also contributed to the development of belatacept as an effective co-stimulatory blocker.

In the phase II study reported in NEJM, 218 patients were randomized to receive cyclosporine or either a less-intensive or more-intensive course of belatacept. All patients received several other drugs that are included in standard post-transplant therapy. At the end of six months, the rates of acute rejection were similar in all patient groups (six to seven percent for belatacept versus eight percent for cyclosporine). Acute rejection usually can be reversed, and study results showed that all patients retained their transplanted kidneys except for one in the intensive belatacept group and one in the cyclosporine group.

After 12 months of post-transplant treatment, the researchers used glomular filtration rate (GFR) -- a measure of the kidney's ability to filter waste -- as an indicator of how well transplanted kidneys were functioning. The GFR was significantly higher at 12 months for patients receiving both the intensive and less intensive belatacept regimens compared to cyclosporine patients. Another indicator of kidney health, chronic allograft nephropathy (scarring of the kidney), also was lower at 12 months among patients receiving either of the belatacept regimens.

Patients in all treatment groups had comparable total cholesterol levels and comparable blood pressure levels at 12 months. However, 53 percent of cyclosporine patients required lipid-lowering medications compared to 32-36 percent of belatacept patients. More than half of cyclosporine treated patients nee ded anti-hypertensive medication compared to one-third of patients in the two belatacept groups.

Over the past 20 years, drugs like cyclosporine (a calcineurin inhibitor) and prednisone (a corticosteroid) have been highly successful in overcoming organ rejection. However, Vincenti said, advances have only been modest in terms of keeping the organ healthy over the course of years. Paradoxically, anti-rejection drugs like cyclosporine contribute to health problems including cardiovascular disease -- the leading cause of death among kidney transplant recipients.

"This trial indicates that belatacept should be able to protect transplanted organs from rejection without the toxicities associated with today's standard drugs," Vincenti said.

Since standard immunosuppressants damage the kidneys, the new class of drugs also promises to reduce the number of patients who need a re-transplant. "This is one of the exciting results of this study, considering that we have a critical shortage of organs for transplant," Vincenti said.

Kidney transplant is the preferred treatment for most people with end-stage kidney failure. The United Network for Organ Sharing reports that more than 16,000 Americans received a kidney transplant in 2004.


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Source:University of California - San Francisco


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