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 fewer 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 (NEJM), 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 UCSF, 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), a National Institutes of Health-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, which will begin this fall to enroll 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 one of those trials.
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.
Bristol-Myers Squibb Company, developer of belatacept, was the sole funder of the NEJM study.
Source: Janet Basu
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