Belatacept ( LEA29Y ), 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 , 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 New England Journal of Medicine, researchers reported 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, of the University of California, San Francisco, and Christian Larsen, 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.

" 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.

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 destruction 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, 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 needed 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.

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.

Source: University of California - San Francisco, 2005


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