NEW YORK (Reuters Health) - Treatment with belatacept, an experimental agent that selectively blocks T cell activation, is just as effective as cyclosporine in preventing acute rejection of renal grafts, but may have less long-term toxicity, new research suggests.

The calcineurin inhibitors, such as cyclosporine, "have proven effective at reducing acute graft rejection and improving graft survival at 1 year," lead author Dr. Flavio Vincenti, from the University of California at San Francisco, told Reuters Health. "Paradoxically, however, these agents also induce toxicities in the kidneys over the long term. So, ultimately, they contribute to shortened long-term graft survival."

Dr. Vincenti said that belatacept works by blocking the costimulatory signal that is needed for full activation of T cells. In contrast, the calcineurin inhibitors block T cell activation as well, he explained, but they have added effects that contribute to their toxicity.

The present study, which is reported in The New England Journal of Medicine (NEJM) for August 25, involved 218 patients who were randomized to receive belatacept, as an intensive or less-intensive regimen, or cyclosporine for maintenance immunosuppression following renal transplantation. Basiliximab, mycophenolate mofetil, and corticosteroids were used as induction therapy in all patients.

The 6-month rate of acute rejection in belatacept groups was around 7%, not significantly different from the 8% rate seen in the cyclosporine group.

At 12-month follow-up, the glomerular filtration rates in the belatacept groups were 66.3 mL/min/1.73 meters-squared. By contrast, the rate in the cyclosporine group was significantly lower -- 53.5 mL/min/1.73 meters-squared. In addition, the rate of chronic allograft nephropathy did not exceed 29% in the belatacept groups, whereas the rate in the cyclosporine group was 44%.

Although lipid-lowering and antihypertensive agents were used more often in the cyclosporine group, patients in the belatacept groups had lipid levels and blood pressure values that were at least as good as their cyclosporine-treated peers.

This was a phase II trial, Dr. Vincenti noted, adding that the drug-maker, Bristol Myers Squibb, is currently involved in two phase III trials of the drug. If all goes well, he estimated that belatacept could be on the market in 3 years.

In a related commentary, Dr. Julie R. Ingelfinger and Dr. Robert S. Schwartz, deputy editors at NEJM, note that it is too early to tell if belatacept and other new drugs will improve transplantation outcomes, "but it is obvious that specific immunosuppressive reagents or manipulations that lead the immune system down the pathway toward immunologic tolerance of tissue antigens in the graft would go far in giving transplant recipients a normal life."

N Engl J Med 2005;353:770-781,836-838

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