Transplant Drug Belatacept Receives Recommendation

March 2010

On March 1, 2010, an outside committee of U.S. regulatory advisers recommended to the U.S. Food and Drug Administration approval of belatacept for the prevention of kidney transplant rejection. The FDA is considering whether to approve the medicine. Belatacept, whose development was significantly contributed to by Dr. Chris Larsen and Dr. Tom Pearson beginning in the 1990s in collaboration with other investigators at Emory University and researchers at Bristol Myers Squibb, is a costimulation blocker that inhibits one of two signals T cells require to trigger an immune response.

Dr. Larsen, Dr. Pearson and their colleagues published the data from two international phase III clinical trials of belatacept in the March 2010 issue of American Journal of Transplantation, concluding that the experimental drug can prevent graft rejection in kidney transplant recipients while better preserving kidney function and maintaining lower blood pressure and cholesterol when compared to standard immunosuppressive drugs. More patients experienced acute rejection under belatacept, though in most cases the rejection was successfully treated with drugs and did not lead to graft failure. The senior author of the paper describing BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) was Dr. Larsen, while Dr. Pearson was co-author on a companion paper describing belatacept's performance on "extended criteria" kidney transplants (kidneys from donors that are older or have other factors associated with shorter graft survival).

The calcineurin inhibitors most transplant patients now rely on to inhibit their immune systems and prevent graft rejection can damage the kidneys and lead to high blood pressure and diabetes. The data from the BENEFIT trial, which tracked 666 kidney transplants at 100 sites around the world, showed that patients taking belatacept had similar graft survival rates to those taking cyclosporine, while maintaining higher kidney function and lower blood pressure and cholesterol. In addition, instead of requiring patients to take pills twice every day, in the case of calcineurin inhibitors, belatacept can be given every few weeks.

The BENEFIT trial, which was sponsored by Bristol Myers Squibb, compared three regimens: a more intensive and a less intensive course of belatacept treatment and a standard cyclosporine course. All patients received a temporary course of an anti-T cell antibody called basiliximab and the standard transplant drugs mycophenolate mofetil and corticosteroids. After one year, the proportion of patients with impaired kidney function (defined through glomerular filtration rate) was 55 percent for more intensive and 54 percent for less intensive, compared to 78 percent for cyclosporine. Patients' blood pressure, cholesterol and blood sugar profiles were also more favorable with belatacept.

In addition to the patients that experienced acute rejection under belatacept (22 percent for more intensive, 17 percent for less compared to 7 percent with cyclosporine), there was a higher incidence of a serious complication called post-transplant lymphoproliferative disorder (PTLD) — five patients total in the BENEFIT trial, compared to one with cyclosporine. PTLD is associated with infection with the Epstein-Barr virus, which many humans have as a low-level chronic infection. The authors say PTLD might be reduced by avoiding use of belatacept in Epstein-Barr-naive patients.