A study of kidney transplant recipients has shown for the first time that the drug belatacept, which controls the immune system and prevents graft rejection, has a better record of patient and organ survival than a calcineurin inhibitor, previously the standard of care.
Emory University School of Medicine dean and professor of surgery Christian Larsen, MD, DPhil, played a key role in developing belatacept, together with Emory Transplant Center executive director Thomas Pearson, MD, DPhil. Belatacept was approved by the FDA in 2011 and is produced by Bristol Myers Squibb.
Results from the worldwide study, led by Larsen and UCSF transplant specialist Flavio Vincenti, will be published in the Jan. 28 issue of the New England Journal of Medicine.
Kidney transplant recipients need to take drugs to prevent their immune systems from rejecting their new organs, but the drugs themselves can cause problems. Long-term use of calcineurin inhibitors can damage the transplanted kidneys and lead to cardiovascular disease and diabetes.
Belatacept acts as a “co-stimulation blocker,” inhibiting one of two signals T cells needed to trigger an immune response. Belatacept carries short-term risks that include an increased possibility for a certain cancer, and research continues at Emory on the best regimens for kidney transplant patients.
“While the best uses of belatacept still need additional definition, these results indicate that using belatacept as standard of care has the potential to improve long-term outcomes that matter to patients,” says Larsen.
“Belatacept is potentially a transformational drug in kidney transplantation because unlike the currently used calcineurin inhibitor drugs cyclosporine and tacrolimus, it is not toxic to the kidney,” Vincenti says. “In fact, it helps preserve the function of the kidney over the long term and is more effective in suppressing antibodies against the kidney, which are important causes of late graft loss.”
The study, called BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) was sponsored by Bristol-Myers Squibb and began in 2006. FDA approval of belatacept in 2011 was partly based on the first three years of results.
The seven-year, multi-center study showed that kidney transplant recipients taking belatacept experienced a rate of mortality and graft loss significantly lower than patients taking a calcineurin inhibitor-based regimen. The risk of death or loss of the transplanted kidney after seven years was 12.7 percent for belatacept, compared to 21.7 percent for cyclosporine A.
Post-transplant drugs can cost tens of thousands of dollars per year, and a belatacept-based regimen is more expensive than one based on calcineurin inhibitors. Many U.S. insurance companies now cover belatacept as medically necessary for kidney transplant patients. Belatacept is given by infusion monthly at a doctor’s office, in contrast to calcineurin inhibitors, which are taken in daily pills at home.
BENEFIT Trial Results
In the BENEFIT study, 666 kidney transplant patients were divided into three groups that received either a more intense belatacept-based regimen (B1), a less intense belatacept-based regimen (B2) or a cyclosporine A-based regimen (CsA). The study followed 447 patients for all 84 months. All groups received additional drugs to inhibit graft rejection (basiliximab, mycophenolate mofetil and corticosteroids) in the weeks immediately after their transplants.
After 84 months, the Kaplan-Meier adjusted mortality rate was 9.2, 8.2 and 14.4 percent for the B1, B2 and CsA groups, respectively. For adjusted graft loss, the rate was 4.7, 5.4 and 9.8 percent. The rate for combined mortality and graft loss was 12.7 percent, 12.8 percent and 21.7 percent.
Immediately after transplant, belatacept-treated patients had a higher rate of acute rejection, a temporary flare up of the immune system against the donated kidney. The acute rejection rates were 24.4 percent in B1 and 18.3 percent in B2, compared with 11.4 percent in CsA. However, in most cases, acute rejection was successfully treated with drugs and did not lead to graft failure.
Patients taking belatacept showed slight improvements in kidney function (glomerular filtration rate) over time, in comparison with a decline in the CsA group, and comparable rates of serious adverse events (70.8, 68.6 and 76 percent). Viral and fungal infections were the most frequent serious adverse events.
Belatacept carries an FDA-mandated warning for an increased risk of developing post-transplant lymphoproliferative disorder (PTLD), a type of cancer where white blood cells grow out of control after an organ transplant. In the BENEFIT study, PTLD occurred in three patients in the B1 group, two in B2 and two in CsA.
The study authors note that the results of the BENEFIT study contrast with those from the companion BENEFIT-EXT study, in which patients received “extended criteria” kidneys from donors who were older than 60 or had chronic diseases. In the BENEFIT-EXT study, mortality and graft loss rates were similar between B1, B2 and CsA groups.
Other contributors to the NEJM study were Lionel Rostaing, MD, PhD, University Hospital and INSERM U563, IFR-BMT, Toulouse, France; Joseph Grinyo, MD, PhD, University Hospital Bellvitge, Barcelona, Spain; Kim Rice, MD, Baylor University Medical Center, Dallas; Steven Steinberg, MD, Sharp Memorial Hospital, San Diego; Luis Gaite, MD, Clínica de Nefrología, Santa Fe, Argentina; Marie-Christine Moal, MD, Hôpital de La Cavale Blanche, Brest, France; Guillermo Mondragon-Ramirez, MD, Instituto Mexicano de Trasplantes, Morelos, Mexico; Jatin Kothari, MD, Hinduja Health Care and Apex Kidney Foundation, Mumbai, India; Martin Polinsky, MD, and Herwig-Ulf Meier-Kriesche, MD, Bristol-Myers Squibb, Princeton; and Stephane Munier, MSc, Bristol-Myers Squibb, Belgium.
Study funding was provided by Bristol-Myers Squibb, and Larsen has received research support from the company.