The Food and Drug Administration (FDA) has approved the drug Nulojix (belatacept) for the prevention of graft rejection after kidney transplants.
Belatacept could be a less toxic alternative to calcineurin inhibitors, the drugs most transplant patients now rely on to inhibit their immune systems, but which can damage the kidneys and lead to high blood pressure and diabetes.
This is the first time a new class of drugs has been developed for transplant since the 1990s. Belatacept has the potential to improve and simplify the medication regimens of kidney transplant recipients, and is also now being tested in experimental clinical trials for liver transplant and pancreatic islet transplant.
Since the early 1990s, Emory surgeon-scientists Christian P. Larsen, MD, DPhil and Thomas C. Pearson, MD, DPhil have been searching for ways to promote immune tolerance of a transplanted organ. They played a leading role in discovering belatacept and driving its development, in collaboration with other investigators at Emory, including the Yerkes National Primate Research Center, and researchers at Bristol Myers Squibb.
Larsen is director of the Emory Transplant Center, Joseph B. Whitehead Professor and chair, Department of Surgery at Emory University School of Medicine. Pearson is co-director of the kidney/pancreas transplant program at the Emory Transplant Center and Livingston professor of surgery.
“Our goal is to achieve a normal life span for kidney transplant patients, and have them survive dialysis-free,” Larsen says. “We believe belatacept can help us move toward that goal.”
“We believe this is an exciting new development which we hope will significantly improve the lives of our patients,” Pearson says.
In two parallel studies with more than 1,200 participants over two years, patients taking belatacept had similar graft survival rates to those taking the calcineurin inhibitor cyclosporine, while maintaining higher kidney function and lower blood pressure and cholesterol. In addition, belatacept can be given every few weeks, in contrast to calcineurin inhibitors, which must be taken twice a day.
Larsen and Pearson were leaders in designing and conducting the clinical trials, along with Flavio Vincenti, MD from University of California, San Francisco, Bernard Charpentier, MD from Bicetre Hospital, Paris and scientists from Bristol-Myers Squibb.
There is still room for improvement. Compared with cyclosporine-treated patients, belatacept-treated patients had a higher rate of early acute rejection – a temporary flare-up of the immune system against the donated kidney. However, in most cases the acute rejection was successfully treated with drugs and did not lead to graft failure. The Emory Transplant Center team is researching approaches to reduce this risk.
Nulojix will carry a Boxed 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. PTLD is associated with the Epstein-Barr virus (EBV), which most humans have as a low-level controlled infection. The risk of PTLD can be reduced by avoiding use of belatacept in Epstein-Barr-naïve patients. The FDA is requiring a blood test showing immunity to EBV before treatment with belatacept.
Research leading to belatacept’s development:
Belatacept acts as a “co-stimulation blocker,” inhibiting one of two signals T cells require to trigger an immune response. It is a modified version of a fusion protein called CTLA4-Ig, which mimics a regulatory molecule found on T cells and acts as a decoy. CTLA4-Ig (also known as abatacept or Orencia) has been FDA-approved to treat rheumatoid arthritis.
In the 1990s, Larsen and Pearson found that CTLA4-Ig could control graft rejection in mice, but it didn’t work as well in non-human primates. Researchers at Bristol Myers Squibb developed a panel of hundreds of modified forms of CTLA4-Ig, and sifted through the mutated proteins to find two that could make CTLA4-Ig bind tighter to its target and work more effectively. Larsen and Pearson then showed that the enhanced version could prevent graft rejection in a non-human primate model for kidney transplant at Yerkes Research Center.
Drs. Larsen and Pearson have received research support from Bristol Myers Squibb for their work with belatacept. This has been reviewed and approved by Emory School of Medicine.
References on initial development:
Initial collaboration with BMS in early 1990s.
Larsen et al. Functional expression of the costimulatory molecule, B7/BB1, on murine dendritic cell populations. J Exp Med. 176:1215-20 (1992).
Pearson et al. Transplantation tolerance induced by CTLA4-Ig.
Transplantation 57: 1701-6 (1994)
Larsen et al. Rational Development of LEA29Y (belatacept), a High-Affinity Variant of CTLA4-Ig with Potent Immunosuppressive Properties
Am J Transplant 5, 443 – 453 (2005).
Article in the journal Immunity describing history of co-stimulation blockers:
Experimental Drug Belatacept Shows Promise for Kidney Transplant
CV/Metabolic risk factors from BENEFIT and BENEFIT-EXT
Two-year results from BENEFIT and BENEFIT-EXT
Some patients have taken belatacept as long as five years
The 2010 papers:
F. Vincenti et al. A Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)
Am J Transplant 10, 535 – 546 (2010).
Durrbach et al. A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT-EXT Study)
Am J Transplant 10, 547 – 557 (2010).
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