June 17, 2011

Emory surgeon-scientists led effort to develop new FDA-approved kidney transplant drug

Christian P. Larsen and Thomas C. Pearson

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 and Thomas C. Pearson 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 the 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 from University of California, San Francisco; Bernard Charpentier, 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.

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