Posts Tagged ‘transplantation therapy’

Hope for Kidney Transplant Patients Confirmed with FDA Approval of Drug Discovered at Emory

After decades of research and testing, the FDA approves belatacept, and a new class of transplant drugs first discovered by Emory doctors.

Back in September, Dr. Christian P. Larsen, Director of the Emory Transplant Center, shared a story with you here on our blog about belatacept, a new medication that was being studied to determine its ability to help block the immune system from graft rejection after kidney transplants. It’s been less than a year since we shared that story on belatacept with you, and since that time, the FDA has now approved belatacept for use for that exact purpose.

Christian Larsen, Emory Transplant Center Director

Dr. Christian Larsen, Director of Emory Transplant Center

Dr. Thomas Pearson

Dr. Thomas Pearson, Surgical Director, Kidney Transplant Program

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. In collaboration with other Emory researchers and researchers at Bristol-Myers Squibb, they played a leading role in discovering belatacept and driving its development. The recent FDA approval of use of belatacept is the first time a new class of drugs has been developed for transplant since the 1990s.

So what led to this approval of a new class of drugs? From a research perspective, in the 1990s, Larsen and Pearson found that CTLA4-Ig, a fusion protein of which belatacept is a modified type, could control graft rejection in mice, but found that it didn’t work as well in non-human primates. Bristol-Myers Squibb researchers then 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.

Once the determination was made that modified versions of the CTLA4-lg fusion proteins could work to prevent graft rejection on primates, belatacept was developed and tested. 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.

There is still room for improvement, though. 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.

“Our goal is to achieve a normal life span for kidney transplant patients, and have them survive dialysis-free,” Larsen, Director of the Emory Transplant Center, says. “We believe belatacept can help us move toward that goal.”

Clinical trials are now also being conducted to determine if belatacept will have similar positive outcomes on liver transplant and pancreatic islet transplant patients.

For more information on belatacept, you can check out the video below. If you have additional questions, leave them in the comments for Dr. Larsen or Dr. Pearson and we’ll make sure they see them and give you a response!

For more information on the FDA’s approval of belatacept, visit: http://shared.web.emory.edu/whsc/news/releases/2011/06/fda-approves-transplant-drug-that-preserves-kidneys,-avoids-toxicity.html

Belatacept Transplant Drug Offers Hope for Preserving Kidney Function

Today, kidney transplantation provides patients with invaluable benefits—it prolongs lifespan and restores vitality and health. However, this hasn’t always been the case. As recently as the 1980s, results of transplants were fairly poor, and kidneys were often lost from rejection. In 1983, the cyclosporine class of drugs entered the equation, revolutionizing transplantation. Short-term outcomes improved greatly, and we expected most of our patients to survive with a functioning graft—90% of them at the 1-year mark.

Unfortunately, while cyclosporine is ideal for short-term outcomes, it causes many side effects that affect long-term outcomes in patients. Cyclosporine is toxic to the kidney—over time, this causes excess scarring and eventually even leads to loss of kidney function.

In approximately one-third of patients, cyclosporine causes post-transplant diabetes, requiring most patients to take blood pressure lowering medications. Additionally, most must take medications to lower their cholesterol. (High blood pressure and increased cholesterol counts are both side effects of cyclosporine.) Ultimately, patients must take the anti-rejection drugs along with a host of other drugs to combat the side effects, all of which can lead to death from cardiovascular disease. On average, the kidney transplant patient survival rate is only 8-10 yrs, which is clearly short of what we’d like to see.

Sufficed to say, there’s been a tremendous need for better drugs to prevent rejection in kidney transplants, without causing life-threatening side effects.

Introducing Belatacept

When kidney patients suffer from transplant rejection, the immune system essentially recognizes the new kidney as a foreign object, causing lymphocytes and T-cells to attack, and generating immune damage to the transplant. Consequently, we introduce drugs to dampen the immune system. The issue with cyclosporine is that it doesn’t just affect the immune response; it hits several other targets throughout the body, causing the negative side effects. Fortunately, there’s hope on the horizon with a newer drug called belatacept.

Like Cyclosporine, belatacept blocks the immune system from transplant rejection. However, the target of belatacept is only expressed in the immune system, so it suppresses undesired immune responses of rejection without the off target side effects (e.g. high blood pressure, increased cholesterol and diabetes) seen with Cyclosporine. We refer to these off-target responses as “costimulatory signals”.

In transplantation, our goal is to achieve a normal life span for our patients, and to ideally have them move on from surgery dialysis-free. At Emory, we’ve dedicated years to developing new and improved therapies that avoid major complications from kidney transplants, including cardiovascular issues, infections and malignancies.

Recent belatacept studies indicate that this drug could quite possibly help us in achieving these goals. Over 1400 patients have been studied with belatacept’s use in kidney transplant, and the results continue to be extremely promising. Further, the drug could conceivably have advantages for other types of organ transplantation, including liver, heart, lung, and intestinal.

Do you have any questions about belatacept, or about kidney transplantation in general? If so, please let me know in the comments.