Jeffrey S. Berns, MD: Hello. This is Jeffrey Berns from the University of Pennsylvania School of Medicine in Philadelphia. I'm Editor-in-Chief of Medscape Nephrology. I am here with Dr. Roy Bloom, who is our Medical Director for Kidney and Pancreas Transplantation, to talk with you briefly today about a new drug that was just approved by the US Food and Drug Administration (FDA) for patients with kidney transplantation.
The drug is called belatacept and it's a selective T-cell costimulation blocker. I don't generally take care of transplant patients, so I'm going to rely on Dr. Bloom to fill us in a little bit about this drug. Roy, can you tell us how this drug works?
Roy Bloom, MD: It's as you indicated, a selective costimulatory signal blocker. When T cells are activated, several signals occur that are necessary for the T cell to become activated. The first signal is through T-cell receptor interaction within the MHC [major histocompatibility complex] antigen CD3 complex. That's the first signal.
The second signal is delivered through other receptor-ligand interactions, typically through CD28 and the previously known B7 pathway. CTLA4Ig has a high affinity for one of these costimulatory molecules and prevents the second signal from being delivered, therefore leading to diminished T-cell responsiveness.
Dr. Berns: What clinical trials were used to provide FDA approval, and what have they shown?
Dr. Bloom: The 2 pivotal trials were known as the BENEFIT [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial] and the BENEFT-EXT [Extended Criteria Trial]. These were both 3-arm trials. The difference between the 2 trials was that BENEFT-EXT used kidneys from donors who were extended-criteria donors.
The control arm was cyclosporine-based therapy with mycophenolate mofetil and prednisone followed basiliximab induction. The 2 treatment arms were lower-intensity and higher-intensity belatacept-based regimens. The lower-intensity arm was just a lower overall dose, and the high intensity was a higher dose. In addition, these patients received basiliximab induction together with mycophenolate mofetil and prednisone. Essentially, the outcomes were similar for both trials in that overall, a higher risk for acute rejection was seen in the belatacept-treated patients, although this did not translate into a higher risk for graft loss.
With the 2-year and (from a recent national meeting) 3-year data reported, kidney function was better in all the belatacept arms compared with the cyclosporine-treated patients, despite the severe incidence of acute rejection.
One of the things that came out, at least at the higher-intensity belatacept dosing, was a higher risk for posttransplant liver proliferative disorder (PTLD), and so in the FDA's approval of the drug they required testing for Epstein-Barr virus in both the donor and the recipient before the transplant.
Dr. Berns: Are there any other major risks associated with this drug?
Dr. Bloom: No, PTLD appears to be the major risk. Progressive multifocal leukoencephalopathy has been reported in a couple of the cases of patients who were in the higher-intensity arm. Some other potential benefits of the drug are that, at least in terms of efficacy, it seems to have a low-cardiovascular-risk profile in terms of hyperlipidemia, posttransplant diabetes (new-onset diabetes after transplant), or hypertension.
So there are clearly potential benefits, although not the primary outcome. Less-specific antibody formation was also seen in the belatacept-treated patients. This is a novel class of drug, not only in terms of the mechanism of action, but it is a biologic agent that is intended to be administered on a chronic basis. We obviously don't know how long "long term" will be. So far, in the drug's phase 2 trials our patients are 8-10 years out with treatment. We don't really know the longer-term dosing for this drug.
Dr. Berns: Should this become part of the standard armamentarium for kidney transplantation?
Dr. Bloom: There is definitely a potential role for it. Clearly, the lower dose had fewer adverse effects in terms of PTLD, and clear benefits both in terms of renal function and the secondary cardiovascular benefit. In that respect, I would say yes.
On the other hand, I would just caution that the control arm here was cyclosporine-based therapy, and most of our patients today get tacrolimus-based therapy, which we know could be less nephrotoxic than cyclosporine. What is really needed is a trial comparing a regimen of belatacept with a regimen of tacrolimus-based therapy.
Dr. Berns: That was interesting, Roy; thanks so much. It's exciting to have a new drug available to help our kidney transplant patients, and I am sure that we will be hearing much more about this as time goes on.
This is Jeff Berns from the University of Pennsylvania School of Medicine. Thanks for listening.
Medscape Nephrology © 2011
Cite this: Jeffrey S. Berns, Roy D. Bloom. Belatacept -- A Welcome New Transplantation Drug - Medscape - Jun 20, 2011.