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12:00 AM
 | 
Mar 08, 2010
 |  BioCentury  |  Regulation

Hope Trumps Doubts on Belatacept

The need for an alternative to calcineurin inhibitors was enough to sway an FDA panel that belatacept from Bristol-Myers Squibb Co. deserves to be approved to prevent organ rejection in renal transplant patients, despite concerns about the compound's efficacy and safety.

Last week, FDA's Cardiovascular and Renal Drugs Advisory Committee voted 13-5 that belatacept had a positive benefit-risk profile for the prevention of organ rejection in renal transplant recipients.

Panel members did have concerns about FDA's reanalysis of data from the Phase III trials, which showed belatacept was numerically worse than cyclosporine in preventing acute rejections. However, because belatacept fell within the 20% noninferiority margin established by the agency, they agreed it demonstrated efficacy.

The committee also was concerned about the rates of post-transplant lymphoproliferative disorder (PTLD) and progressive multifocal leukoencephalopathy (PML) in the belatacept arms of Phase II and Phase III trials.

On the other hand, the panel was impressed with belatacept's improvement of glomerular filtration rate (GFR) compared to cyclosporine - an endpoint FDA agreed to in an SPA but then reneged after the trial was underway.

Given the tradeoffs, the panel endorsed belatacept for use in a restricted population, and only if a strict patient registry was put in place to monitor the rates of PTLD and PML.

Benefits vs. tox

About 17,000 kidney transplants are performed in the U.S. each year. To prevent graft loss, patients must take a series of immunosuppressants.

The standard of care for prevention of rejection is a calcineurin inhibitor (CNI), such as cyclosporine, in combination with an IL-2 receptor antagonist, CellCept mycophenolate mofetil from Roche and corticosteroids.

CNIs are not approved to preserve a functioning allograft.

BMS is seeking approval of belatacept for prevention of graft rejection and preservation of a functioning allograft as an alternative to CNIs.

Since CNIs were first introduced more than 20 years ago, short-term outcomes for transplant patients have improved. Immunosuppressive regimens that include CNIs have one-year graft survival rates of 90% for deceased donor grafts and 95% for recipients of living donor grafts, with acute rejection rates of 10-20% during the first year of transplant.

Acute rejection generally occurs within the first three months after transplant but rarely results in the loss of the graft. It generally manifests in symptoms including an unexplained rise in serum creatinine >25% from baseline, unexplained decrease in urine output, fever and graft tenderness, and serum creatinine that remains elevated within 14 days of transplant.

Due to toxic side effects of CNIs, however, long-term outcomes are not as good. CNIs are associated with renal, cardiovascular and metabolic toxicities, which can cause renal impairment, hypertension, hypercholesterolemia and diabetes.

According to BMS, CNIs have 5- and 10-year rates of patient survival with a functioning graft of 68% and 39% for recipients...

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