Compound Name:BelataceptMolecular Target:CD80, CD86Molecular Structure:CTLA fused to the Fc portion of human IgG1Licensed Indication:Prophylaxis of organ rejection after kidney transplantManufacturer and/or Distributor:Bristol-Meyers-SquibbInitial FDA Approval2011SummaryBelatacept (Nulojix) is a fusion protein composed of the Fc portion of human IgG1 linked to the extracellular domain of CTLA-4. Binding of the fusion protein to CD80 and CD86 prevents co-stimulation of T-cells. Because of the introduction of two mutations in its ligand-binding region, belatacept has a higher avidity for CD80 and CD86 than a similar drug, abatacept. It is reported to be more immunosuppressive than abatacept in non-human primates. The drug has been marketed by Bristol-Myers-Squibb since June, 2011, when it was approved for prophylaxis of rejection of renal allografts, and to be used in combination with basiliximab, mycophenolate mofetil (MMF), and corticosteroids. It is administered intravenously every four weeks.

 The rationale for development of this class of drugs is that the nephrotoxic and cardiac effects of calcineurin inhibitors compromised long-term survival of the allograft. Two clinical studies led to approval of the drug. In the first study by Vincenti et al., 666 recipients of kidneys were randomized to one of two doses of belatacept or to standard treatment containing cyclosporine. All patients also received basiliximab (a monoclonal antibody to the α-chain of the IL-2 receptor). Patient and graft survival and renal function were greater in the patients treated with the approved dose of belatacept (10 mg/Kg) than the cyclosporine-treated patients or the patients treated with a more intensive program of belatacept. The second study included donors who qualified under the extended donor criteria. At 3 years, survival was equivalent between the treatment groups, and renal function was greater in the belatacept group. Two long term follow-up studies (5 years) performed from the original cohorts have shown no significant benefit in reduction of rejection in patients treated with belatacept versus calcineurin inhibitor based therapies, although those treated with belatacept had better overall renal function, less elevated blood pressure, better lipid profiles, and lower incidence of new-onset diabetes after transplant. Long-term, 7-year study of belatacept regimen demonstrated statistically significant relative risk reduction of death or graft loss over cyclosporine regimen in kidney transplant. The FDA package insert contains the “black box” warning concerning the risk (0-4%) of post-transplant lymphoproliferative disease (PTLD) of the central nervous system, which is associated with primary EBV infections. Progressive multifocal leukoencephalopathy has also been reported. The drug should not be used in patients who are seronegative for Epstein-Barr virus prior to transplantation. Other infections and malignancies are potential concerns. Use in liver transplantation has, at this time, not been beneficial and is not recommended.References

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1.  Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012 Jan;12(1):210-217.

2.  Vincenti F, Dritselis A, Kirkpatrick P. Belatacept. Nat Rev Drug Discov. 2011 Sep;10(9):655-656.

3.  Durrbach A, Pestana JM, Pearson T, Vincenti F, Garcia VD, Campistol J, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010 Mar;10(3):547-557.

4.  Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010 Mar;10(3):535-546.

5.  Pestana JO, Grinyo JM, Vanrenterghem Y, Becker T, Campistol JM, Florman S, et al. Three-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys. Am J Transplant. 2012 Feb

6.  Satyananda V, Shapiro R. Belatacept in kidney transplantation. Curr Opin Organ Transplant 2014 Dec;19(6):573-7.

7. Charpentier B, Medina Pestana JO, Del C Rial M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys. Am J Transplant. 2014;13:2884–2891.

8. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43.