General Information

Nulojix (belatacept) is a selective T-cell (lymphocyte) costimulation blocker, which supresses the immune system. Without immunosuppression, the body can reject a transplanted organ because the immune system recognizes the new organ as foreign.

Nolojix is specifically indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. It is approved for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.

Nolojix is supplied as a powder for reconstitution into a solution for intravenous infusion. The total infusion dose of Nulojix should be based on the actual body weight of at the time of transplantation, and should not be modified during the course of treatment unless there is a change in body weight of greater than 10%. The recommended dose is as follows:

Dosing for Initial Phase
Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose): 10 mg per kg
End of Week 2 and Week 4 after transplantation: 10 mg per kg
End of Week 8 and Week 12 after transplantation: 10 mg per kg
Dosing for Maintenance Phase
End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter: 5 mg per kg

Clinical Results

FDA Approval
The FDA approval of Nulojix was based on two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of Nulojix, the recommended dosage regimen and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. The Nulojix recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every four weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, Nulojix was administered at the maintenance dose of 5 mg per kg every four weeks (plus or minus 3 days). Nulojix was administered as an intravenous infusion over 30 minutes. Efficacy data are from the Nulojix recommended regimen.

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys
A total of 666 subjects were enrolled. Discontinuation from treatment at the end of three years occurred in 25% of subjects receiving Nulojox recommended regimen and 34% receiving the cyclosporine regimen. Efficacy was based on biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. By three years, recurrent BPAR occurred with similar frequency across treatment groups.
Study 2: Recipients of Extended Criteria Donor Kidneys
A total of 543 subjects were enrolled. At the end of three years, 35% of subjects receiving the Nulojix recommended regimen and 44% of subjects receiving the cyclosporine regimen had discontinued from treatment. By three years, recurrent BPAR occurred with similar frequency across treatment groups.

In both studies belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and reduced incidence of new-onset diabetes after transplant compared to cyclosporine.

Mechanism of Action

Nulojix (belatacept) is a a selective T-cell (lymphocyte) costimulation blocker. It binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-y, interleukin-4, and TNF-cx. Activated T lymphocytes are the predominant mediators of immunologic rejection.

Literature References

Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Grinyó J, Neumayer HH, Lang P, Larsen CP, Mancilla-Urrea E, Pestana JM, Block A, Duan T, Glicklich A, Gujrathi S, Vincenti F Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011 May 15;91(9):976-83

Gupta G, Womer KL Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation. Drug Design, Development and Therapy 2010 Dec 1;4:375-82.