A Multicenter, Open-Label, Study to Determine the Safety of BG9588 (Anti-CD40L Antibody) Therapy Compared to Standard Treatment in Renal Allograft Transplantation

This protocol is an open label, non-randomized study designed to test whether treatment with BG9588, a humanized monoclonal antibody specific for CD154, can induce a state of allograft tolerance following renal allotransplantation in humans. This study is designed to primarily assess the safety and efficacy of BG9588 when given alone or in combination with steroids and mycophenolate to prevent renal allograft rejection without the use of calcineurin inhibitors or other chronic anti-rejection therapies. Efficacy parameters will include the incidence of acute and chronic rejection episodes, and immunological graft loss. Additional evaluation will be performed to specifically assess the development of donor-specific immune hyporesponsiveness resulting from the use of BG9588. This study is based on extensive use of BG9588 in non-human primates and pilot evaluation in humans. Up to five patients in each group receiving primary renal allografts will be treated with a 12-month course of BG9588 with or without steroids and mycophenolate to prevent allograft rejection. The recruitment will be performed first in the group with steroids and mycophenolate. Subjects will receive BG9588 at a dose of 70 mg/kg (based on ideal body weight at baseline) via a continuous 60 minute IV infusion within 24 hours pre-operatively followed by a 30 mg/kg dose via a continuous 30 minute IV infusion on the following days: within 24 hours post-transplantation, and on days 3, 10, 18, 28, then monthly through 12 months post-transplantation. The enrollment will be staggered such that early efficacy will be demonstrated in 5 patients prior to completing enrollment. Following 12 months of therapy, patients may be extended to receive additional monthly therapy. Long-term follow up will occur through 30 months after the last dose of BG9588. Mechanistic evaluations testing for allograft tolerance will be performed throughout the study including evaluations for allospecific T cell deletion, allospecific T cell anergy, and alloantibody production. The donor population for this study will include both living donors and cadaveric donors. This is being done to address the theoretical concern that ischemic reperfusion injury may negatively affect the efficacy of BG9588.