Date: 2015-05-06
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 2015 American Transplant Congress (ATC) in Philadelphia
Company: BMS (USA - NY)
Product: Nulojix® (belatacept)
Action
mechanism: fusion protein. Belatacept is a selective T-cell costimulation blocker indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant, in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Nulojix should only be used in patients who are EBV seropositive. This fusion protein consists of the functional binding domain of modified human cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the Fc domain of human monoclonal immunoglobulin of the IgG1 subclass. The intended function of belatacept is to inhibit CD28 binding to CD80/CD86 by blocking/binding to CD80/CD86. Belatacept binds to CD80/CD86 by containing CD80/CD86 binding elements from CTLA-4, a surface molecule normally expressed on activated T cells that serves as a vital molecule for the selfregulating/inhibiting part of an adaptive T cell immune response. The CD80/CD86 binding motif MYPPPY is shared by both CTLA-4 and CD28, but CTLA-4 binds to CD80/CD86 with much higher avidity (10 to 100 times). The inhibited CD28 binding deprives the T cells of the second activation signal needed for the full induction of an adaptive immune response. Belatacept is a further development of abatacept (centrally approved in 2007 as Orencia®, indicated in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis) as to intended function, i.e. to inhibit costimulation of T cells. In belatacept BMS has made two point mutations in the amino acid sequence of abatacept to increase binding to CD80 and CD86 in order to increase the immunsuppressive capability of belatacept in comparison to abatacept.
Disease: kidney transplantation
Therapeutic area: Transplantation
Country: Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, France, Germany, Hungary, India, Israel, Italy, Mexico, Poland, South Africa, Spain, Sweden, Switzerland, Turkey, USA
Trial
details: The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) is an open-label, randomized, comparative, multicenter study that enrolled 666 renal transplant recipients of standard criteria deceased donor (SCD) and living donor kidneys in 3 cohorts. SCD kidneys were defined as organs from deceased donors with an anticipated cold ischemia time (CIT) of less than 24 hours and not meeting the definition of extended criteria donor (ECD) organs. CIT refers to the time the organ is cooled after organ procurement until implantation at the time of transplant. In the study, Nulojix was compared with cyclosporine; 1 cohort received a less intensive dose of Nulojix (n=226) and 1 received cyclosporine (n=221). All patients also received basiliximab induction, MMF and corticosteroids. The trial excluded recipients undergoing first transplant with current panel reactive antibodies (PRA, a measure of pre-existing antibodies that may negatively impact the kidney transplant) ≥50% and recipients undergoing retransplantation with current PRA ≥30%; patients with HIV, hepatitis C or evidence of current hepatitis B infection, active tuberculosis, and those in whom intravenous access was difficult to obtain. (NCT00256750)
Latest
news: * On May 6, 2015, BMS announced results from a 7-year, long-term follow-up from a prospective, randomized Phase III trial (BENEFIT) in kidney transplant patients, which demonstrated a statistically significant 43% relative risk reduction of death or graft loss (transplant failure) in patients receiving the Nulojix® (belatacept) FDA-approved dosing regimen over those receiving a cyclosporine regimen (hazard ratio=0.57, p=0.0286). Data also showed that there was a statistically significant survival benefit of 52% relative risk reduction of death or graft loss at 5 years post-transplant (hazard ratio=0.477, p=0.0045). In the long-term follow-up (years 3-7) on BENEFIT participants, the safety profile of the Nulojix regimen was similar to the cyclosporine regimen. Nulojix is the first selective T-cell costimulation blocker indicated in combination with basiliximab induction, mycophenolate mofetil (MMF) and corticosteroids for the prophylaxis of organ rejection in adult Epstein-Barr Virus (EBV) seropositive patients receiving a kidney transplant. The 7-year BENEFIT results were presented in the plenary session at the 2015 American Transplant Congress (ATC) in Philadelphia. In the BENEFIT 7-year study follow-up, the rates of serious adverse events were similar across treatment groups (69% among patients receiving the Nulojix regimen and 76% among patients receiving the cyclosporine regimen). The incidence rates (calculated as per 100-person years) were also similar among both groups for fungal infections (6.7 and 7.6, respectively), viral infections (14.2 and 15.7, respectively) and malignancies (1.7 and 2.6, respectively). Post-transplant lymphoproliferative disease (PTLD) occurred in 2 patients in the Nulojix regimen group and 2 patients in the cyclosporine regimen group. Both PTLD cases in the group treated with the Nulojix regimen occurred before month 12. In addition to the graft survival benefit, 7-year results demonstrate a statistically significant difference in renal function of patients receiving the Nulojix regimen versus those receiving the cyclosporine regimen (p=0.0286). At month 84, mean calculated GFR (cGFR) was 78 ml/min/1.73m2 for the Nulojix regimen group and 51 ml/min/1.73m2 for the cyclosporine regimen group. Rates and grades of acute rejection were higher in the Nulojix regimen group than in the cyclosporine regimen group, particularly in the first treatment year. By year 3, acute rejection was observed in 17.7% (39/226) of patients receiving the Nulojix regimen and 9.7% (19/221) of patients receiving the cyclosporine regimen. Between year 3 and year 7, there was one additional event of acute rejection in the Nulojix regimen group and two additional events of acute rejection in the cyclosporine regimen group. The Nulojix regimen demonstrated lower rates of de novo DSA formation at 7 years compared to cyclosporine (3.1% versus 11.6%).
