The FINANCIAL — Bristol-Myers Squibb Company on May 6 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, according to Bristol-Myers Squibb Company.
The BENEFIT trial is a 36-month clinical study with long-term follow-up through 84 months, with primary endpoints of composite patient and graft survival by 12 months, rate of acute rejection by 12 months, and composite measured glomerular filtration rate (GFR, a measure of renal function) <60 at month 12 or a decrease in measured GFR from month 3 to month 12. Secondary endpoints were measured at 36 months.
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.
“Advances in kidney transplant care have led to impressive improvements in short-term survival; conversely, long-term allograft survival has not appreciably improved. It is therefore very encouraging to see a therapeutic intervention associated with a long-term survival advantage,” said Flavio Vincenti, M.D., Professor of Clinical Medicine, University of California, San Francisco, Division of Nephrology. “It is heartening for treating physicians and their patients to see a survival benefit as early as 5 years that continues out to 7 years post-transplant.”
Nulojix was approved by the U.S. Food and Drug Administration (FDA) in June 2011 for the prophylaxis of organ rejection in adult EBV seropositive patients receiving a kidney transplant (not for transplanted organs other than the kidney), in combination with basiliximab induction, MMF, and corticosteroids. FDA approval was based on data from BENEFIT and BENEFIT-EXT: two 3-year, Phase III, open-label, randomized, multicenter, active-controlled studies.
The most serious adverse reactions reported with Nulojix are PTLD, predominantly CNS PTLD, and other malignancies, as well as serious infections, including JC virus-associated progressive multifocal leukoencephalopathy (PML, often a rapidly progressive and fatal opportunistic infection) and polyoma virus nephropathy. Due to increased risks, including PTLD and PML, higher than recommended doses or more frequent dosing of Nulojix is not recommended. Nulojix is only indicated in EBV seropositive patients.
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%).
“The 7-year BENEFIT results mark a significant research milestone for Nulojix and represent our commitment to this patient population,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “Bristol-Myers Squibb recognizes the importance of continuing to advance immunosuppressive therapeutic options.”