Given the promising Phase II trial results, two Phase III trials were undertaken. Both trials have provided important data on the role of belatacept for the prevention of acute rejection as part of a CNI-free regimen.
The first study, Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT),23
was a multicenter, randomized, active-controlled, parallel-group Phase III trial. Adult patients receiving a living donor or standard criteria deceased donor kidney were eligible. First-time patients with a panel reactive antibody ≥50%, retransplants with a panel-reactive antibody ≥30%, recipients of prior or concurrent nonrenal solid organ transplants, and recipients of extended criteria donor kidneys were excluded. Patients were randomized to one of three regimens for maintenance immunosuppression, ie, a MI regimen of belatacept, a LI regimen of belatacept, or cyclosporine (). Patients in all treatment arms received basiliximab induction and were maintained on mycophenolate mofetil and corticosteroids. Lymphocyte-depleting therapy was permitted in the cyclosporine group for delayed or anticipated delayed graft function. Patients with acute rejection ≥Grade IIB could be treated with T-cell-depleting therapy at the investigator’s discretion.
All patients received induction with basiliximab and maintenance therapy with mycophenolate mofetil and corticosteroids.
The trial was designed with three coprimary outcomes, ie, composite patient and graft survival, a composite renal impairment endpoint, and incidence of acute rejection. The noninferiority margin for patient and graft survival and for acute rejection was set at 10% and 20%, respectively. Protocol biopsies were performed at implantation and at week 52. A total of 527 patients were randomized to three treatment groups, transplanted, and completed the initial 12-month treatment phase. Recipient demographics and baseline characteristics as well as donor characteristics were similar between the three groups.
Both belatacept regimens were noninferior to cyclosporine for the primary endpoint of patient and graft survival. At 1 year, patients enrolled in the MI, LI, and cyclosporine treatment groups had 95%, 97%, and 93% patient and graft survival, respectively. The mean measured glomerular filtration rate (GFR) was 65 mL/min/1.73 m2, 63.4 mL/min/1.73 m2, and 50.4 mL/min/1.73 m2 in the MI-treated, LI-treated, and cyclosporine-treated patients, respectively (P < 0.0001 for both MI and LI versus cyclosporine). The prevalence of chronic allograft nephropathy on protocol biopsies was lower in belatacept-treated patients compared with cyclosporine-treated patients (18% MI, 24% LI, 32% cyclosporine).
There was a higher incidence of acute rejection at 12 months in the belatacept-treated groups compared with the cyclosporine-treated group (22% MI, 17% LI, 7% cyclosporine). The incidence of acute rejection met the noninferiority cutoff for the LI group versus the cyclosporine group, but not for the MI group versus the cyclosporine group. Almost 100% of these rejections occurred within the first 6 months post-transplantation. Belatacept-treated patients had more type IIa and IIb rejections compared with cyclosporine-treated patients but were not associated with an increase in donor-specific antibody. The mean measured GFR at month 12 was higher in belatacept-treated patients with acute rejection compared with cyclosporine-treated patients without acute rejection ().
Measured glomerular filtration rate (GFR) by month 12 in patients with and without rejection in BENEFIT.
Belatacept-treated patients had a significantly lower mean blood pressure (MI 133/79 mmHg, LI 131/79 mmHg) compared with cyclosporine-treated patients (139/82 mmHg, P ≤ 0.0273 for MI or LI versus cyclosporine in all comparisons). The mean change in non-high-density lipoprotein cholesterol from baseline was significantly different in belatacept-treated patients (MI 0.21 mmol/L, LI 0.21 mmol/L) compared with cyclosporine-treated patients (0.47 mmol/L, P = 0.0115 for MI and P = 0.0104 for LI versus cyclosporine). The incidence of new-onset diabetes mellitus after transplant (NODAT) was not significantly different between the three groups, ie, MI 7%, LI 4%, and cyclosporine 10% (P = NS for MI or LI versus cyclosporine).
Two-year and 3-year data are available for BENEFIT.24
Between months 12 and 24, a total of eight patients had an acute rejection episode (MI, n = 4; cyclosporine, n = 4) for a total of 24% (MI) and 9% (cyclosporine) from baseline to month 24.24
The 3-year data demonstrate that there were no new cases of acute rejection in the belatacept groups from year 2 to year 3.25
However, one patient in the cyclosporine group experienced acute rejection after year 2. By year 3, donor-specific antibodies occurred more commonly in cyclosporine-treated patients (MI 6%, LI 5%, cyclosporine 11%). In patients who had an acute rejection episode by year 3, the proportion of patients with donor-specific antibodies was 12% (MI), 8% (LI), and 19% (cyclosporine). In regard to renal function at year 3, the mean calculated GFR was 65.2 ± 26.3 mL/min/1.73 m2
(MI), 65.8 ± 27.0 mL/min/1.73 m2
(LI), and 44.4 ± 23.6 mL/min/1.73 m2
< 0.0001 MI or LI versus cyclosporine). The mean calculated GFR in belatacept-treated patients was consistently higher compared with cyclosporine-treated patients throughout the study period.
The issue of PTLD, which was raised in the Phase II trial, also merits a discussion from the Phase III data. By 12 months, one patient, two patients, and one patient in the MI, LI, and cyclosporine groups developed PTLD, respectively. Additionally, between years 1 and 2, two additional patients in the MI group developed PTLD affecting the central nervous system. Four of the six patients who developed PTLD had known risk factors. One patient had EBV-negative serology pretransplant, one patient received lymphocyte-depleting therapy as treatment for an acute rejection, and two patients had EBV-negative serology and received lymphocyte-depleting therapy. Lastly, two patients with EBV-negative serology received transplants from EBV-seropositive donors. No new cases of PTLD were reported in any group between years 2 and 3.25
The second study was the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT),26
a randomized, multicenter Phase III trial conducted in patients who received a kidney transplant from an extended criteria donor defined as: aged ≥60 years; aged ≥50 years with at least two other risk factors (cerebrovascular accident, hypertension, serum creatinine >132.6 μmol/L); anticipated cold ischemia time ≥24 hours; or donation after cardiac death. Patients were treated with basiliximab induction, mycophenolate mofetil, and corticosteroids, and were then randomized to receive either belatacept MI, belatacept LI, or cyclosporine. Lymphocyte-depleting therapy was allowed for anticipated delayed graft function in cyclosporine-treated patients. Patients with acute rejection ≥Grade IIB could be treated with T-cell-depleting therapy at the investigators’ discretion.
The primary outcomes were the composite endpoint of patient and graft survival as well as the composite endpoint of renal impairment at 12 months. Note that unlike BENEFIT, BENEFIT-EXT did not include the incidence of acute rejection as a primary outcome measure. The noninferiority margin was set at 10% for patient and graft survival. Secondary outcomes included measured GFR, calculated GFR using the Modification of Diet in Renal Disease equation, prevalence of biopsy-proven chronic allograft nephropathy, and incidence and severity of biopsy-proven acute rejection. Protocol biopsies were performed at implantation and at week 52. A total of 543 patients were randomized and transplanted (n = 184 MI, n = 175 LI, n = 184 cyclosporine). There were no differences in baseline characteristics between the three groups.
Both belatacept regimens were noninferior to cyclosporine on the primary endpoint of patient and graft survival. Graft loss or death occurred in 14%, 11%, and 15% of patients treated with MI, LI, and cyclosporine, respectively. The prevalence of biopsy-proven chronic allograft nephropathy was similar between the three groups (MI 45%, LI 46%, cyclosporine 52%). The mean measured GFR at 12 months was 52.1 mL/min/1.73 m2 (P = 0.0083 versus cyclosporine), 49.5 mL/min/1.73 m2 (P = 0.1039 versus cyclosporine), and 45.2 mL/min/1.73 m2 for the MI-treated, LI-treated, and cyclosporine-treated groups, respectively. The difference in measured GFR was significantly better in the MI-treated patients versus the cyclosporine-treated patients (P = 0.0083) but was not significantly different for the LI group compared with cyclosporine (P = 0.1039).
Mean systolic and diastolic blood pressure was lower for both belatacept groups compared with the cyclosporine-treated group (MI 141/78 mmHg, LI 141/78 mmHg, cyclosporine 150/82 mmHg). The incidence of NODAT was significantly lower in the MI group compared with the cyclosporine group (MI 2% versus cyclosporine 9%, P = 0.0308). However, there was no significant difference in NODAT in the LI group compared with cyclosporine (LI 5%, P = 0.2946). The mean change in non-high-density lipoprotein cholesterol from baseline was significantly different in the MI (0.33 mmol/L) and LI (0.29 mmol/L) groups compared with cyclosporine (0.76 mmol/L, P = 0.0016 MI versus cyclosporine; P = 0.0006 LI versus cyclosporine).
There was no significant difference in the incidence of acute rejection between the three groups (MI 17.9%, LI 17.7%, cyclosporine 14.1%). However, more type IIB rejections occurred in belatacept-treated patients compared with cyclosporine-treated patients (MI 9%, LI 5%, cyclosporine 3%). The majority of rejections occurred within the first 3 months (81%), and nearly all occurred within 6 months. The numbers were small, but it should be noted that more patients in the MI group (n = 5) experienced more than one episode of acute rejection compared with the LI (n = 1) and cyclosporine (n = 2) groups. The most common treatment for acute rejection was corticosteroids, whereas T-cell-depleting therapy was used in 13, five, and four patients in the MI, LI, and cyclosporine groups, respectively.
Three-year data are now available for BENEFIT-EXT.27
One patient in each treatment group experienced acute rejection after year 2. By 3 years, the rate of acute rejection was 18%, 19%, and 16% for MI-treated, LI-treated, and cyclosporine-treated patients, respectively. Similar to what was found in the BENEFIT study, the development of donor-specific antibodies was lower in belatacept-treated patients. At baseline, the presence of donor-specific antibodies was similar and low across the treatment groups (6% MI, 5% LI, and 8% cyclosporine). The incremental increase in donor-specific antibodies occurred at a lower frequency in belatacept-treated patients compared with cyclosporine-treated patients by year 3 (MI 7%, LI 6%, and cyclosporine 15%). Among those who had acute rejection, the frequency of donor-specific antibodies was 9% (MI), 6% (LI), and 26% (cyclosporine). In regard to renal function at 3 years, the mean calculated GFR in the intention-to-treat population was 42.7 ± 27.6 mL/min/1.73 m2
, 42.2 ± 25.2 mL/min/1.73 m2
, and 31.5 ± 22.1 mL/min/1.73 m2
in MI-treated, LI-treated, and cyclosporine-treated patients. To look at this another way, compared with cyclosporine, both belatacept regimens had more patients with calculated GFR values within chronic kidney disease (CKD) stages 1 and 2 (31% MI and 22% LI versus 8% cyclosporine) and fewer patients within stages 4 and 5 (30% MI and 27% LI versus 44% cyclosporine, ). This is an important issue because the higher intercept GFR seen in the belatacept-treated patients may translate into improved long-term allograft outcome.
Percentage of patients at chronic kidney disease stages at 3 years in BENEFIT-EXT.
One patient (0.5%) in the MI group and two patients (1%) in the LI group developed PTLD during the 12-month follow-up period. One additional patient in each of the belatacept groups developed PTLD after month 12. Three of the five PTLD patients had negative EBV serology pretransplant. None of the patients who developed PTLD were exposed to lymphocyte-depleting therapy. By 3 years, PTLD was reported in two MI patients and three LI patients; four cases involved the central nervous system and one case (LI) involved the renal allograft and lymph nodes. Four additional cases of PTLD (three LI and one cyclosporine) occurred after 3 years; one case involved the central nervous system (LI), one involved the renal allograft (LI), one involved the gastrointestinal tract (LI), and the other involved bone marrow (cyclosporine).