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Keywords:

  • Belatacept;
  • cyclosporine;
  • kidney;
  • renal function

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Belatacept, a costimulation blocker, may preserve renal function and improve long-term outcomes versus calcineurin inhibitors in kidney transplantation. This Phase III study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) assessed a more intensive (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. The coprimary endpoints at 12 months were patient/graft survival, a composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m2 at Month 12 or a decrease in mGFR ≥10 mL/min/1.73 m2 Month 3–Month 12) and the incidence of acute rejection. At Month 12, both belatacept regimens had similar patient/graft survival versus cyclosporine (MI: 95%, LI: 97% and cyclosporine: 93%), and were associated with superior renal function as measured by the composite renal impairment endpoint (MI: 55%; LI: 54% and cyclosporine: 78%; p ≤ 0.001 MI or LI versus cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p ≤ 0.001 MI or LI versus cyclosporine). Belatacept patients experienced a higher incidence (MI: 22%, LI: 17% and cyclosporine: 7%) and grade of acute rejection episodes. Safety was generally similar between groups, but posttransplant lymphoproliferative disorder was more common in the belatacept groups. Belatacept was associated with superior renal function and similar patient/graft survival versus cyclosporine at 1 year posttransplant, despite a higher rate of early acute rejection.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Although advances in posttransplantation immunosuppressive management have reduced rates of acute rejection and improved 1-year outcomes, commensurate improvements in long-term renal allograft survival rates have not been observed (1). The kidney allograft survival rate is 95% for transplants from living donors and 89% for transplants from deceased donors during the first year, with rates decreasing to 80% and 67%, respectively, at 5 years posttransplantation (2). The leading causes of death and graft loss are cardiovascular disease and chronic allograft nephropathy, respectively (3). Among the reasons for diminished long-term graft survival may be the chronic toxicities associated with calcineurin inhibitors, the current immunosuppression standard of care. Calcineurin inhibitors may contribute to diminished long-term allograft survival rates through nephrotoxicity, which can lead to chronic allograft nephropathy, continued decline in renal function and, ultimately, graft failure (4).

In addition, since calcineurin inhibitors affect a broad range of nonimmunologic targets, they are associated with worsening hypertension (5), diabetes (6,7) and dyslipidemia (8), which can contribute to increased cardiovascular morbidity and mortality (9–12)—the most common cause of death among transplant recipients 1 year posttransplant (13,14). The current long-term outcomes in renal transplant recipients indicate a need for selective immunosuppressants that may improve long-term patient and allograft survival by avoiding the chronic toxicities of nonselective immunosuppressive therapies.

Belatacept, a selective costimulation blocker, is a human fusion protein combining a modified extracellular portion of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with the constant-region fragment (Fc) of human IgG1 (15). The specificity of belatacept is designed to provide effective immunosuppression and avoid both the renal and nonrenal toxicities associated with calcineurin inhibitors. In a Phase II study in adult kidney transplant patients, belatacept demonstrated a similar incidence of acute rejection and better renal function compared with a cyclosporine-based regimen (16).

The Phase II study results suggested that belatacept-based regimens may provide adequate immunosuppressive efficacy while avoiding the renal toxicity associated with calcineurin inhibitors and the chronic nonrenal effects of calcineurin inhibitors that can negatively impact patient/graft survival. With this in mind, the objective of this Phase III study was to assess whether treatment with belatacept-based immunosuppression would achieve superior renal function, similar patient and graft survival, and a similar rate of acute rejection by 12 months in kidney transplant recipients compared with a cyclosporine-based regimen. The study was designed to continue past the 12-month primary endpoint, to a total of 3 years, in order to characterize longer-term efficacy and safety of the belatacept-based regimens.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Design

BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide (see Supporting Information, for complete list of study centers). Primary outcomes were prespecified to be assessed at 12 months posttransplant. Enrollment began in January 2006, and primary efficacy endpoints were assessed in June 2008 when all patients were at least 12 months posttransplant. A data and safety monitoring board assessed cumulative safety and efficacy data on a regular basis throughout the trial, which remains ongoing. The study was conducted in accordance with ethical principles that have their origin in the current Declaration of Helsinki, and was consistent with International Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory requirements. The study protocol and any amendments were reviewed and approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for each site prior to initiation of the study. BENEFIT is registered with ClinicalTrials.gov (id: NCT00256750).

Patients

BENEFIT included patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time of <24 h. Recipients of extended criteria kidneys were excluded: donors ≥60 years old; donors ≥50 years old who had at least two other risk factors (cerebrovascular accident, hypertension and serum creatinine >1.5 mg/dL); an anticipated cold ischemia time of ≥24 h; and donation after cardiac death. Additional exclusion criteria included prior or concurrent nonrenal solid organ transplants, and first-time patients with a panel reactive antibody ≥50% or retransplants with a panel reactive antibody ≥30%. All patients provided signed informed consent.

Interventions

Patients were randomized 1:1:1, using an interactive voice response system and stratified by study site, to receive a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immunosuppression (Figure 1). The study was blinded to patients and study personnel with respect to belatacept dose regimen assignment and open-label with respect to allocation to belatacept or cyclosporine, primarily due to the need for therapeutic dose monitoring in cyclosporine-treated patients. Placebo infusions were utilized to maintain the blind between the belatacept dose regimens. Each patient was treated with basiliximab induction (20 mg i.v. on the day of transplantation and 4 days posttransplantation), mycophenolate mofetil (2 g/day p.o. in divided doses) and corticosteroids (initiated at 500 mg IV preoperatively and tapered to no less than 2.5 mg/day by Day 15). After Month 12, patients were to remain on the maintenance doses of study medications through Month 36. T-cell-depleting therapy was permitted in patients treated with cyclosporine who experienced impaired allograft function or were anticipated to experience delayed graft function after transplantation.

image

Figure 1. Patient disposition and dosing regimen. The dose of cyclosporine was chosen to achieve prespecified ranges of serum levels. All patients received induction therapy with basiliximab, MMF and corticosteroids.

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Patients with acute rejection ≤Grade IIA (Banff ’97 classification) (17) were treated with corticosteroids, while patients with acute rejection ≥Grade IIB could be treated with T-cell-depleting therapy at the investigator's discretion. The protocol recommended antiviral prophylaxis to all patients for at least 3 months posttransplant, and for 3 months upon initiating T-cell-depleting agents, as well as 6 months of prophylaxis against pneumocystis.

Outcomes

The primary objective of the BENEFIT study assessed each belatacept-based regimen compared with the cyclosporine-based regimen on three coprimary outcomes at 12 months: (1) composite patient and graft survival, (2) composite renal impairment endpoint and (3) incidence of acute rejection. For the composite patient/graft loss endpoint, graft loss and the cause of graft loss and death were adjudicated by committees blinded to treatment assignment. The composite renal impairment endpoint was defined as the percent of patients exhibiting a measured glomerular filtration rate <60 mL/min/1.73 m2 at Month 12 or a decrease in measured glomerular filtration rate ≥10 mL/min/1.73 m2 from Month 3 to Month 12. The measured glomerular filtration rate was assessed using a 0.5 mL dose of subcutaneously administered cold iothalamate (18). The endpoint of acute rejection was defined as histologically confirmed rejection as determined by the central pathologist, in which there were protocol-defined reasons for clinical suspicion of rejection (unexplained rise of serum creatinine ≥25% from baseline, unexplained decrease in urine output; fever and graft tenderness or serum creatinine that remains elevated within 14 days posttransplantation) or treatment for acute rejection with other reasons for clinical suspicion. The decision to treat acute rejection was based on the local reading of allograft biopsy. In addition, scheduled (protocol) allograft biopsies were performed on all patients in the study at the time of implantation and at Week 52.

The presence of antidonor human leukocyte antigen (HLA) antibodies was assessed at study baseline, at Months 6 and 12, and at the time of any suspected rejection episode. Assessment of antidonor HLA antibodies was performed at Emory University (Atlanta, GA) (19–21).

Secondary outcomes

Secondary outcomes at Month 12 included the mean measured glomerular filtration rate, mean calculated glomerular filtration rate using the modification of diet in renal disease (MDRD) equation (22,23), and the prevalence of chronic allograft nephropathy on protocol biopsies at Week 52 (Banff ’97 classification) (17). Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplant (NODAT), and mean changes in serum lipids. Patients were determined to have NODAT if they received an antidiabetic medication for ≥30 days or had ≥2 fasting plasma glucose tests ≥126 mg/dL. The primary dyslipidemia assessment was the change in non-high-density lipoprotein (non-HDL) cholesterol (total cholesterol minus HDL cholesterol) from baseline to Month 12. The intensity of antihypertensive therapy and dyslipidemic therapy was assessed at Month 12. Patients were assessed for delayed graft function by determining whether they had been treated with dialysis within the first week posttransplantation.

Statistical methods

All analyses were conducted on the intent-to-treat (ITT) population, which was defined as randomized patients who received a transplant. A sequential testing procedure was employed for testing the coprimary and key secondary hypotheses (24), with a testing hierarchy as follows: (1) patient and graft survival by 12 months using a 10% noninferiority margin, (2) the superiority test of the composite renal impairment endpoint at 12 months, (3) acute rejection experience by 12 months utilizing a 20% noninferiority margin and (4) the superiority test on chronic allograft nephropathy at 12 months. A primary measure was tested between a particular belatacept arm and the cyclosporine arm only if all preceding endpoints were met (either within the prespecified noninferiority margin or statistically significant for superiority depending on the endpoints). To account for multiple comparisons, the nominal type I error rate was set at 2.7% (two-sided) for each belatacept arm versus the cyclosporine arm and at 5% overall for the entire study.

Primary efficacy outcomes were assessed between treatment groups using 97.3% confidence intervals (CIs). For composite patient/graft survival, if the lower bound of the CI (belatacept-cyclosporine) was ≥10%, then the corresponding belatacept regimen was considered as not inferior to cyclosporine. For the composite renal impairment endpoint, a continuity corrected chi-square test was performed to assess the difference between each belatacept regimen and cyclosporine regimen at 12 months. For acute rejection, if the upper bound of the CI (belatacept–cyclosporine) was <20%, then the corresponding belatacept regimen was considered as noninferior to cyclosporine. Imputation methodology for missing data in all primary outcomes is listed in Supporting Information.

The 10% noninferiority margin for composite patient/graft survival was chosen based on precedent in other trials of tacrolimus and mycophenolate and allowed at most a 3% absolute difference in patient/graft survival between the belatacept and cyclosporine groups (25,26). A 20% noninferiority margin for acute rejection was selected to demonstrate that belatacept had some antirejection effect, based on the estimated effects of cyclosporine on this endpoint (27–30); however, it was not intended to demonstrate that there was no difference in the incidence of acute rejection between treatment groups.

Measured glomerular filtration rate at Month 12 was analyzed using an analysis of variance (ANOVA) model with factor for treatment to assess the difference between each of the belatacept treatment groups and cyclosporine. The prevalence of chronic allograft nephropathy at 12 months was summarized between treatment groups using point estimates and a 97.3% CI. In addition, a continuity corrected chi-square test was performed to assess the difference between each belatacept regimen and cyclosporine treatment. The calculated glomerular filtration rate was summarized descriptively.

The intensity of antihypertensive therapy was assessed using the number of unique antihypertensive medications that the subject was taking at Month 12. Analyses were performed using a cumulative logit model with treatment groups as the covariate. Odds ratios between each of the belatacept treatment groups and cyclosporine, and the corresponding 97.3% CIs obtained by exponentiating the constructed 97.3% CIs for the treatment effect estimates were provided. Chi-square test (Wald chi-square) was used to test the treatment differences between each belatacept treatment group and cyclosporine group at the 0.027 significance level.

Assuming the true subject and graft survival rate is 92% at 12 months for all three regimens, a sample size of 220 subjects per arm would be required to detect noninferiority margin of 10% between each belatacept regimen and the cyclosporine regimen with 95% power, and ensures that the absolute rate of subject and graft survival could not differ between belatacept and cyclosporine by more than 3% and still satisfy the noninferiority margin. For the renal function endpoint, 220 subjects per group would afford 99% power to detect a decrease of 25% in the proportion of subjects meeting the composite renal endpoint for each belatacept regimen compared to the cyclosporine regimen, assuming 75% of cyclosporine subjects meet this endpoint with 25% drop-outs per group. Given a noninferiority margin of 20%, 220 subjects per group would provide 99% power to ascertain that the upper bound of the 97.3% two-sided CIs for the absolute difference will not exceed 20%, assuming the true acute rejection rate by 12 months is 15% for all three groups. Overall, a sample size of 220 patients per treatment group would have a 93% power to detect one belatacept regimen that met all coprimary endpoints with overall Type I error controlled at the 0.05 significance level (Dunnett adjustment for multiplicity).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Patient characteristics and disposition

Six hundred eighty-six patients were randomized to three treatment groups, of whom 666 were transplanted (Figure 1). One hundred thirty-three patients discontinued treatment during the first 12 months posttransplant. The most common reasons for discontinuation were adverse events and lack of efficacy. Of the patients who discontinued study drug, 29/46 patients in the MI group, 28/45 in the LI group and 22/42 cyclosporine group were switched to tacrolimus. Five hundred twenty-seven patients completed the initial 12 month treatment phase.

Transplant recipient demographic and baseline characteristics were well balanced and are listed in Table 1. Demographic and baseline characteristics of the donors in each group were also well balanced (data not shown), including the types of donors (living or deceased), donor age and cold ischemia time. Fifty-eight percent of all transplants were from living donors (42% related; 16% unrelated). The mean age among living donors was 42 years, and was 38 years among deceased donors. The mean cold ischemia time was 1.4 h for living donor transplants and 16.3 h for deceased-donor transplants. The percentage of patients with delayed graft function was similar between groups (MI: 16%, LI: 14% and cyclosporine: 18%), as was the prevalence of chronic allograft nephropathy (CAN) at baseline (MI: 4%, LI: 2% and cyclosporine: 3%).

Table 1.  Transplant recipients demographic and baseline characteristics
Recipient characteristicBelatacept MI (n = 219)Belatacept LI (n = 226)Cyclosporine (n = 221)
Mean age, years43.642.643.5
Male, %696575
Race, %
 White605963
 Black/African American7108
 Asian121312
 Other211817
Geographic region, %
 North America434143
 South America161615
 Europe252826
 Other151516
Reported cause of ESRD, %
 Glomerulonephritis223225
 Diabetes141012
 Polycystic kidneys141414
 Hypertensive nephrosclerosis101010
 Tubular and interstitial diseases556
 Congenital, familial, and metabolic433
 Other causes322631
Previous number of transplants, %
 0969794
 1224
 2100
 Not available112
Categorized PRA, %
 <20%878590
 ≥20%11138
History of diabetes, %171517

Patient/graft survival

Each belatacept regimen (MI and LI) was demonstrated to be noninferior to cyclosporine on the primary endpoint of patient and graft survival at 1 year at the prespecified margin of 10% (Table 2). In addition, an even more rigorous threshold of 5% was also met for both belatacept regimens. There was no imbalance in the causes of graft loss between groups. Acute rejection as a cause of graft loss was reported for one patient in the belatacept MI group and two patients each in the LI group and the cyclosporine groups. Information on patient/graft survival (coprimary outcome) was available for 99.5% of all ITT patients at Month 12.

Table 2.  Outcomes: Patient/graft survival, renal function and structure and acute rejection
Month 12 endpointsBelatacept MI (n = 219)Belatacept LI (n = 226)Cyclosporine (n = 221)
Patient/graft survival
Patients surviving with functioning graft, n (%)209 (95)218 (97)206 (93)
 95% CI92.7–98.294.1–98.989.9–96.5
 Difference from CsA (97.3% CI)2.2 (−2.9, 7.5)3.2 (−1.5, 8.4)
Graft loss or death, n (%)10 (5)8 (4)15 (7)
 Graft loss4 (2)5 (2)8 (4)
 Death6 (3)4 (2)7 (3)
 Death with functioning graft6 (3)3 (1)6 (3)
 Imputed as graft loss or death, n (%)0 (0)0 (0)1 (1)
Renal function and structure
mGFR <60 mL/min/1.73 m2 or decrease115 (55)116 (54)166 (78)
Month 3–12 ≥10 mL/min/1.73 m2, n (%)
 95% CI48.3–61.847.5–60.972.4–83.5
 Difference from CsA (97.3% CI)−22.9 (−32.6, −12.9)−23.7 (−33.3, −13.7)
 p-Value<0.0001<0.0001
Mean mGFR, mL/min/1.73 m2 (SD)65.0 (30.0)63.4 (27.7)50.4 (18.7)
 Estimated difference from CsA (97.3% CI)14.6 (8.8, 20.3)12.9 (7.2, 18.6)
 p-Value<0.0001<0.0001
CAN, n (%[95%CI])40 (18 [13.1–23.4])54 (24 [18.3–29.5])71 (32 [26.2–38.6])
 Difference from CsA (97.3% CI)−14.2 (−23.2, −5.0)−8.5 (−17.9, 0.9)
Mild CAN (stage I), n (%)21 (10)29 (13)41 (19)
Moderate CAN (stage II), n (%)5 (2)6 (3)9 (4)
Severe CAN (stage III), n (%)4 (2)6 (3)6 (3)
Acute rejection
Acute rejection, n (%)49 (22)39 (17)16 (7)
 95% CI16.9–27.912.3–22.23.8–10.7
 Difference from CsA (97.3% CI)15.1 (7.9, 22.7)10.0 (3.3, 17.1)
Banff grade, n (%)
 Mild acute (IA)7 (3)4 (2)3 (1)
 Mild acute (IB)3 (1)8 (4)5 (2)
 Moderate acute (IIA)17 (8)16 (7)6 (3)
 Moderate acute (IIB)20 (9)10 (4)2 (1)
 Severe acute (III)2 (1)1 (<1)0

Renal function and structure

At 12 months, renal function was superior in patients receiving belatacept versus cyclosporine as demonstrated by the coprimary composite renal impairment endpoint (Table 2), mean measured glomerular filtration rate (Table 2) and mean calculated glomerular filtration rate (Figure 2, top panel). Measured glomerular filtration rate data at Month 12 were available for 88% of the ITT patients who survived with a functioning graft by Month 12. At Month 12, the mean measured glomerular filtration rate was 13–15 mL/min higher and the mean calculated glomerular filtration rate was 15 mL/min higher in the belatacept groups versus cyclosporine. The prevalence of biopsy-proven chronic allograft nephropathy at Month 12 was lower in the belatacept groups compared with cyclosporine (18% MI; 24% LI; 32% cyclosporine; Table 2). Protocol biopsies were available for 79% of all patients at Month 12. Additional information on renal function and structure can be found in Supporting Table S1.

image

Figure 2. Calculated (MDRD) glomerular filtration rate over time (top). Iothalamate-measured glomerular filtration rate in patients with or without acute rejection by Month 12 (bottom).

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Acute rejection

The incidence of acute rejection at 12 months was higher in the belatacept groups compared with CsA (22% MI; 17% LI; 7% cyclosporine). The incidence of acute rejection met the noninferiority criteria between the belatacept LI and cyclosporine groups, but not between the belatacept MI and cyclosporine groups (Table 2). The difference in the incidence of acute rejection between the belatacept MI and cyclosporine group was 15.1% (97.3% CI: 7.9, 22.7) and was 10.0% (3.3, 17.1) between the belatacept LI group and cyclosporine. Since the upper-bound of the 97.3% CI for the difference in acute rejection incidence between the MI group and cyclosporine exceeded the 20% noninferiority margin, it was deemed significantly different. More belatacept patients had Banff grade IIB rejection, particularly in the MI group, compared with cyclosporine. Eighty-two percent of acute rejection episodes occurred within the first 3 months, and nearly all occurred within 6 months. In the belatacept MI, LI and cyclosporine groups, 6 (3%), 3 (1%) and 2 (1%) patients experienced >1 episode of acute rejection, respectively. Centrally read biopsies were available for 94% of patients with clinically suspected acute rejection. Data on antiHLA antibody production by Month 12 was available for 44/49 patients with acute rejection in the belatacept MI group, 37/39 patients in the LI group and 14/16 patients in the cyclosporine group. Observed rates of donor-specific anti-HLA antibody production were lower in belatacept-treated patients versus cyclosporine. In belatacept MI, LI and cyclosporine patients, 3%, 1% and 7% of all patients and 5%, 0% and 7% of those with acute rejection, respectively, developed anti-HLA antibodies by Month 12.

The most common treatment for acute rejection was corticosteroids. By Month 12, 21% of patients in the belatacept MI group, 17% in the LI group and 7% in the cyclosporine group were treated for acute rejection. Initial T-cell-depleting therapy for AR was used in 13, 10 and 2 patients in the MI, LI and cyclosporine groups, respectively. Thirteen patients (6%) in the belatacept MI group and 10 (4%) in the LI group experienced corticosteroid-resistant acute rejection; while no patients in the cyclosporine group experienced corticosteroid-resistant acute rejection. Of the patients with acute rejection by Month 12, 45/48, 36/39 and 15/16 in the belatacept MI, LI and cyclosporine groups survived with a functioning graft. Among patients with acute rejection, 56% in the belatacept MI group, 68% in the LI group and 69% in the cyclosporine group recovered to within 110% of their baseline serum creatinine. Of note, the mean measured glomerular filtration rate at Month 12 was higher in belatacept patients with acute rejection than in cyclosporine patients without acute rejection (Figure 2, bottom panel). Rates of subclinical rejection at Month 12 were similar and low across treatment groups (belatacept MI: 4%, LI: 5% and cyclosporine: 5%).

Cardiovascular and metabolic outcomes

Blood pressure and serum lipids were improved in the belatacept groups compared with cyclosporine (Table 3). Mean systolic and diastolic blood pressure were lower in patients treated with belatacept regimens versus cyclosporine (p ≤ 0.0273 for MI or LI versus cyclosporine in all comparisons), despite that at Month 12, 35% of patients treated with cyclosporine used ≥3 antihypertensive medications compared with 26–29% of belatacept-treated patients (p = 0.0887 MI versus cyclosporine; p = 0.0223 LI versus cyclosporine).The mean change from baseline in non-HDL cholesterol was significantly different in patients treated with the belatacept MI (p = 0.0115) or LI regimen (p = 0.0104) compared to cyclosporine, as was the mean change in serum triglycerides (p = 0.0165 MI versus cyclosporine; p = 0.0047 LI versus cyclosporine). Although non-HDL cholesterol levels increased in all treatment groups, the increase was lower in the belatacept arms compared with cyclosporine, despite a higher proportion of cyclosporine patients who used ≥1 antihyperlipidemic medication (MI: 40%, LI: 37% and cyclosporine: 50%). The incidence of NODAT was 7%, 4% and 10% in the MI, LI and cyclosporine groups, respectively (p = NS for MI or LI versus cyclosporine).

Table 3.  Secondary outcomes: cardiovascular/metabolic endpoints
Month 12 endpointsBelatacept MI (n = 219)Belatacept LI (n = 226)Cyclosporine (n = 221)
Incidence of NODAT, n (%)11 (7)7 (4)16 (10)
 Difference from CsA (97.3% CI)−2.8 (−10.2, 4.4)−5.7 (−12.6, 0.5)
 p-Value0.48250.0687
Serum lipids
 Non-HDL cholesterol
   Mean change from baseline, mg/dL (SE)8.1 (2.8)8.0 (2.8)18.3 (2.8)
   Estimated difference (97.3% CI)−10.1 (−19.0, −1.3)−10.3 (−19.1, −1.4)
   p-Value0.01150.0104
 Triglycerides
   Mean change from baseline, mg/dL (SE)−17.0 (7.0)−21.2 (6.9)6.6 (6.9)
   Estimated difference (97.3% CI)−23.6 (−45.4, −1.8)−27.8 (−49.5, −6.1)
   p-Value0.01650.0047
Blood pressure, mmHg (SD)
 Mean systolic BP133 (16.2)131 (16.5)139 (20.1)
   p-Value versus CsA0.001<0.0001
 Mean diastolic BP79 (11.6)79 (10.9)82 (11.2)
   p-Value versus CsA0.02730.005

Safety

Among the most common (>25%) adverse events (anemia, urinary tract infection, hypertension, constipation, diarrhea, nausea and peripheral edema), none occurred more frequently in any one treatment group (data not shown). Acute infusion-related adverse events (within the first hour after belatacept infusion) were reported by four patients each in the belatacept MI and LI groups. All acute infusional adverse events were mild to moderate in intensity and none led to discontinuation of study therapy. The only serious adverse event that occurred in >5% of patients was urinary tract infection and there were no differences between the groups (Table 4).

Table 4.  Most common serious adverse events, malignancies and infections
 Belatacept MI (n = 219)Belatacept LI (n = 226)Cyclosporine (n = 221)Total (n = 666)
  1. Some patients had >1 event.

  2. Adverse events listed by MEDRA term; PTLD in discussion encompasses the MEDRA terms ‘PTLD’ and ‘lymphoma’.

  3. 1Includes events within 56 days of treatment discontinuation; one case of PTLD occurred in a CsA patient >56 days after discontinuation.

Serious adverse events, n (%)112 (51)100 (44)126 (57)338 (51)
 Urinary tract infection10 (5)9 (4)15 (7)34 (5)
 Pyrexia10 (5)7 (3)9 (4)26 (4)
 CMV infection9 (4)10 (4)6 (3)25 (4)
 Serum creatinine increased4 (2)9 (4)10 (5)23 (4)
 Graft dysfunction4 (2)6 (3)10 (5)20 (3)
 Acute renal failure2 (1)2 (1)7 (3)11 (2)
 Renal impairment4 (2)6 (3)1 (1)11 (2)
 Pneumonia2 (1)3 (1)5 (2)10 (2)
 Diarrhea1 (1)3 (1)5 (2)9 (1)
 Lymphocele2 (1)2 (1)5 (2)9 (1)
Malignancies, n (%) (excluding nonmelanoma skin cancer)5 (2)4 (2)1 (1)10 (2)
 PTLD11 (1)1 (<1)02 (<1)
 Bone neoplasm1 (1)001 (<1)
 Breast cancer1 (1)001 (<1)
 Breast neoplasm1 (1)001 (<1)
 Chronic myeloid leukemia001 (1)1 (<1)
 Leukemia001 (1)1 (<1)
 Malignant lung neoplasm1 (1)001 (<1)
 Lymphoma01 (<1)01 (<1)
 Renal cell carcinoma01 (<1)01 (<1)
 Sarcoma1 (1)001 (<1)
 Thyroid neoplasm01 (<1)01 (<1)
Infectious adverse events, n (%)152 (69)158 (70)157 (71)467 (70)
 Urinary tract infection54 (25)63 (28)50 (23)167 (25)
 Upper respiratory tract infection24 (11)22 (10)26 (12)72 (11)
 CMV infection13 (6)17 (8)19 (9)49 (7)
 Nasopharyngitis15 (7)10 (4)20 (9)45 (7)
 Influenza15 (7)17 (8)10 (5)42 (6)
 Oral candidiasis12 (6)6 (3)13 (6)31 (5)
 BK virus infection10 (5)3 (1)9 (4)22 (3)
 Bronchitis9 (4)7 (3)5 (2)21 (3)
 Gastroenteritis9 (4)4 (2)7 (3)20 (3)
Serious infectious adverse events, n (%)44 (20)42 (19)47 (21)133 (20)
 Urinary tract infection10 (5)9 (4)15 (7)34 (5)
 CMV infection9 (4)10 (4)6 (3)25 (4)
 Pneumonia2 (1)3 (1)5 (2)10 (2)
 Sepsis2 (1)1 (<1)4 (2)7 (1)

Five, four, and one patient in the MI, LI and cyclosporine groups developed malignancies (excluding nonmelanoma skin cancer) during the first 12 months (Table 4). One patient in the belatacept MI group, two in the LI group and one in the cyclosporine group developed posttransplant lymphoproliferative disorder by Month 12. Two additional patients in the MI group developed posttransplant lymphoproliferative disorder after Month 12; both cases involved the central nervous system. Of the six recipients who developed posttransplant lymphoproliferative disorder, four had known risk factors for posttransplant lymphoproliferative disorder: having Epstein-Barr virus (EBV) negative serology only pretransplant (n = 1); receiving T-cell-depleting therapy as treatment for acute rejection only (n = 1), or having both EBV negative serology and receiving T-cell-depleting therapy (n = 2). Two of the recipients with EBV negative serology received allografts from donors who were seropositive for EBV.

Overall, the frequency of bacterial, viral and fungal infections was similar among groups, (Table 4) as was the incidence of cytomegalovirus infection and BK virus infections. Tuberculosis was reported in one patient in the cyclosporine group by Month 12.

Tremor was reported more frequently in the cyclosporine group (16%) compared with the MI (4%) or LI (5%) groups.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

In BENEFIT, one of the largest studies in kidney allograft recipients, belatacept was associated with similar patient and graft survival, superior renal function, a trend toward less chronic allograft nephropathy and an improved cardiovascular and metabolic profile compared with cyclosporine 1 year posttransplant, despite an increase in acute rejection in the early posttransplant period. Belatacept was generally safe and well tolerated. There appeared to be no additional efficacy gained using the belatacept MI regimen compared with the LI regimen. Belatacept is a new immunosuppressive therapy that avoids the renal and nonrenal toxicities associated with calcineurin inhibitors.

The potential long-term impact of improved kidney function and structure using a belatacept-based immunosuppressive regimen is significant since several studies have noted the relationship between 1 year posttransplant renal function and long-term patient and graft survival (31–34). The 13–15 mL/min glomerular filtration rate renal function improvement in patients who received belatacept compared with cyclosporine is generally better than the 4–5 mL/min improvement observed with sirolimus- or tacrolimus-based immunosuppression regimens in kidney transplant recipients (35,36). Since the glomerular filtration rate generally declines by approximately 1–2 mL/min/1.73 m2/year in kidney transplant patients and ultimately leads to graft failure (37), the 13–15 mL/min benefit associated with belatacept 1 year posttransplantation may translate to improved long-term allograft and patient survival. In addition, the costs of dialysis or retransplant and the increased morbidity and mortality associated with graft failure place a premium on preserving graft function (38). The strength of the superior renal function demonstrated in BENEFIT is supported by the fact that measured glomerular filtration rate data were collected from 88% of all patients. The impact of improved renal function with belatacept should be considered with other aspects of belatacept's clinical profile—including overall safety, impact on and characteristics of acute rejection episodes and cardiovascular and metabolic profile—to determine the net impact on long-term outcomes.

The rates and grades of acute rejection were unexpectedly higher in the belatacept-based regimens compared with cyclosporine. The higher incidence of acute rejection between the LI group (17%) and the cyclosporine group (7%), while within the prespecified noninferiority margin, could be clinically meaningful. However, the acute rejection rates in the belatacept groups in BENEFIT are similar to rates observed in other trials of calcineurin inhibitor-based regimens in kidney transplant recipients, which range from 12% to 30% (7,35,39–43). Further, the rate of acute rejection in the cyclosporine arm in BENEFIT is notably lower than observed with cyclosporine in the aforementioned studies. Most acute rejection episodes in BENEFIT occurred within the first 3 months, did not recur, were not antibody mediated, and generally resolved with treatment. Receptor occupancy data in renal transplant patients treated with belatacept indicate that acute rejection likely did not result from inadequate CD80/86 receptor saturation (44). Early, cellular-based acute rejection that results in recovery of renal function has been proposed to have minimal impact on long-term graft survival (32,34,45–47). Despite significant reductions in rates of acute rejection over the last decade, long-term patient/graft outcomes have not improved (1). Glomerular filtration rate at 1 year has emerged as an important predictor of long-term graft survival (32). Continued observation of BENEFIT over the study period of 3 years could confirm whether glomerular filtration rate, and not acute rejection, is a better predictor of long-term patient/graft survival.

The overall impact of acute rejection episodes did not negate the relative benefits of belatacept on renal function, since measured glomerular filtration rate in belatacept patients with acute rejection remained numerically higher than the measured glomerular filtration rate in cyclosporine patients without acute rejection. One-year patient and graft survival were similar between all treatment groups, and acute rejection was rarely associated with graft loss. The findings in BENEFIT suggest that the immune-selectivity of belatacept may affect the composition of rejection infiltrate differently from cyclosporine, resulting in reduced graft damage. A recent report indicated that graft biopsies in belatacept-treated patients had a significantly greater number of FOXP3(+) T-regulatory cells during acute rejection compared with calcineurin inhibitor-treated patients (48). The presence of T regulatory cells in acute rejection infiltrates has been proposed to impart improved outcome of acute rejection, as suggested in a study in which FOXP3 mRNA levels in urine were significantly higher in patients with successful reversal of acute rejection (49,50). The preservation of good renal function in patients with acute rejection treated with belatacept may indicate that costimulatory blockade may facilitate recovery from acute rejection through specific immune regulatory mechanisms. Further immunophenotypical characterization of acute rejection biopsies might help elucidate the biology of acute rejection in belatacept-treated patients.

The finding that the belatacept LI regimen was associated with a lower rate of acute rejection compared to the MI regimen is intriguing. Data from experimental studies suggest that B7 blockade may interfere with CTLA4-B7 negative signaling that may be required to curtail alloresponses (51). In a Phase II trial with CTLA4lg in psoriasis patients, humoral immune response to keyhole limpet hemocyanin immunization was abrogated in lower doses of CTLA4lg but not with the highest dose, 50 mg/kg (52).

Treatment with belatacept-based regimens was generally safe—there did not appear to be an increased incidence of serious adverse events, cytomegalovirus or BK polyoma virus infection or fungal infections through Month 12. Infusional events were rare and mild or moderate in nature. There were numerically more patients with malignancies in the belatacept groups at Month 12, although most types of malignancies occurred in only 1 patient each, and no specific type of malignancy appeared to occur more often in any treatment group. However, including post-1-year data, posttransplant lymphoproliferative disorder, particularly CNS posttransplant lymphoproliferative disorder, was more common in belatacept-treated patients (especially the MI regimen) compared with cyclosporine. Posttransplant lymphoproliferative disorder cases occurred in recipients with known risk factors, particularly EBV negative status, administration of T-cell-depleting therapy, and in those who developed cytomegalovirus disease. The incidence of posttransplant lymphoproliferative disorder on belatacept may be reduced by minimizing use in patients with EBV negative serology, selectivity using T-cell-depleting therapy and utilizing prophylaxis for cytomegalovirus infection.

BENEFIT has several strengths and limitations. The size of the study, the assessment of a gold-standard, iothalamate-based glomerular filtration rate, inclusion of 12-month protocol biopsies and the completeness of key assessments support the overall conclusions. The study was open-label with respect to patient assignment to belatacept or cyclosporine, primarily due to the need for periodic assessments of cyclosporine serum concentrations. However, the primary endpoints were objective, and the causes of graft loss and death were adjudicated by independent external committees. Although we cannot exclude the potential for bias for or against belatacept in other endpoints due to the open-label nature of the assignment to belatacept versus cyclosporine, the overall results are consistent with the previous Phase II study and with the literature regarding cyclosporine (5–8,16). Furthermore, the favorable differences in some outcomes (e.g. blood pressure and serum lipids) occurred despite more intensive use of antihypertensive or dyslipidemia medications in the cyclosporine group.

Belatacept is a first-in-class costimulation blocker that selectively blocks T-cell activation. Results from BENEFIT suggest that this selectivity allows effective immunosuppression, better preservation of renal function, an improved cardiovascular/metabolic risk profile and less toxicity compared with calcineurin inhibitors. Treatment with belatacept was generally safe, although there was a higher incidence of PTLD in belatacept patients with known risk factors. Outcomes will continue to be monitored over the duration of this 3-year study to help assess the overall profile of belatacept-based immunosuppression.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

The authors thank the writing and editorial assistance of Brian Atkinson, PhD, Bristol-Myers Squibb.

Funding source: This study was sponsored by Bristol-Myers Squibb.

Conflict of Interest Statements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

The BENEFIT study was supported by Bristol-Myers Squibb. Dr Vincenti has received research support from Bristol-Myers Squibb, Pfizer, Novartis, Astellas, Genzyme, Genentech and Roche. Dr Vanrenterghem has served as an advisory board member for Astellas Pharma United States. Drs Agarwal, Di Russo, Lin and Garg are employees of Bristol-Myers Squibb. Dr Larsen has received research support and served as an advisor to Bristol-Myers Squibb.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest Statements
  9. References
  10. Supporting Information

Table S1. Additional detail on renal function and structure

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AJT_3005_sm_TableS1.pdf181KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.