University Hospital of Bicêtre,
78 Rue du Général Leclerc,
94275 Kremlin-Bicêtre, France;
Research Unit INSERM/
University Paris-Sud 11 U 1014, France
Kidney transplantation is the best treatment for patients with end-stage renal disease and is associated with improved patient survival and quality of life when compared with patients on dialysis. Recipients of kidney transplants generally require long-term immunosuppression to prevent rejection of the allograft, which have deleterious adverse events. The introduction of calcineurin inhibitors (CNIs), such as cyclosporine and tacrolimus, and antiproliferative drugs for maintenance immunosuppression has led to important decreases in acute kidney allograft rejection rates, but long-term graft outcomes have seen little improvement over the last decade. In addition to death with a functioning graft, chronic allograft nephropathy (CAN) is a primary cause of long-term graft loss inducing gradual worsening of renal function assessed with the measurement of the glomerular filtration rate (GFR). Studies have also demonstrated that GFR is also a predictor of long-term graft survival.(1) Acute and chronic nephrotoxicity from CNIs is well documented as leading to renal damage, associated with immunologic and non-immunologic detrimental factors in chronic damage to the kidney.(2)
However, treatments with CNIs are associated with renal and non-renal toxicities that negatively affect long-term graft outcomes, including increases in cardiovascular risk factors, such as hypertension, hyperlipidaemia, and new onset diabetes after transplantation (NODAT). Other agents such as mTOR inhibitors have demonstrated efficacy in replacing CNIs but are themselves associated with serious adverse events, including mouth ulcers, hyperlipidaemia, angioedema, hypertriglyceridaemia, and wound-healing complications. New immunosuppressants that prevent acute and chronic graft rejection while optimising long-term safety for the kidney transplant recipient are needed.
Belatacept and T-cell activation
Acute rejection (AR) of kidney allografts is mediated by T-cell activation that needs costimulatory signals (signal 2) associated signal 1 given by the T-cell receptor. In T-cell costimulation, the CD80/CD86-CD28/CTLA4 pathway is of critical importance for T-cell activation.
Belatacept is a second-generation cytotoxic CTLA4-Ig fusion protein that blocks CD80/CD86-CD28 interaction. Belatacept comprises the Fc domain of a human IgG1 antibody fused to the extracellular domain of CTLA4, which has been modified through two amino acid substitutions to increase the agent’s avidity for CD80 and CD86.(3) Unlike other immunosuppressants, belatacept is administered intravenously.
Belatacept was evaluated in phase II and III clinical trials using two dosage regimens: a more-intensive (MI) and less-intensive (LI) regimen. The LI regimen is now the recommended dosage regimen for kidney transplant recipients, and consists of belatacept at 10mg/kg dose on day 1 (day of transplantation, before implantation), on day 5, at the end of weeks 2, 4, 8, and 12, followed by the maintenance dose of 5mg/kg every four weeks from week 16 onward. The MI regimen consisted of higher cumulative doses and more frequent dosing than the LI regimen.
The efficacies of the MI and LI belatacept regimens were assessed in a phase II, multicentre trial that enrolled 218 de novo kidney transplant recipients. Patients were randomised to receive either belatacept on the LI or MI regimen or cyclosporine, and all patients received basiliximab induction therapy, MMF and steroids.(4) Both the MI and LI regimens included an early phase (10mg/kg) and a late phase (5mg/kg at four- or eight-week intervals), with a longer early phase (six months vs three months) and more frequent dosing in the MI regimen compared with the LI regimen. At six months post-transplant, AR rates were similar between the groups (7% and 6% in the MI and LI groups vs 8% in the cyclosporine group), while mean measured GFR was significantly higher in patients receiving belatacept MI and LI (66.3 and 62.1ml/min/1.73m2, respectively) compared with patients receiving cyclosporine (53.5ml/min/1.73m2) (p=0.01 for belatacept MI vs CsA and p=0.04 for belatacept LI vs cyclosporine). Renal biopsies at one year showed a lower incidence of CAN with belatacept LI or MI (29% and 20%, respectively) compared with cyclosporine (44%). The five-year results were found to be similar to the one-year results, demonstrating stable GFR and low incidences of death/graft loss or AR in patients receiving belatacept.(5)
Based on clinical data from the phase II trial, LI and MI regimens were used for testing in the phase III trials.
Both pivotal phase III trials compared belatacept MI and LI regimens with cyclosporine; these trials consisted of de novo kidney transplant recipients receiving organs from living and standard criteria deceased donors (BENEFIT) and from extended criteria deceased donors (BENEFIT-EXT). Extended criteria donors were defined as deceased donors with at least one of the following characteristics: donor age ≥60 years, or donor age ≥50 years and other comorbidities; donation after cardiac death; anticipated cold ischaemia time ≥24 hours.
In BENEFIT, 226 patients received the belatacept LI regimen, 219 patients received the belatacept MI regimen, and 221 received the control cyclosporine regimen. At years 1 and 3, both belatacept regimens had similar patient/graft survival compared with cyclosporine and were associated with superior renal function at all time points.(6,7) Long-term modelling data suggest that the observed improvements in renal function might translate to an approximate two-year benefit in allograft half-life with belatacept compared with cyclosporine.
Surprisingly, belatacept-treated patients experienced a higher incidence and grade of AR episodes compared with cyclosporine-treated patients (cumulative AR rates of 24% and 17% in the MI and LI groups vs 10% in the cyclosporine group at year 3), a finding that had not previously been seen in the phase II trial. However, the AR episodes in belatacept-treated patients occured early, did not recur, and generally responded well to treatment.
In BENEFIT-EXT, 174 patients received the recommended (LI) regimen, 183 patients received the belatacept MI regimen, and 179 received the control cyclosporine regimen.(8,9) As was seen with BENEFIT, at years 1 and 3, both belatacept regimens had similar patient/graft survival and better renal function compared with cyclosporine. Unlike rates observed in BENEFIT, AR incidence was similar in BENEFIT-EXT between all three groups (18% and 19% in the MI and LI groups at year 3 vs 16% in the cyclosporine group).
Given the side-effects associated with prolonged CNI usage, there is a rationale for switching stable renal transplant recipients to immunosuppressive regimens associated with lower toxicities. A phase II open-label trial examined the efficacy and safety of switching to belatacept from CNI-based maintenance immunosuppression. Patients with stable renal function receiving CNI-based immunosuppression (tacrolimus or cyclosporine) were randomised to either continue on CNI-based immunosuppression (n=89) or to switch to a belatacept-based regimen (n=84).(10) After 1- and 2-year follow-up, switching from CNI to belatacept resulted in an increase in mean calculated GFR, with similar frequency of AR observed between the two groups, suggesting that switching stable kidney transplant recipients from a CNI-based regimen to a belatacept-based regimen may be safe and feasible and could allow for improved renal function.
As both CNIs and corticosteroids are associated with toxic adverse events, an exploratory phase II trial examined the use of belatacept-based regimens for avoidance of CNIs and corticosteroids in kidney transplant recipients. In the randomised, open-label, multicentre trial, EBV seropositive patients (n=89) received belatacept with MMF, belatacept with sirolimus, or tacrolimus with MMF.(11) All patients received thymoglobulin induction therapy. The study found that both belatacept-based regimens provided better renal function than the tacrolimus +MMF regimen, as mean calculated GFR at month 12 was 8–10ml/min/1.73 m2 higher in the belatacept groups than in the tacrolimus + MMF groups. At month 12, more than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens. Interestingly, AR rates were comparable between the belatacept + sirolimus and tacrolimus + MMF regimens (4% and 3%, respectively), and they were higher in the belatacept + MMF regimen at month 6 (12%). Overall, most AR episodes occurred within the first three months. Although this study contained a relatively small sample size, the results are encouraging for the use of a belatacept-based, non-steroid regimen in de novo kidney transplant recipients.
Safety data pooled from 1425 patients in the phase II trial and the two phase III trials indicate that belatacept is generally well tolerated.(12) In BENEFIT and BENEFIT-EXT, assessment of cardiovascular and metabolic end points showed that belatacept treatment resulted in better lipid profiles and reduced mean systolic and diastolic blood pressures than cyclosporine at year 1. Fewer belatacept-treated patients had received lipid-lowering medications and fewer antihypertensive medications were used on average compared with cyclosporine-treated patients.(13) In addition, there was a lower incidence of NODAT in belatacept regimens compared with cyclosporine (5% and 5% in the MI and LI regimens, respectively, vs 10% with cyclosporine at one year).
The most serious adverse events reported with belatacept are post-transplant lymphoproliferative disorder (PTLD), other malignancies, and serious infections, including progressive multifocal leukoencephalopathy (PML) and polyomavirus nephropathy.(12) Analysis of data from the long-term extension of the phase II study pooled with two-year data from the phase III trials revealed that 16 cases of PTLD occurred overall: eight in belatacept MI patients, six in belatacept LI patients, and two in cyclosporine patients. Nine of these cases (six in belatacept MI and three in belatacept LI) involved the CNS; of these, frequency was highest among EBV(−) patients, occurring in 5 of 96 (5%) of EBV(−) patients and in 4 of 805 (0.5%) of EBV (+) patients. As EBV seronegativity was found to be associated with an increased risk of CNS PTLD, belatacept is contraindicated in patients who are EBV seronegative or with unknown EBV serostatus.
Despite the increased incidence of PTLD, the LI regimen was associated with fewer deaths and serious infections than cyclosporine-based treatment. The overall frequency of malignancies was similar between the LI and cyclosporine treatment groups and was higher in the belatacept MI group. CNS infections, while uncommon, also occurred with similar frequency in the LI and cyclosporine treatment groups, and with higher frequency in the MI treatment group.
These safety results, in combination with the similar patient and graft survival and preserved renal function in both belatacept regimens, demonstrated that the LI regimen offers a more favourable benefit-risk balance than the MI regimen and, thus, support the recommended use of the LI regimen in kidney transplant recipients.(14)
The approval of belatacept for the prophylaxis of AR in kidney transplant recipients is an important advance in immunosuppression regimens. Treatment with belatacept resulted in comparable patient/graft survival and superior preservation of renal function than treatment with cyclosporine. Given the correlations observed between renal function and long-term graft outcomes, these results suggest that patients receiving belatacept may demonstrate improvements in long-term graft survival, although additional follow-up is still needed. Patients treated with belatacept in the phase III trials had higher rates of AR, which occurred early, did not recur, were generally not associated with DSAs, and few belatacept patients had graft loss due to rejection. Safety data have indicated an increased risk of PML and PTLD with belatacept use, but these safety risks are being further evaluated in several post-marketing surveillance studies.
- Kidney transplantation is the best treatment for patients with end-stage renal disease and is associated with improved patient survival and quality of life compared with dialysis.
- Recipients of kidney transplants generally require long-term immunosuppression to prevent