REVIEW URRENT C OPINION

Belatacept in kidney transplantation Vikas Satyananda and Ron Shapiro

Purpose of review Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a selective costimulation blockade agent, is the first biological agent approved for maintenance immunosuppression in renal transplantation. Recent findings Studies have shown better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared with CNIs. More recent studies have shown that belatacept can be an effective first-line immunosuppressive agent with complete avoidance of CNIs and corticosteroids. Summary Newer biological agents like belatacept may replace CNIs/corticosteroids in renal transplant recipients, with a benefit of better short-term and long-term renal function, better compliance, and ultimately a possible improvement in long-term renal allograft survival. Keywords belatacept, calcineurin inhibitor toxicity, costimulation blockade, immunosuppression, kidney transplantation

INTRODUCTION

MECHANISM OF ACTION

Better immunosuppression has played an important role in improving short-term outcomes after kidney transplantation. However, long-term graft survival has not improved over the past 25 years [1]. Prominent among the factors that have compromised long-term outcomes has been the nephrotoxicity associated with calcineurin inhibitors (CNIs) [2]. The search for alternative small molecules for maintenance immunosuppression has not been convincingly successful. Sirolimus-based regimens have been associated with higher rejection rates, and although there have been studies demonstrating comparable graft survival outcomes (that is, the Symphony and ORION trials), registry analyses have suggested worse patient and graft survival rates [3,4]. The ZEUS study showed that an everolimus-based regimen had a higher glomerular filtration rate (GFR) with similar graft and patient outcomes, but with higher rejection rates at 24 and 36 months compared with a cyclosporine (CsA)-based regimen [5]. In addition to the search for more effective small molecules, there has also been an attempt to discover biological agents that can target specific immune pathways resulting in efficacious immunosuppression, but perhaps with a better side-effect profile compared with CNI-based regimens [6]. Belatacept is the first biological agent approved for maintenance immunosuppression in kidney transplantation.

T cells orchestrate the adaptive immune response to foreign antigens. Naı¨ve T cells require two signals for activation [7]. Signal 1 is provided when the antigen-presenting cells (APCs) present the antigenic peptide complex with the major histocompatibility complex to the T-cell receptor. Signal 2 is costimulation, in which several ligands on the APCs interact with T-cell receptors, which leads to amplification of the T-cell response. If the costimulation is blocked, the T-cell becomes anergic and eventually undergoes apoptosis. Several costimulatory pathways are involved in T-cell regulation, which can either upregulate or downregulate T-cell activation [6]. One of the best-characterized costimulatory reactions is between CD28/CTLA4 on T cells and CD80 and CD86 on APC. The interaction between CD28 and CD80/CD86 leads to T-cell activation [8]. CTLA4 is a structural homolog of CD28, binds with Multiorgan Transplant Surgery, Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Correspondence to Dr Ron Shapiro, Professor of Surgery, Robert J. Corry Chair in Transplantation Surgery, Associate Clinical Director, Starzl Transplantation Institute, UPMC, Montefiore, 7 South, 3459, Fifth Avenue, Pittsburgh, PA 15213-3236, USA. Tel: +1 412 647 5800; fax: +1 412 647 5070; e-mail: [email protected] Curr Opin Organ Transplant 2014, 19:573–577 DOI:10.1097/MOT.0000000000000134

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Immunosuppression

KEY POINTS  Belatacept is an effective maintenance immunosuppressive agent and is noteworthy for having no nephrotoxicity.  Newer regimens combining depleting antibody induction with steroid avoidance and belatacept have been associated with excellent outcomes in small trials.  The promise of belatacept in renal transplant patients leading to an improvement in long-term outcomes may be of enormous importance to the field.  Issues related to PTLD in EBV-seronegative patients need to be studied further in careful trials of monitoring for EBV infection and prophylaxis in high-risk patients.

CD80/CD86 with higher avidity, and is a negative regulator of T cells. The receptor fusion protein CTLA4-Ig, comprising the extracellular-binding domain of CTLA4 linked to the modified Fc domain of human immunoglobulin IgG1 was developed to inhibit costimulation and T-cell activation by binding to CD80/ CD86 [9]. Abatacept is the first-generation molecule, and belatacept (LEA29Y) is the second-generation molecule. Belatacept binds CD80 twice as well and CD86 four times as well, and provides 10-fold more potent T-cell inhibition than abatacept [10]. Belatacept was developed after abatacept proved to be unsuccessful in nonhuman primate kidney transplant trials [11]; belatacept was found to be an effective agent, and this success led to the first clinical trials.

PHASE II TRAILS Phase II, a partially blinded, randomized, parallel group, multicenter study compared two intensity doses of belatacept with CsA in adult renal allograft non-human leucocyte antigen (non-HLA) identical recipients [12], in which the safety and efficacy of belatacept was compared to CsA. Induction was with basiliximab, and maintenance with mycophenolate mofetil (MMF) 2 g daily and corticosteroids. The three groups were randomized to more-intensive belatacept, less-intensive belatacept, and CsA for maintenance. The belatacept groups showed equivalent patient and graft survival when compared with CsA and were associated with better renal function and histology. The measured GFR (mGFR) was 66.3 ml/min/1.73 m2 with more-intensive belatacept, 62.1 ml/min/1.73 m2 with lessintensive belatacept, and 53.5 ml/min/1.73 m2 (P ¼ 0.01) with CsA (P ¼ 0.01 and 0.04, respectively). 574

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Lipid levels and blood pressure values were similar or slightly lower in the belatacept groups. The other phase II trail involved a randomized trial of switching kidney transplant recipients between 6 and 36 months with stable graft function on a CNI-based regimen to belatacept-based therapy [13]. At 12 months, 7% of patients in belatacept arm and 0% of patients in CNI arm developed acute rejection, whereas the GFR was about 5 ml/min higher in the belatacept group.

PHASE III TRAILS The US Food and Drug Administration approval for use of belatacept as a first-line immunosuppressive agent in July 2011 was based on the results of two phase III trials, the Belatacept Evaluation of Nephroprotection and Efficacy as a First-line Immunosuppression Trial, BENEFIT [14 ], and BENEFIT-EXT [15 ], the same trial but with extended criteria donors (defined as – donation after cardiac death donors, anticipated cold ischemia time >24 h, donors >60 years, or donors >50 years with at least two of the following factors – serum creatinine >1.5 mg/dl, cerebrovascular disease, or hypertension). All patients were induced with basiliximab and maintained on MMF and corticosteroids. Patients were randomized to three maintenance groups: more-intensive belatacept, less-intensive belatacept, and CsA. The primary end points of BENEFIT trail were composite patient and graft survival, composite renal impairment endpoint, and incidence of acute rejection. In total, 527 individuals were randomized among the three groups, which had similar demographic and donor characteristics. At 1 year, there were 95, 97, and 93% graft survival rates with a mean mGFR of 65, 63.4, and 50.5 ml/min/1.73 m2, in the more intensive, less intensive, and CsA groups, respectively, with P < 0.0001 for both moreintensive and less-intensive groups versus CsA. This continued by the end of year 3, when the mGFR was higher in the belatacept arms, 65.2 þ/ 26.3 (more intensive) and 65.8 þ/ 27.0 (less intensive) than in the CsA arm, 44.4 þ/ 23.6 ml/173 m2. The incidence of acute rejection at 12 months was higher in the belatacept arms, 22% in more intensive, 17% in less intensive, and 7% in CsA arms, most of which occurred in the first 6 months. There was a higher incidence of IIa and IIb rejections but not associated with an increase in donor specific antigen (DSA). Belatacept arms also had a significantly lower mean blood pressure (more intensive 133/79 mmHg, less intensive 131/79 mmHg) versus 139/82 mmHg &

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Belatacept in kidney transplantation Satyananda and Shapiro

with CsA arm, with a P < 0.0273, for both arms. The incidence of new-onset diabetes after transplant was similar between the arms at 7 (more intensive), 4 (less intensive), and 10% (CsA). Belatacept arms had a mean change in nonhigh-density lipoprotein cholesterol of 8.1 mg/dl (more intensive) and 8.0 mg/dl (less intensive) compared with 18.3 mg/dl in CsA-treated arm, which was statistically significant with P-value of 0.0115 for more intensive and 0.0104 for less intensive versus CsA group. The incidence of post transplant lymphoproliferative disorder (PTLD) at the end of 12 months was one, two, and one patient in more intensive, less intensive, and CsA arms, respectively; between 12–24 months two more patients in the moreintensive arm developed CNS PTLD. Two of the six patients were Epstein–Barr virus (EBV) negative and had received lymphocyte depletion therapy. Five-year outcomes of BENEFIT [16 ] showed that the two belatacept arms continued to have a higher GFR with a difference of 21–23 ml/min when compared with CsA arm, with a better lipid and blood pressure profiles. BENEFIT-EXT is a 3-year randomized, multicenter trial, whose primary outcomes were composite endpoint of patient and graft survival and renal impairment at the end of 12 months (n ¼ 543). Graft loss or death occurred in 14, 11, and 15% of patients in the more intensive, less intensive, and CsA arms, respectively, at 1 year, and 20 (more intensive), 18 (less intensive), and 20% (CsA) groups at 3 years (Pestana). Chronic allograft nephropathy was similar between the three groups at 45 (more intensive), 46 (less intensive), and 52% (CsA), and mGFR was 52.1 (more intensive), 49.5 (less intensive), and 45.2 nl/min/1.73 m2 (CsA), respectively. The difference in mGFR was significant between the more intensive versus CsA groups (P ¼ 0.0083) but was not significant (P ¼ 0.1039) between less intensive and CsA groups. This advantage seemed to be maintained at the end of year 3, with cGFR 42.7, 42.2, and 31.5 ml/min/1.73 m2 in more intensive, less intensive, and CsA group, respectively. The acute rejection (AR) rates were similar among the arms 17.9% in more intensive, 17. 7% in less intensive, and 14.1% in CsA groups, with a higher incidence of type IIb rejections in belatacept arm, which continued to be the same at the end of year 3, 22% in more intensive, 24% in less intensive, and 23% in CsA groups. The incidence of new-onset diabetes after transplant was significantly higher in the CsA arm when compared with more-intensive arm 9 versus 2% but not in less-intensive arm (5%). The mean change &&

in non-high-density lipoprotein cholesterol was significantly different in the more-intensive and less-intensive groups versus CsA group. The incidence of EBV-negative PTLD was higher in belatacept arms when compared with CsA at the end of 3 years. Long-term follow-up of BENEFIT-EXT showed a higher GFR in the belatacept groups at the end of 5 years by 11–14 ml/min versus the CsA groups [17 ]. Another interesting study evaluated corticosteroid avoidance using belatacept through an open label, randomized controlled trail with two belatacept-based regimens compared with a tacrolimusbased, steroid-avoiding regimen (n ¼ 89) [18 ]. The three arms were belatacept-MMF, belataceptsirolimus (SRL), and tacrolimus-MMF. All patients received induction with four doses of thymoglobulin (maximum 6 mg/kg) for induction with a short course of corticosteroids. Acute rejection was seen in four, one, and one patient in the belatacept-MMF, SRL-MMF, and tacrolimus-MMF groups, by the end of month 6, respectively, with more than two-thirds of patients remaining in the belatacept groups, with complete CNI and steroid avoidance and a cGFR 8–10 ml/min higher in belatacept groups versus tacrolimus-MMF. The authors concluded that primary immunosuppression with belatacept utilizing depleting antibody induction may enable the simultaneous avoidance of CNIs and corticosteroids in living and standard criteria deceased donors. The limitations of the study included a relatively small sample size and potential for observer bias, as it was an open labeled study. Interstitial fibrosis/tubular atrophy was not assessed in the study. A recently published study by Kirk et al. [19 ] demonstrated the efficacy of belatacept and SRL in live donor kidney transplantation with CNI and corticosteroid avoidance (n ¼ 20). The regimen included alemtuzumab induction, monthly belatacept, daily SRL, and 1 : 1 randomization to unfractionated donor bone marrow (there was ultimately no effect of the bone marrow infusion in this trial), with withdrawal of SRL in selected patients at the end of 1 year. The eGFR at 12 and 36 months was 89  3.56 ml/min and 88  3.48 ml/min. Ten patients elected to undergo an attempt at weaning of SRL; ultimately, seven were able to be maintained successfully on belatacept monotherapy (five had acute rejection and were put back on SRL, and two of them were subsequently re-weaned off SRL). Seven patients declined weaning and three were maintained on oral immunosuppression because of associated medical conditions; of those 10 patients, all remained rejection free. The authors concluded that in immunologically low-risk patients, alemtuzumab induction with belatacept

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Immunosuppression

and SRL maintenance is an attractive option, with a complete avoidance of CNIs and corticosteroids. However, additional multicenter studies, including high-risk populations such as African-Americans, will be needed to further develop this approach to immunosuppression. That said, this innovative study may lead to a paradigm shift in immunosuppression and may allow for significant prolongation of half-lives with minimal morbidity.

CONCLUSION The huge success in increased short-term graft and patient survival after kidney transplantation with the introduction of CNIs has not translated to an increase in long-term graft or patient outcomes in the United States. The improved GFR at the end of 3–5 years with the use of belatacept is encouraging, and further favorable cardiac and metabolic end points with belatacept make it a very attractive alternative over CNIs in maintenance immunosuppression for renal transplantation. However, whether these results will translate to an improved long-term graft and patient survival will require longer term follow-up. Belatacept is an intravenous infusion, monitored by medical personnel and administered every 4 weeks, and this might well be associated with lower rates of nonadherence. This might be particularly attractive in adolescent recipients, in whom noncompliance is a substantial contributor to graft loss. The areas of concern include the increased incidence of acute rejection at the end of 1 year with belatacept versus CNIs and the increased incidence of PTLD in EBV-seronegative patients receiving belatacept. Potential explanations for these adverse side-effects include the fact that belatacept is known to decrease T-regulatory cells and increase differentiation of Th-17 cells into effector cells, thus increasing the effector/T-regulatory ratio which may contribute to increase risk of AR [20]. Another reason could also be that it has no effect on inhibition of memory cells. The increased incidence of PTLD could be explained by the fact that B7:CD28 blockade can reduce effector viral response against EBV infection [17 ]. However, the more likely issue is that EBV-seropositive donor/seronegative recipients undergoing transplantation in these adult trials received neither surveillance nor prophylaxis for primary EBV infection (EBV seronegativity is uncommon in adults). This is a preventable problem.

the predominant CNI used in kidney transplantation; thus, studies comparing belatacept with tacrolimus will need to be carried out. In addition, many innovative current protocols include depleting antibody induction and steroid avoidance/early withdrawal. In this context, the studies of Grinyo and others and Kirk et al. [19 ] have shown early success with belatacept-based regimens with both CNI and corticosteroid avoidance, and represent potentially exciting developments. These results need to be validated in large, multicenter randomized trails. With a more selective immunosuppressive action, avoidance of nephrotoxicity, and a better metabolic and cardiovascular side-effect profile, costimulation blockade seems to be a very promising new paradigm in kidney transplantation, with belatacept being the prototype molecule. Various other costimulatory blockers like anti-CD40 mAb are now being tried in human kidney transplantation, which hold the promise of targeted immunosuppression. Currently, the use of belatacept is contraindicated in EBV-seronegative patients (although this issue should perhaps be studied more carefully in trials employing better surveillance and prophylaxis), and there is little information about its use in highly sensitized patients. It may be of particular benefit in recipients of high kidney donor profile index (KDPI) [extended criteria donors (ECD)] kidneys, and potentially in young patients at risk for nonadherence. &&

Acknowledgements None. Conflicts of interest There is no conflict of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest

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FUTURE The studies on belatacept have all been in comparison with CsA, while tacrolimus (FK-506) has been 576

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1. Lamb KE, Lodhi S, Meier-Krische HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011; 11:450–462. 2. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Eng J Med 2003; 349:2326–2333. 3. Eckberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitor in renal transplantation. N Eng J Med 2007; 357:2562–2576. 4. Flechner SM, Glyda M, Cokfield S, et al. The ORION study: comparison of two-sirolimus based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. Am J Transplant 2011; 11:1633–1644. 5. Budde K, Lehner F, Sommerer C, et al. Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study. Am J Transplant 2012; 12:1528–1540. 6. Yamada A, Salama AD, Sayegh MH. The role of novel T cell co-stimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002; 13:559–575.

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Belatacept in kidney transplantation Satyananda and Shapiro 7. Bretscher PA. A two-step, two signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A 1999; 96:185–190. 8. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD 28 and CTLA-4. Nat Rev Immunol 2001; 1:220–228. 9. Judge TA, Tang A, Spain LM, et al. The in-vivo mechanism of action of CTLA4Ig. J Immunol 1996; 156:2294–2299. 10. Latek R, Fleener C, Lamian V, et al. Assessment of belatacept mediated costimulation blockade through evaluation of CD80/86 receptor saturation. Transplantation 2009; 87:926–933. 11. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y, a high affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5:443–453. 12. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353:770–781. 13. Rostaing L, Massari P, Garcia VD, et al. Switching from calcineurin inhibitor based regimen to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol 2011; 6:430–439. 14. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of & belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10:535– 546. Large randomized trial comparing belatacept to CsA in living and standard criteria donor renal transplants recipients.

15. Durrbach A, Pestana JM, Pearson T, et al. A phase II study of belatacept versus cyclosporine in kidney transplant from extended criteria donors (BENEFIT-EXT study). Am J Transplant 2010; 10:547–557. Large randomized trail comparing belatacept to CsA in extended criteria donor kidney transplant recipients. 16. Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure && maintains efficacy and safety at 5 years: results from the long-term extension of BENEFIT study. Am J Transplant 2013; 13:2875–2883. Study looking at 5-year outcomes of BENEFIT study – looking at the nephroprotection and efficacy as first-line therapy. 17. Charpentier B, Medina Pestana JO, Del C Rial M, et al. Long-term exposure to & belatacept in recipients of extended criteria donor kidneys. Am J Transplant 2013; 13:2884–2891. Study looking at 5-year outcomes of BENEFIT-EXT study. 18. Ferguson R, Grinyo J, Vincenti F, et al. Immunosuppression with Belatacept&& based, corticosteroid-avoiding regimens in de-novo kidney transplant recipients. Am J Transplant 2011; 11:66–76. First study using tacrolimus versus belatacept and also corticosteroid avoidance. 19. Kirk AD, Guasch A, Xu H, et al. Renal transplantation using belatacept without && maintenance steroids or calcineurin inhibitors. Am J Transplant 2014; 14:1142–1151. First study with complete CNI and steroid avoidance. 20. Reilla LV, Sayegh MH. T-cell costimulatory blockade in transplantation: two steps forward one step back! Expert Opin Biol Ther 2013; 13:1557–1568. &

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Belatacept in kidney transplantation.

Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a sele...
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