Description
Nulojix (belatacept) is a soluble fusion protein designed to be a selective co‐stimulation blocker that binds to a specific site (CD80 and CD86) on antigen‐presenting cells of the immune system to block the second signal necessary to activate naïve T‐cells, which coordinate immune‐mediated rejection of transplanted organs.

Nulojix (belatacept) is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant, used in combination with basiliximab induction, a mycophenolic acid (MPA), and corticosteroids.

Limitations of use Nulojix (belatacept) should only be used in patients who are Epstein‐Barr virus (WBV) seropositive use has not been established for the prophylaxis of organ rejection in transplanted organs other than the kidney.

Belatacept is available as Nulojix in 250mg lyophilized powder for injection.

Policy 
Initial criteria

1. For prophylaxis of organ rejection in adult patients receiving a kidney transplant, AND
2. Member does not have a history of liver transplant, AND
3. Medication will be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids, AND
4. Member is Epstein-Barr virus (EBV) seropositive, AND
5. Prescribed by or in consultation with a nephrologist or transplant specialist

Auth duration: 6 months

Reauthorization criteria

1. Documentation that member is responsive to therapy as demonstrated by no signs or symptoms of kidney rejection

Auth duration: 12 months

Rationale
In renal transplant patients, Nulojix® (belatacept) was shown to be non-inferior to cyclosporine (CsA) for patient and graft survival and had significantly higher GFRs, a result which held up in long term studies as well. Incidences of acute rejection episodes, defined differently in each study, were often significantly higher in the Nulojix (belatacept) patients, although without direct correlation to graft loss or death, and these events occurred early in therapy. Secondary outcomes were often focused on the common drawbacks to oral calcineurin inhibitors (CNIs), namely BP, lipid panels, and diabetic complications. For Nulojix (belatacept), blood pressures and reductions in non-HDL cholesterol were significantly better, while fewer incidences of new onset diabetes occurred with Nulojix (belatacept) (significant to borderline significant depending on patient population), but long term follow up in one study extension showed these benefits were not preserved over time between agents. Some studies were complicated by patients 
being switched to tacrolimus, another more-favored CNI, yet were included in analysis, while other extensions were limited in size. 

Nulojix® (belatacept) was introduced as an infused alternative to oral CNIs, which can contribute to weight gain, hypertension, post-transplant diabetes (increasing the risk of 
mortality and graft failure), and a decline in renal function. Belatacept was primarily compared to CsA in studies, as that was the predominant CNI used at the time of most trials’ instigation. CsA has fallen out of favor compared to tacrolimus in guidelines, due to greater graft survival and less acute rejection but there is limited evidence available (one small trial) comparing these two agents.

Nulojix® (belatacept) has a black box warning concerning post-transplant lymphoproliferative disorder (PTLD), which occurred in belatacept patients who were Epstein-Barr virus (EBV) negative or previously used T-cell depleting therapies. The warning also contains cautions of malignancies, which can be opportunistic due to immunosuppression, and progressive multifocal leukoencephalopathy (PML), which was rare, but reported in studies. While general and serious AEs were similar compared to both CsA and tacrolimus, with more discontinuation of study drug with the latter, malignancies were varied in nature and fairly balanced across all arms in the pivotal studies. Non-life or graft-threatening infusion-related reactions occurred among belatacept patients, and while infections in general were higher in likelihood among all agents compared, fungal infections tended to be higher in belatacept patients when compared to tacrolimus.

In 2021, information regarding the risk of rejection with conversion from a CNI based maintenance regimen was added to the prescribing information. Conversion of patients 
receiving a CNI based maintenance regimen to a belatacept based maintenance regimen increases the risk of acute rejection. In two randomized controlled studies, kidney transplant recipients at least six months post-transplant and stable on a CNI based regimen who were converted to a belatacept based regimen experienced higher rejection rates mostly during the first year post-conversion than patients maintained on their CNI based regimens. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant.

In 2-year follow up from a Phase II RCT of belatacept vs. caleineurin inhibitors cyclosporine or tacrolimus (CNI), year 2 data showed a mean cGFR of 62.0 ml/min (belatacept) vs. 55.4 ml/min (CNI). The mean change in cGFR from baseline was +8.8 ml/min (belatacept) and +0.3 ml/min (CNI). Higher cGFR was observed in patients switched from either cyclosporine (+7.8 ml/min) or tacrolimus (+8.9 ml/min). The frequency of acute rejection in the LTE cohort was comparable between the belatacept and CNI groups by Year 2. All acute rejection episodes occurred during Year 1 in the belatacept patients and during Year 2 in the CNI group. There were more non-serious mucocutaneous fungal infections in the belatacept group. Switching to a belatacept-based regimen from a CNI-based regimen resulted in a continued trend toward improved renal function at 2 years after switching. The results support the previous hypothesis of a prolonged renal-sparing effect of belatacept, since it avoids some of the toxicities commonly observed with CNI.

Similarly, in the 3-year extension of the Phase III BENEFIT-EXT trial in patients receiving extended donor criteria kidneys (ECD) where poorer outcomes are normally expected, patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in Nulojix® (belatacept)-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR < 30 mL/min (chronic kidney disease [CKD] stage 4/5) than Nulojix® (belatacept)-treated patients (27 – 30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

References

1. 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 Mar;10(3):535-46.
2. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010 Mar;10(3):547-57.
3. Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010 Dec 27;90(12):1528-35.
4. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005 Aug 25;353(8):770-81.
5. Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010 Sep;21(9):1587-96.
6. Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011 Jan;11(1):66-76.
7. Rostaing L, Massari P, Garcia VD et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011 Feb;6(2):430-9. Epub 2010 Nov 4.
8. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation 2009; 9(Suppl 3): S1–S157.
9. Vanrenterghem Y, Bresnahan B, Campistol Jet al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidneytransplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011May 15;91(9):976-83.
10. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2012 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2014. Available at: https://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/2012_SRTR_ADR.pdf Accessed September 17, 2021.
11. Posselt AM, Szot GL, Frassetto LA, et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on Tcell adhesion or costimulation blockade. Transplantation. 2010;90(12):1595-1601.
12. Klintmalm GB, Feng S, Lake, JR, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-Year experience from a phase II study. Oral presentation at: Annual Meeting of the American Transplant Congress; April 30-May 4, 2011; Philadelphia.
13. NULOJIX (Belatacept) prescribing information. Bristol Meyers Squibb. Princeton, NJ. Revised July, 2021. 
14. Bremer S, Vethe NT, Rootwelt H, et al. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. J Transl Med. 2009 Jul 27;7:64.
15. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy. 2011 Apr;31(4):394-407. Review. The role of belatacept in transplantation: results and implications of clinical trials in the context of other new biological immunosuppressant agents. Clin Transplant. 2012 Dec 2. doi: 10.1111/ctr.12044 . Transplantation. 2018 Sep;102(9):1440-1452.Heemann U, Viklicky O.
16. Grinyo J, Alberu J, et al. Transpl Int. 2012 Oct;25(10):1059-64. Available online at: Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study.Available at: http://www.ncbi.nlm.nih.gov/pubmed/22816557 Accessed September 17 ,2021.
17. Pestana JO, Grinyo JM, et al. Three-year outcomes from BENEFIT-EXT: a Phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012 Mar;12(3):630-9. https://www.ncbi.nlm.nih.gov/pubmed/22300431 Accessed September 17, 2021.
18. Bassil N, Rostaing L, Mengelle C, et al. Prospective monitoring of cytomegalovirus, Epstein-Barr virus, BK virus, and JC virus infections on belatacept therapy after a kidney transplant. Exp Clin Transplant. 2014 Jun;12(3):212-9.
19. Vincenti F1, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43.
20. Schwarz C, Mahr B, Muckenhuber M, Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results. Expert Rev Clin Immunol. 2018 Jul;14(7):583-592. doi: 10.1080/1744666X.2018.1485489. Epub 2018 Jun 25.Perez CP, Patel N, Mardis CR, Belatacept in Solid Organ Transplant: Review of Current Literature Across Transplant Types. 
21. Hardinger K, Brennan D. Kidney transplantation in adults: Maintenance immunosuppressive therapy. UpToDate. Accessed September 17, 2021.
22. McDonald R. Kidney transplantation in children: Immunosuppression. UpToDate. Accessed September 17, 2021.

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