Medical Policy



Subject: Belatacept (Nulojix®)
Document #: DRUG.00049 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of belatacept (Nulojix) (Bristol-Myers Squibb, Princeton, New Jersey). Belatacept is an intravenous drug that is a selective T-cell co-stimulation blocker indicated for the prophylaxis of organ rejection in Epstein-Barr virus (EBV) seropositive adults receiving a kidney transplant.

Note: Please see the following related document for additional information:

Position Statement

Medically Necessary:

Belatacept is considered medically necessary for prevention of organ rejection in adults receiving a kidney transplant who are Epstein-Barr virus (EBV) seropositive. 

Investigational and Not Medically Necessary:

Belatacept is considered investigational and not medically necessary when the above criteria are not met.

Rationale

The U.S. Food and Drug Administration (FDA) approved belatacept (Nulojix) on June 15, 2011 for prophylaxis of organ rejection in combination with other immunosuppressants (specifically basiliximab, mycophenolate mofetil, and corticosteroids) in adults receiving a kidney transplant who are EBV seropositive. Belatacept is used during an initial phase beginning on the day of kidney transplantation prior to implantation and also for a maintenance phase post kidney transplantation (Nulojux PI, 2017). Use of this drug has not been established for the prophylaxis of organ rejection in transplanted organs other than the kidney. The FDA approval of belatacept was based on two open-label, randomized, multicenter phase III trials using cyclosporine as a comparator (Durrbach, 2010; Vincenti, 2010). All groups in both trials received basiliximab induction, mycophenolate mofetil, and corticosteroids. Both trials evaluated two dosing regimens consisting of a more intensive (MI) or less intensive (LI) regimen of belatacept versus (vs.) cyclosporine.

Vincenti and colleagues (2010), in the phase III Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT Study), randomized 686 adults age 18 and older of whom 666 were recipients of living donor or standard criteria deceased donor kidneys. A total of 527 recipients completed the initial 12-month treatment phase. The co-primary endpoints at 12 months were recipient/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 > or =10 mL/min/1.73 m2 month 3-month 12) and the incidence of acute rejection. At 12 months, both belatacept regimens had similar recipient/graft survival vs. 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< or =0.001 MI or LI vs. cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p< or =0.001 MI or LI vs. cyclosporine). Safety was similar between groups, but posttransplant lymphoproliferative disorder (PTLD) was more common in the belatacept groups. Belatacept was associated with superior renal function and similar recipient/graft survival vs. cyclosporine at 1 year post-transplant, despite a higher rate of early acute rejection.

In 2012, Vincenti and colleagues further evaluated outcomes of the BENEFIT Study to determine if the previously reported results were sustained at 3 years. A total of 471 of the original kidney transplant recipients (n=158 MI; n=170 LI; n=143 cyclosporine) completed at least 3 years of study therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) recipients survived with a functioning graft. The mean calculated GFR (cGFR) was ∼21 mL/min/1.73 m2 higher in the belatacept groups vs. cyclosporine at year 3. From month 3 to year 3, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m2 /year (MI) and +1.2 mL/min/1.73 m2 /year (LI) vs. a decline of -2.0 mL/min/1.73 m2 /year (cyclosporine). A single cyclosporine-treated individual experienced acute rejection between year 2 and year 3. There were no new safety signals and no new cases of PTLD after 18 months. The authors concluded that 3-year results confirmed the persistence of renal function benefits of belatacept over time. These benefits appeared to balance the early risks associated with belatacept in the study subjects, namely increased occurrence of acute rejection and PTLD.

Durbach and colleagues (2010), in the Extended Criteria Trial (BENEFIT-EXT Study), randomized 578 adults, of whom 543 were age 18 and older, and were transplanted with extended criteria donor (ECD) kidneys. ECD was defined as all deceased donors age 60 years and older and donors age 50 years and older with any two of the following criteria: hypertension, cerebrovascular cause of brain death, or pre-retrieval serum creatinine (SCr) level >1.5 mg/dL. The co-primary endpoints at 12 months were composite recipient/graft survival and a composite renal impairment endpoint. Recipient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer individuals in the belatacept group reached the composite renal impairment endpoint vs. cyclosporine (71% MI, 77% LI, 85% cyclosporine; p=0.002 MI vs. cyclosporine; p=0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept vs. cyclosporine (p=0.008 MI vs. cyclosporine; p=0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept vs. cyclosporine. Acute rejection, rates of infection and malignancy were similar between groups, but more cases of PTLD occurred in the central nervous system (CNS) of those on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar recipient/graft survival, improved renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile as compared to those treated with cyclosporine.

Vanrenterghem and colleagues (2011) evaluated the cardiovascular and metabolic endpoints from the BENEFIT and the BENEFIT-EXT studies. Cardiovascular disease, one of the most common causes of death in kidney transplant recipients with a functioning graft, can be exacerbated by immunosuppressive drugs. The authors reported that from the individuals randomized and transplanted across the two studies, at month 12, the belatacept regimen was associated with better cardiovascular and metabolic risk profiles, with better serum lipids and lower blood pressure and less new onset diabetes after transplant vs. cyclosporine. The overall profile of belatacept continues to be assessed.

In 2012, Pestana and colleagues evaluated 3-year outcomes of the BENEFIT-EXT Study. A total of 323 kidney transplant recipients completed treatment by year 3. Individual 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 the belatacept-treated group vs. those treated with cyclosporine (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated recipients (44%) progressed to GFR < 30 mL/min (chronic kidney disease stage 4/5) than those treated with belatacept (27-30%). Rates of acute rejection were similar between groups. PTLD occurrence was higher in belatacept-treated recipients (2 in MI, 3 in LI), most of which occurred during the first 18 months. Tuberculosis was reported in 2 MI, 4 LI and no cyclosporine recipients. The authors concluded that the 3-year study results demonstrated similar individual and graft survival, sustained improvements in renal function over time, with no new safety issues identified in those receiving belatacept. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Grinyo and colleagues (2012), in a long-term extension of a phase II trial, addressed whether improvement continued at 2 years. Individuals receiving cyclosporine or tacrolimus were randomized to switch to belatacept or continue calcineurin inhibitor (CNI). Of 173 randomized subjects, 162 completed the 12-month main study and entered into the long-term extension (LTE) of this phase II, randomized multi-center clinical trial. The study subjects were adult recipients of a renal allograft from a deceased or living donor at least 6 months, but no more than 36 months prior to enrollment. Only 2 subjects (n=1 each group) had graft loss between the first and second years. At year 2, mean cGFR was 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 reported in those 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 group and during year 2 in the CNI group. There were more non-serious mucocutaneous fungal infections in the belatacept group. The authors concluded that results of this study suggest that switching from either cyclosporine or tacrolimus based therapy to belatacept may result in improved renal function. However, they further noted that these results should be confirmed in a Phase III study.

A Cochrane review by Masson and colleagues (2014) analyzed five studies that compared belatacept and CNI in 1535 kidney transplant recipients. At up to 3 years post kidney transplant, both belatacept and CNI-treated recipients were found to have similar risks of acute rejection, death, and loss of transplant and returning to dialysis. Recipients treated with belatacept were 28% less likely to have chronic kidney scarring and also had better graft function than those treated with CNI. Additionally, those treated with belatacept had lower blood pressure and a decreased incidence of new-onset diabetes. The risk of PTLD was similar in both belatacept and CNI-treated recipients. However, the authors noted a lack of clarity regarding whether the short-term advantages of belatacept could be maintained over the medium to long term or translate into better cardiovascular outcomes or longer kidney transplant survival.

In 2016, Vincenti and colleagues reported 7-year results of the phase III BENEFIT study of belatacept-based immunosuppression compared to cyclosporine-based immunosuppression. Of the 660 treated kidney transplant recipients the following were monitored for the entire 7 year (84 month) period: 153 of the 219 subjects treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen. Previous significant improvements in renal function that had been observed with belatacept as compared to cyclosporine were sustained at 7 years. Subjects randomized to either the more or less intensive belatacept regimen had a 43% reduction in the risk of death or graft loss as compared to those randomized to the cyclosporine regimen. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but decreased with the cyclosporine regimen. The cumulative frequencies of serious adverse events at final follow-up were similar across treatment groups. The authors concluded that in their study the risk of death or graft loss at year 7 was significantly lower for the belatacept-treated group than for the cyclosporine-treated group and the survival benefit emerged as early as 5 years after transplantation.

In clinical trials belatacept was found to be associated with risks including PTLD and progressive multifocal leukoencephalopathy (PML). The risk of PTLD was higher in EBV seronegative individuals as compared to those who were EBV seropositive. Due to risks involved, the FDA did not approve belatacept for individuals who are EBV seronegative. The FDA has issued black boxed warnings regarding the increased risk for developing PTLD, predominantly involving the CNS and warns that "recipients without immunity to EBV are at a particularly increased risk; therefore use in EBV seropositive individuals only."

Background/Overview

A serious complication of kidney transplantation is rejection of the donated kidney. Immunosuppressant drugs are used to help prevent the organ recipient from rejecting the donor kidney. Belatacept is FDA approved for the prophylaxis of kidney transplant rejection in EBV positive adults and is used in combination with other immunosuppressants, specifically basiliximab, mycophenolate mofetil, and corticosteroids.

The 2017 FDA Product Information label includes the following information related to adverse reactions, black boxed warnings and other warnings / precautions:

Adverse Reactions:

The most common adverse events seen in 20% or more of subjects in clinical trials treated with the recommended dose and frequency of belatacept were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. Spontaneous reports during the postmarketing experience included a case of anaphylaxis, which was observed in a kidney transplant recipient whose belatacept therapy had been interrupted for 2 months during treatment of a systemic varicella infection (Nulojix PI, 2017).

Black Boxed Warnings:

Other Warnings and Precautions:

Risk Evaluation and Mitigation Strategy (REMS):

There is a Risk Evaluation and Mitigation Strategy (REMS) in place for belatacept. The goals of the REMS is to inform healthcare providers of the associated increased risks of PTLD and PML, and also to inform individuals taking the drug of the serious risks. The REMS requires the drug sponsor to dispense a medication guide with each infusion and implement a communication plan to healthcare providers.

As a result of the REMS, all kidney transplanted individuals treated with belatacept should be enrolled in the ENLiST (Evaluating Nulojix Long-term Safety in Transplant) registry in order to further evaluate the drug's safety profile.

Definitions

Immunosuppressant: Drugs used to control or reduce the immune system response.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met: 

HCPCS    
J0485 Injection, belatacept, 1 mg [Nulojix]  
     
ICD-10 Diagnosis  
N18.6 End stage renal disease  
Z48.22 Encounter for aftercare following kidney transplant  
Z94.0 Kidney transplant status  

When services are Investigational and Not Medically Necessary:
For the codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Archdeacon P, Dixon C, Belen O, et al. Summary of the US FDA Approval of Belatacept. Am J Transplant. 2012; 12(3):554-562.
  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; 10(3):547-557.
  3. Grinyo J, Alberu J, Contieri FL, et al. 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. Transpl Int. 2012; 25(10):1059-1064.
  4. Pestana JO, Grinyo JM, Vanrenterghem Y, 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; 12(3):630-639.
  5. Vanrenterghem Y, Bresnahan B, Campistol J, et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011; 91(9):976-983.
  6. 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(3):535-546.
  7. Vincenti F, Larsen CP, Alberu J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant. 2012; 12(1):210-217.
  8. Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016; 374(4):333-343.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. Belatacept Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio. Lexi-Comp., Inc. Last updated March 8, 2017. Accessed on March 10 , 2017.
  2. Belatacept. Risk Evaluation and Mitigation Strategy (REMS). Bristol-Myers Squibb Company, June 2011. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM261934.pdf. Accessed on March 10, 2017.
  3. Belatacept. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 21, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 10, 2017.
  4. Masson P, Henderson L, Chapman JR, et al. Belatacept for kidney transplant recipients. Cochrane Database Syst Rev. 2014 Nov 24; 11:CD010699.
  5. Nulojix [Product Information], Princeton, New Jersey. Bristol-Myers Squibb Company, February 2017. Available at: http://packageinserts.bms.com/pi/pi_nulojix.pdf. Accessed on March 10, 2017.
Index

Belatacept
Nulojix

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Rationale, Background and References sections updated.
Reviewed 05/05/2016 MPTAC review. Rationale, Background and Reference sections updated. Removed ICD-9 codes from Coding section.
Reviewed 05/07/2015 MPTAC review. Description, Rationale and Reference sections updated.
Reviewed 05/15/2014 MPTAC review. Rationale, Background and Reference sections updated.
Reviewed 05/09/2013 MPTAC review. Rationale and Reference sections updated.
  01/01/2013 Updated Coding section with 01/01/2013 HCPCS changes; removed C9286 deleted 12/31/2012.
New 05/10/2012 MPTAC review. Initial document development.