Coverage Policy Manual
Policy #: 2021033
Category: Pharmacy
Initiated: October 2021
Last Review: June 2022
  Belimumab (e.g., Benlysta)

Description:
Belimumab is a human monoclonal antibody that prevents the survival of B lymphocytes by blocking binding of B lymphocytes to the B lymphocyte stimulator protein (BLyS) receptors; this reduces their activity and the autoimmune response.
 
Regulatory Status
 
On March 9, 2011, the Food and Drug Administration (FDA) approved Belimumab (e.g., Benlysta) for the treatment of adult patients with systemic lupus erythematosus. In July 2017, a self-injectable formulation of Belimumab (e.g., Benlysta) was approved by the FDA. In April 2019, the FDA approved Benlysta for intravenous use in children with systemic lupus erythematosus aged five years and above.  
 
On December 16, 2020, the Food and Drug Administration approved Belimumab (e.g., Benlysta) as the first treatment for lupus nephritis, approved for adult patients receiving standard therapy.
 
Coding
 
J0490 Injection, belimumab, 10 mg

Policy/
Coverage:
The use of Belimumab subcutaneous injection is not covered under the medical benefit. Please check member’s pharmacy benefit for coverage of Belimumab subcutaneous injection.   
  
The use of Belimumab intravenous injection (J0490) is covered under medical benefit.
 
Effective October 1, 2021, Prior Approval is required for Belimumab.
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective December 7, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Belimumab meets member benefit certificate primary coverage that there be scientific evidence of effectiveness for the treatment of the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Active systemic lupus erythematosus (SLE)
a.  Individual is aged 5 years and older (FDA, 2020; Furie, 2011; Brunner, 2020) AND
b,  Individual meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria for SLE (ACR, 2019) AND has +  ANA, low complement (>1 test finding showing low C3/C4[less than the lower limit of normal]), and/or + ds ANA (Ginzler, 2022) AND
c.  Receiving standard therapy (e.g. corticosteroids, aspirin, non-steroidal anti-inflammatory drugs [NSAIDs], anti-malarials [hydroxychloroquine, chloroquine], or non-biologic immunosuppressants [azathioprine, methotrexate, cyclosporine, oral cyclophosphamide]), alone or in combination therapy (FDA, 2011); AND
d.  Individual must have failed, not tolerated, or have a contraindication to a trial of hydroxychloroquine/chloroquine, AND
e.  No evidence of severe active central nervous system lupus (FDA, 2011); AND
f.  No evidence of renal disease.
 
OR
 
2. Active lupus nephritis
    Meets all of the below criteria (FDA, 2020; Furie NEJM, 2020)
a.  Age > 18 years; AND
b.  Individual meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria for SLE (ACR, 2019) or has renal biopsy (as below) consistent with lupus nephritis in the presence of + ANA or anti-dsDNA.
c.  Has been receiving a regimen including mycophenolate or cyclophosphamide for the past 3 months without a significant clinical response and one of these drugs will be continued in combination with belimumab; AND
d.  If prior use with belimumab, patient did not have disease progression to lupus nephritis while on belimumab therapy for SLE; AND
e.  Not currently being treated with intravenous cyclophosphamide OR intravenous cyclophosphamide will be discontinued before starting therapy with belimumab, AND
f.  Not concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, AND
g.  No previous use of dialysis in the past 12 months, AND
h.  Estimated glomerular filtration rate (eGFR) >30 ml/min per 1.73 m2 of body surface area (BSA).
 
Continued Approval (12 months)
        1. Individual previously met all criteria above for SLE or active lupus nephritis AND
        2. Documentation of positive clinical response
 
Limitations of Use: The efficacy of  Belimumab has not been evaluated in patients with severe active central nervous system lupus. (FDA, 2011)
 
Belimumab has not been studied in combination with other biologics. Use of Belimumabis not recommended in these situations.
 
Dosage and Administration
 
The recommended intravenous dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.
 
The diluted solution of Belimumab should be administered by intravenous infusion over a period of 1 hour.
 
Belimumab intravenous injection should be administered by healthcare providers prepared to manage anaphylaxis.
 
Belimumab intravenous injection should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of  Belimumab with other agents.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Belimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence for any other indication than those outlined above.
 
For members with contracts without primary coverage criteria, Belimumab for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 1, 2022 to December 6, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Belimumab meets member benefit certificate primary coverage that there be scientific evidence of effectiveness for the treatment of the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    1. Active systemic lupus erythematosus (SLE)
        1. Patient is aged 5 years and older (FDA, 2020; Furie, 2011; Brunner, 2020) AND
        2. Member meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria for SLE (ACR, 2019), AND  
        3. Receiving standard therapy (e.g. corticosteroids, aspirin, non-steroidal anti-inflammatory drugs [NSAIDs], anti-malarials [hydroxychloroquine, chloroquine], or non-biologic immunosuppressants [azathioprine, methotrexate, cyclosporine, oral cyclophosphamide]), alone or in combination therapy (FDA, 2011); AND
        4. Member must have failed, not tolerated, or have a contraindication to a trial of hydroxychloroquine/chloroquine, AND
        5. No evidence of severe active central nervous system lupus (FDA, 2011); AND
        6. No evidence of renal disease.
 
OR
 
2. Active lupus nephritis
 Meets all of the below criteria (FDA, 2020; Furie NEJM, 2020)
        1. Age > 18 years; AND
        2. Member meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria for SLE (ACR, 2019) or has renal biopsy (as below) consistent with lupus nephritis in the presence of + ANA or anti-dsDNA.
        3. Has been receiving a regimen including mycophenolate or cyclophosphamide for the past 3 months without a significant clinical response and one of these drugs will be continued in combination with belimumab; AND
        4. If prior use with belimumab, patient did not have disease progression to lupus nephritis while on belimumab therapy for SLE; AND
        5. Not currently being treated with intravenous cyclophosphamide OR intravenous cyclophosphamide will be discontinued before starting therapy with belimumab, AND
        6. Not concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, AND
        7. No previous use of dialysis in the past 12 months, AND
        8. Estimated glomerular filtration rate (eGFR) >30 ml/min per 1.73 m2 of body surface area (BSA).
 
Continued Approval (12 months)
        1. Member previously met all criteria above for SLE or active lupus nephritis AND
        2. Documentation of positive clinical response
 
Limitations of Use: The efficacy of  Belimumab has not been evaluated in patients with severe active central nervous system lupus. (FDA, 2011)
 
Belimumab has not been studied in combination with other biologics. Use of Belimumabis not recommended in these situations.
 
Dosage and Administration
 
The recommended intravenous dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.
 
The diluted solution of Belimumab should be administered by intravenous infusion over a period of 1 hour.
 
Belimumab intravenous injection should be administered by healthcare providers prepared to manage anaphylaxis.
 
Belimumab intravenous injection should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of  Belimumab with other agents.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Belimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence for any other indication than those outlined above.
 
For members with contracts without primary coverage criteria, Belimumab for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial (BLISS-LN) conducted at 107 sites in 21 countries, adults with biopsy-proven, active lupus nephritis were assigned in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of 0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or 60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or 90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed.
 
A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.
 
In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (NCT01639339). (Furie R, Rovin BH, Houssiau F, et. al., 2020)
 
Patients (5 to 17 years) were randomized to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and '30 alternative' definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing.
 
Ninety-three patients were randomized (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.
 
The belimumab intravenous pharmacokinetics and benefit-risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate. (Brunner HI, Abud-Mendoza C, Viola DO, 220)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.
 
December 2022 Update
EMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52-week multicenter, double-blind, placebo-controlled trial in adults of self-identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the double-blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI-2K) (SRI-SLEDAI-2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose.
 
The modified intent-to-treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI-SLEDAI-2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI-SLEDAI-2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double-blind phase withdrawals (belimumab 5.4%, placebo 6.7%).
 
The primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry. (Ginzler E, Guedes Barbosa LS, D'Cruz D,et.al., 2022)

CPT/HCPCS:
J0490Injection, belimumab, 10 mg

References: Arlinger M et al,(2019) 2019 EULAR/ACR Classification Criteria for SLE, Arthritis Rheumatol. 2019 Sep; 71(9): 1400-1412. Doi: 10.1002/art.40930.

BENLYSTA [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2021.

Brunner HI, Abud-Mendoza C, Viola DO, et. al.,(2020) Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus Ann Rheum Dis. 2020 Oct;79(10):1340-1348. doi: 10.1136/annrheumdis-2020-217101. Epub 2020 Jul 22. PMID: 32699034; PMCID: PMC7509523.

Furie R, Petri M, Zamani O, et al.(2011) BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011 Dec;63(12):3918-30. doi: 10.1002/art.30613.

Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB, Saxena A, Green Y, Ji B, Kleoudis C, Burriss SW, Barnett C, Roth DA.(2020) Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020 Sep 17;383(12):1117-1128. doi: 10.1056/NEJMoa2001180. PMID: 32937045.

Ginzler E, Guedes Barbosa LS, D'Cruz D, Furie R, Maksimowicz-McKinnon K, Oates J, Santiago MB, Saxena A, Sheikh S, Bass DL, Burriss SW, Gilbride JA, Groark JG, Miller M, Pierce A, Roth DA, Ji B.(2022) Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022 Jan;74(1):112-123. doi: 10.1002/art.41900. Epub 2021 Dec 9. PMID: 34164944; PMCID: PMC9300099.

GlaxoSmithKline.(2020) Benlysta (belimumab) for injection for intravenous use and subcutaneous use. Highlights of prescribing information. December 2020. Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU.PDF. Last accessed April 2021.

IPD Analytics accessed April 14, 2021 at https://secure.ipdanalytics.com/User/Pharma/Drug/Benlysta?ForecastType=Biologic®ion=USA#57196297-848b-4eeb-af83-b76da9154212


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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