Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2021033
Category:	Pharmacy
Initiated:	October 2021
Last Review:	June 2023

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 individuals 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 individuals receiving standard therapy.

On July 26, 2022, the Food and Drug Administration approved the expansion of the approved indication of IV Benlysta for the treatment of individuals with active lupus nephritis who are receiving standard therapy to now include patients 5 to 17 years of age.

Coding

See CPT/HCPCS Code section below.

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 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 January 2024

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 in improving health outcomes for the treatment of the following indications:

ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

1. Individual is aged 5 years or older;  AND

2. Individual has diagnosis of active moderate-severe systemic lupus erythematosus (SLE) supported by the submitted medical records as seen by the following:

a. Individual has antinuclear antibodies (ANA) at a titer of > 1:80 AND has at least one clinical criterion from the 2019 EULAR/ACR guidelines AND has a score > 10 on the additive criteria scale from the 2019 EULAR/ACR guidelines (see policy guidelines) (EULAR/ACR, 2019); OR

b. Individual has at least four SLICC criteria (see policy guidelines), with at least one clinical criterion AND one immunologic criterion. (2012 Petri M, et. al.); OR

c. Individual has lupus nephritis in the presence of ANA or anti-dsDNA antibodies; AND

3. SLE remains active and moderate-severe while receiving standard therapy alone or in combination (FDA, 2011):

a. Glucocorticoids [e.g., prednisone, methylprednisolone, dexamethasone]

b. Anti-malarial [e.g., hydroxychloroquine, chloroquine],

c. Immunosuppressants [e.g., azathioprine, methotrexate, mycophenolate, cyclosporine, cyclophosphamide, leflunomide ]); AND

4. Individual must have failed, not tolerated, or have a contraindication to a trial (>3 months) of hydroxychloroquine/chloroquine (KDIGO 2021); AND

5. Individual is not using the medication in combination with other biologic, for example: TNF inhibitors (i.e., Humira, Cimzia etc), IL inhibitors (i.e., Nucala, Tremfya etc), B cell inhibitors (i.e., Rituxan, Riabini and Truxima), and Selective Co-stimulation modulators (i.e., Orencia); AND

6. Individual has no evidence of severe active central nervous system lupus (FDA label, 2021); AND

7. Individual has no evidence of severe active lupus nephritis (defined as proteinuria greater than 6 gm/d, serum creatinine greater than 2.5 mg/dl, or requiring dialysis); (FDA Label,2021); AND

8. The individual has no evidence of human immunodeficiency virus (HIV) infection, hepatitis B virus infection, or hepatitis C virus infection; AND

9. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 1 year:

1. Documentation is provided showing improvement in disease activity following treatment indicating a therapeutic response;  AND

2. Individual has no evidence of severe active central nervous system lupus (such as psychosis or seizures); AND

3. Individual has no evidence of severe active lupus nephritis (defined as proteinuria greater than 6 gm/d, serum creatinine greater than 2.5 mg/dl, or requiring dialysis); AND

4. Individual is using in combination with standard therapy (for example, corticosteroids, antimalarials, and/or immunosuppressants; AND

5. Individual is not using the medication in combination with other biologic for example: TNF inhibitors, IL inhibitors, B cell inhibitors, and Selective Co-stimulation modulators; AND

6. Must be dosed in accordance with the FDA label.

ACTIVE LUPUS NEPHRITIS

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

1. Individual is aged 5 years and older; AND

2. Documentation is submitted that the individual has a diagnosis of active lupus nephritis (LN) and has Class III, IV or V lupus nephritis confirmed by a kidney biopsy (Must submit results) (NEJM 2020; KDIGO 2021); AND

3. Has been receiving a regimen for at least 3 months without a significant clinical response and one or more of these drugs will be continued in combination with belimumab including:

a. Antimalarial (i.e., Chloroquine, Hydroxychloroquine, Doxycycline); OR

b. Glucocorticoids (i.e., Methylprednisolone, prednisone); OR

c. Mycophenolate mofetil (e.g, Cellcept); OR

d. Tacrolimus (e.g., Prograft, Astagraft, Envarsus); OR

e. Cyclophosphamide (e.g., Cytoxan); OR

f. Azathioprine (e.g., Imuran, Azasan); AND

4. If prior use with belimumab, individual did not have disease progression to lupus nephritis while on belimumab therapy for SLE; AND

5. Individual must have failed, not tolerated, or have a contraindication to a trial (>3 months) of hydroxychloroquine/chloroquine (KDIGO 2021); AND

6. Not concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, (FDA, 2021); 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 square meters of body surface area (BSA); AND

9. Will not be used with active central nervous system lupus (FDA, 2021); AND

10. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 1 year:

1. Documentation is provided showing improvement in disease activity following treatment indicating a therapeutic response; AND

2. Individual has no evidence of severe active central nervous system lupus (such as psychosis or seizures); AND

3. Individual is using in combination with standard therapy (for example, corticosteroids, antimalarials, and/or immunosuppressants; AND

4. Will not be used concurrently with other biologics active SLE; AND

5. Must be dosed in accordance with the FDA label

Policy Guidelines

2019 EULAR/ACR Guideline Criteria

1. Do not count a criterion if there is a more likely explanation than SLE.

2. Occurrence of a criterion on at least one occasion is sufficient.

3. SLE classification requires at least one clinical criterion and greater than or equal to 10 points.

4. Criteria need not occur simultaneously.

5. Within each domain, only the highest weighted criterion is counted to the total score.

Clinical Domains and criteria Weight

Constitutional

Fever 2

Hematologic

Leukopenia 3

Thrombocytopenia 4

Autoimmune Hemolysis 4

Neuropsychiatric

Delirium 2

Psychosis 3

Seizure 5

Mucocutaneous

Non-scarring alopecia 2

Oral ulcers 2

Subacute cutaneous OR discoid lupus 4

Acute cutaneous lupus 6

Serosal

Pleural or pericardial effusion 5

Acute pericarditis 6

Musculoskeletal

Joint involvement 6

Renal

Proteinuria greater than 0.5/24h 4

Renal biopsy Class II or V lupus nephritis 8

Renal biopsy Class III or IV lupus nephritis 10

Immunology domains and Criteria Weight

Antiphospholipid Antibodies

Anti-Cardiolipin antibodies OR

Anti-β2GP1 antibodies OR

Lupus anticoagulant 2

Complement Proteins

Low C3 or low C4 3

Low C3 and low C4 4

SLE-specific antibodies

Anti-dsDNA antibody OR

Anti-Smith antibody 6

2012 SLICC Criteria (2012 Petri M, et. al.)

The SLICC criteria for SLE classification require:

1) Fulfillment of at least 4 criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.

Clinical Criteria:

1. Acute cutaneous lupus

2. Chronic cutaneous lupus

3. Oral ulcers: palate

4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs)

5. Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness in two or more joints and thirty minutes or more of morning stiffness.

6. Serositis

7. Renal

8. Neurologic

9. Hemolytic anemia

10. Leukopenia (< 4000/mm3 at least once)

11. Thrombocytopenia (<100,000/mm3) at least once

Immunological Criteria:

1. ANA above laboratory reference range

2. Anti-dsDNA above laboratory reference range, except ELISA: twice above laboratory

3. Anti-Sm

4. Antiphospholipid antibody: any of the following

5. Low complement

6. Direct Coombs test in the absence of hemolytic anemia

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose for adult and pediatric individuals is 10 mg/kg at 2-week intervals for the first 3 doses then every 4-weeks thereafter.

Belimumab is available as a 120 mg or 400 mg single dose vial for reconstitution.

Belimumab should be administered as an intravenous injection by a healthcare professional prepared to manage anaphylaxis.

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, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes.

For members with contracts without primary coverage criteria, Belimumab, for any indication or circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective June 21, 2023 - December 31, 2023

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 in improving health outcomes for the treatment of the following indications:

INITIAL APPROVAL STANDARD REVIEW for up to 12 months:

ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Individual is aged 5 years and older (FDA, 2020; Furie, 2011; Brunner, 2020) AND
Individual meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria or 2012 SLICC 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
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
Individual must have failed, not tolerated, or have a contraindication to a trial of hydroxychloroquine/chloroquine, AND
No evidence of severe active central nervous system lupus (FDA, 2011); AND
No evidence of renal disease AND
Must be dosed in accordance with the FDA label.

ACTIVE LUPUS NEPHRITIS

Meets all of the below criteria (FDA, 2020; Furie NEJM, 2020)

Individual is aged 5 years and older; AND
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.
Has been receiving a regimen including mycophenolate, azathioprine, 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
If prior use with belimumab, individual did not have disease progression to lupus nephritis while on belimumab therapy for SLE; AND
Not concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, AND
No previous use of dialysis in the past 12 months, AND
Estimated glomerular filtration rate (eGFR) >30 ml/min per 1.73 square meters of body surface area (BSA) AND
Must be dosed in accordance with the FDA label.

Continued Approval (12 months):

Individual previously met all criteria above for SLE or active lupus nephritis AND
Documentation of positive clinical response

Limitations of Use: The efficacy of Belimumab has not been evaluated in individuals with severe active central nervous system lupus. (FDA, 2011)

Belimumab has not been studied in combination with other biologics. Use of Belimumab is not recommended in these situations.

Dosage and Administration

Dosing per FDA Guidelines

The recommended intravenous dosage regimen for adult and pediatric individuals 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

The use of Belimumab for any indication or circumstance not outlined above does not meet member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes.

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 February 15, 2023 to June 20, 2023

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:

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 or 2012 SLICC 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, azathioprine, 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 concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, AND

f. No previous use of dialysis in the past 12 months, AND

g. Estimated glomerular filtration rate (eGFR) >30 ml/min per 1.73 m2 of body surface area (BSA).

Continued Approval (12 months)

Individual previously met all criteria above for SLE or active lupus nephritis AND
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 Belimumab is 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.

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

Effective December 7, 2022 to February 14, 2023

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:

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 or 2012 SLICC 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)

Individual previously met all criteria above for SLE or active lupus nephritis AND
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.

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.

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:

Active systemic lupus erythematosus (SLE)

Patient is aged 5 years and older (FDA, 2020; Furie, 2011; Brunner, 2020) AND
Member meets requirements for diagnosis of systemic lupus erythematosus (SLE) either by 2019 EULAR/ACR classification criteria or 2012 SLICC criteria for SLE (ACR, 2019), AND
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
Member must have failed, not tolerated, or have a contraindication to a trial of hydroxychloroquine/chloroquine, AND
No evidence of severe active central nervous system lupus (FDA, 2011); AND
No evidence of renal disease.

OR

2. Active lupus nephritis

Meets all of the below criteria (FDA, 2020; Furie NEJM, 2020)

Age > 18 years; AND
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.
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
If prior use with belimumab, patient did not have disease progression to lupus nephritis while on belimumab therapy for SLE; AND
Not currently being treated with intravenous cyclophosphamide OR intravenous cyclophosphamide will be discontinued before starting therapy with belimumab, AND
Not concurrently using another biologic agent OR the biologic agent will be discontinued before starting therapy with belimumab, AND
No previous use of dialysis in the past 12 months, AND
Estimated glomerular filtration rate (eGFR) >30 ml/min per 1.73 m2 of body surface area (BSA).

Continued Approval (12 months)

Member previously met all criteria above for SLE or active lupus nephritis AND
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.

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.

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)

2023 Update

Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] ≤0.7, eGFR no more than 20% below open-label baseline value or ≥60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR <0.5, eGFR no more than 10% below open-label baseline value or ≥90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria.

Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-to-belimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28.

No new safety signals were identified, and efficacy was generally maintained throughout the open-label phase. (Furie R, Rovin BH, Houssiau F, 2022)

CPT/HCPCS:

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.

BENLYSTA [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2023

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.

Chalhoub, N.E., Wenderfer, S.E., Levy, D.M., et. al.(2022) International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis. Arthritis Rheumatol, 74: 263-273. https://doi.org/10.1002/art.41930.

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, Contreras G, Teng YKO, Curtis P, Green Y, Okily M, Madan A, Roth DA.(2022) Safety and Efficacy of Belimumab in Patients with Lupus Nephritis: Open-Label Extension of BLISS-LN Study. Clin J Am Soc Nephrol. 2022 Nov;17(11):1620-1630. doi: 10.2215/CJN.02520322. Epub 2022 Oct 27. PMID: 36302567; PMCID: PMC9718049.

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

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021.

Petri M, Orgai A-M, Alarocón GS, et. al.(2012) Derivation and validation of Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64:2677-2686.

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.
CPT Codes Copyright © 2024 American Medical Association.