This policy only targets subcutaneous Benlysta.

TARGET AGENT

Benlysta® (belimumab)

Brand (generic)	GPI	Multisource Code	Quantity Limit
Benlysta (belimumab)
200 mg/mL autoinjector	9942201500D520	M, N, O, or Y	4 prefilled autoinjectors/ 28 days
200 mg/mL prefilled syringe	9942201500E520	M, N, O, or Y	4 prefilled syringes/ 28 days

CRITERIA FOR APPROVAL

Initial Evaluation

Benlysta (belimumab) will be approved when ALL of the following are met:

1. ONE of the following:
   1.  

       i.  The patient has a diagnosis of active systemic lupus erythematosus (SLE) disease AND

ALL of the following:

1. The patient is 18 years of age or over

AND

2. BOTH of the following:
   1. The patient has a history of positive antinuclear antibody (ANA) and/or positive anti-dsDNA results

AND

1. 2. The patient has a history of at least 3 additional SLE related disease manifestations (SLE related disease manifestations include, but are not limited to: malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis [involving 2 or more peripheral joints], pleuritis/pericarditis, renal disorder [persistent proteinuria >0.5 grams/day or cellular casts], seizures/psychosis, or hematologic disorder [hemolytic anemia (with reticulocytosis), leukopenia, lymphopenia, thrombocytopenia]

AND

3. ONE of the following:

1. BOTH of the following:
   1. 1. 1.  

a.  The patient has had inadequate response to TWO of the following: corticosteroids, antimalarials (hydroxychloroquine), nonsteroidal anti-inflammatory drugs (NSAIDS), and/or immunosuppressives (azathioprine, methotrexate, oral cyclophosphamide, or mycophenolate)

AND

1. 1. 1. 1. 2. The patient is currently on a standard of care SLE treatment regimen comprised of at least one of the following: corticosteroids, antimalarials (e.g. hydroxychloroquine), nonsteroidal anti-inflammatory drugs (e.g. NSAIDS), and/or immunosuppressives (e.g. azathioprine, methotrexate, oral cyclophosphamide, or mycophenolate)

OR

2. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to ALL the standard of care drug classes listed above

AND

1. 4. ONE of the following:

                           1.  The patient has a Safety of Estrogen in Lupus Erythematosus National Assessment – Systemic                                           Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of 6-12

OR

1. 1. 1.  

                           2.  The patient has a ≥2 British Isles Lupus Assessment Group (BILAG) B organ domain scores

OR

1. 1.  

                 ii.  The patient has another FDA labeled indication for the requested agent

AND

2. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., rheumatologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis

AND

3. The patient does not have an active infection

AND

4. The patient has not received a live vaccine within 30 days prior to starting therapy with the requested agent AND will not receive a live vaccine concurrently with the requested agent

AND

5. The patient does NOT have severe active lupus nephritis requiring inter-current treatment with cyclophosphamide or other biologic therapy or the initiation of other immunosuppressive therapy

AND

6. The patient does NOT have severe active central nervous system lupus complications requiring inter-current treatment with cyclophosphamide or other biologic therapy or the initiation of other immunosuppressive therapy

AND

7. The patient will NOT be using the requested agent in combination with another biologic agent OR intravenous cyclophosphamide

AND

8. The patient does not have any FDA labeled contraindications to the requested agent

AND

9. ONE of the following:
   1. The requested quantity (dose) is NOT greater than the program quantity limit

OR

1. 2. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit AND
      2. The requested quantity (dose) is less than or equal to the FDA labeled dose AND
      3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the limit

OR

0. 3. ALL of the following:

                          i.  The requested quantity (dose) is greater than the program quantity limit AND

                          ii.  The requested quantity (dose) is greater than the FDA labeled dose AND

                         iii.  The prescriber has submitted documentation in support of therapy with a higher dose for the intended                                 diagnosis (must be reviewed by the Clinical Review pharmacist)

Length of Approval:  12 months

Renewal Evaluation

Benlysta (belimumab) will be approved when ALL of the following are met:

1. The patient has been previously approved for Benlysta through the plan’s Prior Authorization process

AND

2. ONE of the following:
   1. The patient is currently on a standard of care SLE treatment regimen comprised of at least one of the following: corticosteroids, antimalarials (e.g. hydroxychloroquine), nonsteroidal anti-inflammatory drugs (e.g. NSAIDS), and/or immunosuppressives (e.g. azathioprine, methotrexate, oral cyclophosphamide, or mycophenolate)

OR

1. 2. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to ALL the standard of care drug classes listed above

AND

3. The patient has had a decrease in symptoms or stabilization as indicated by at least ONE of the following:
   1. Improvement in the SELENA-SLEDAI score of ≥4 points

OR

1. 2. No new BILAG-A organ domain score or 2 new BILAG-B organ domain scores

OR

1. 3. No worsening (<0.30-point increase) in Physician’s Global Assessment (PGA) score

OR

1. 4. Seroconverted (negative)

AND

4. The patient does not have an active infection

AND

5. The patient has not received a live vaccine within 30 days prior to starting therapy with the requested agent AND will not receive a live vaccine concurrently with the requested agent

AND

6. The patient does NOT have severe active lupus nephritis requiring inter-current treatment with cyclophosphamide or other biologic therapy or the initiation of other immunosuppressive therapy

AND

7. The patient does NOT have severe active central nervous system lupus complications requiring inter-current treatment with cyclophosphamide or other biologic therapy or the initiation of other immunosuppressive therapy

AND

8. The patient will NOT be using the requested agent in combination with another biologic agent OR intravenous cyclophosphamide

AND

9. The patient does not have any FDA labeled contraindications to the requested agent

AND

10. ONE of the following:

1. The requested quantity (dose) is NOT greater than the program quantity limit

OR

2. ALL of the following:

                           i.  The requested quantity (dose) is greater than the program quantity limit AND

                          ii.  The requested quantity (dose) is less than or equal to the FDA labeled dose AND

                         iii.  The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does                                 not exceed the limit

OR

3. ALL of the following:

                          i.  The requested quantity (dose) is greater than the program quantity limit AND

                         ii.  The requested quantity (dose) is greater than the FDA labeled dose AND

                        iii.  The prescriber has submitted documentation in support of therapy with a higher dose for the intended                                 diagnosis (must be reviewed by the Clinical Review pharmacist)

Length of Approval:  12 months

FDA APPROVED INDICATIONS AND DOSAGE¹

Agent	Indication*	Dosage
Benlysta (belimumab) Subcutaneous solution	Treatment of adult patients with active autoantibody positive, systemic lupus erythematosus who are receiving standard therapy	SC (adults only): 200 mg once weekly (must be 18 years and older)

* Limitation of use:  efficacy has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.  It has not been studied in combination with other biologics or intravenous cyclophosphamide so is not recommended in these situations.

CLINICAL RATIONALE

Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown cause. It has a broad range of clinical and serological manifestations and can affect many organs. Clinical symptoms of SLE include fatigue, fever, arthralgia, myalgia, changes in weight, skin and mucus membrane lesions and ulcers, and vascular disease. SLE can also include cardiac, renal, pulmonary, and neurologic involvement. Due to its multisystem involvement and likelihood of changes in presentation, the diagnosis of SLE may be difficult.²

The American College of Rheumatology (ACR) recommend referral to a rheumatologist and/or another appropriate specialist to establish the diagnosis of SLE; assess activity and severity level; and management of the disease.³ The American College of Rheumatology published criteria to aid in diagnosing patients with SLE. The criteria requires the patient has, at any time in his or her medical history, at least four of the following diagnostic criteria: malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, serositis (e.g. pleuritis/pericarditis), renal disorder [e.g. persistent proteinuria >0.5 grams/day or cellular casts], seizures/psychosis, hematologic disorder [e.g. hemolytic anemia (with reticulocytosis), leukopenia, lymphopenia, or thrombocytopenia], and/or immunologic disorder (e.g. positive finding of antiphospholipid antibodies or anti-Sm antibodies).³

In the 2012 revised American College of Rheumatology (ACR) SLE classification criteria, a person is classified as having SLE in the presence of biopsy-proven lupus nephritis with antinuclear antibodies (ANA) or anti-dsDNA antibodies or if 4 of the ACR diagnostic criteria, including at least 1 clinical and 1 immunologic criterion have been established.⁴ When SLE is suspected standard laboratory evaluations include CBC with differential, serum creatinine, and urinalysis with microscopy.³ 

The 2019 update of the EULAR recommendations for the management of SLE recommend the following⁶:

• Hydroxychloroquine is recommended for all patients with SLE, unless contraindicated, at a max dose of 5 mg/kg/real body weight (BW)
• Glucocorticoids may be used for rapid symptoms relief, but long-term goals should be to minimize daily glucocorticoid dose to ≤7.5 mg/day prednisone equivalent or discontinue
• Immunosuppressive therapies should be initiated in patients that are not responding to hydroxychloroquine (alone or in combination with glucocorticoids) OR in patients that are unable to reduce the glucocorticoid dose to the recommended maintenance dose
• Immunosuppressive therapies include methotrexate, azathioprine, or mycophenolate
• Cyclophosphamide can be used for severe organ or life threatening SLE as well as rescue therapy for those patients that do not respond to other immunosuppressive agents
• Add on treatment with belimumab should be considered in patients with inadequate response to standard of care therapy (combinations of hydroxychloroquine and glucocorticoids with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses
• Rituximab may be considered in organ-threatening refractory disease or in those with intolerance/contraindication to standard immunosuppressive agents

HHS notes that the same management strategies apply to children and adolescents with SLE.⁴

Safety and Efficacy¹

The safety and efficacy of belimumab was evaluated in two randomized, double-blind, placebo-controlled, phase III studies involving patients age 18 and older with SLE (BLISS-52 and BLISS-76 study). The design of these studies was based on the results of a phase II study which identified that patients who were autoantibody-positive had a better response to belimumab. As a result, BLISS-52 and BLISS-76 limited the study population to only include autoantibody-positive SLE patients. Patients were on a standard of care SLE treatment regimen comprising of at least one of the following: corticosteroids, antimalarials, nonsteroidal anti-inflammatory drugs (NSAIDS), and/or immunosuppressives (azathioprine, methotrexate, or mycophenolate). Patients with severe active lupus nephritis and severe central nervous system (CNS) lupus were excluded. Patients using other biologics including B-cell targeted therapies such as rituximab or intravenous cyclophosphamide in the previous six months were also excluded.

BLISS-52 (N=865) and BLISS-76 (N=826) had similar designs with the exception of duration. BLISS-76 was 76 weeks in duration and BLISS-52 was 52 weeks in length. Eligible patients had active SLE disease which was defined as a Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score >6. Patients were randomly assigned to receive belimumab 1 mg/kg, 10 mg/kg, or placebo in addition to standard of care. The study medication was administered on Days 0, 14, 28, and then every 28 days for 48 weeks in BLISS-52 and 72 weeks in BLISS-76.

In both BLISS-52 and BLISS-76, the proportion of SLE patients achieving a SLE Responder Index-4 (SRI-4) response was significantly higher in the belimumab 10 mg/kg group than placebo while the effect on SRI-4 was not consistently significantly different for the belimumab 1 mg/kg group.

The safety and efficacy of Benlysta in pediatric patients was evaluated in an international, randomized, double-blind, placebo-controlled, 52-week study conducted in 93 patients with a clinical diagnosis of SLE according to the ACR classification criteria. Patients had a SELENA-SLEDAI score >6 and positive autoantibodies at screening. Patients were on stable SLE treatment regimen and had similar inclusion and exclusion criteria as in the adult studies. The primary endpoint was the same as the adult trials, and there was a numerically higher proportion of pediatric patients achieving a response in SRI-4 and its components in patients receiving Benlysta plus standard therapy compared with placebo plus standard therapy (53% vs 44%, odds ratio 1.49 [CI 0.64, 3.46]).

REFERENCES

1. Benlysta Prescribing Information. GlaxoSmithKline. September 2019. 
2. Lam NC, Ghetu MV, Bieniek ML. Systemic lupus erythematosus: primary care approach to diagnosis and management. Am Fam Physician. 2016;94(4):284–294.
3. Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999; 42(9):1785–1796.
4. Levy, D. M., & Kamphuis, S. (2012). Systemic lupus erythematosus in children and adolescents. Pediatric clinics of North America, 59(2), 345–364. doi:10.1016/j.pcl.2012.03.007.
5. Aringer, M., Costenbader, K., Daikh, D., Brinks, R., et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol, 71: 1400-1412. doi:10.1002/art.40930.
6. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Annals of the Rheumatic Diseases 2019;78:736-745.

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
 
The purpose of pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
 
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

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