Commercial

Belimumab (Benlysta®) for Intravenous Use
08.00.99d

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 
Belimumab (Benlysta) for intravenous use is considered medically necessary and, therefore, covered when used for the treatment of individuals with systemic lupus erythematosus ((SLE) five years of age and older who meet all of the following criteria:
  • Active systemic lupus erythematosus (SLE) 
  • Positive autoantibody test (e.g., antinuclear antibody test [ANA], antibodies to DNA [Anti-dsDNA], Anti-Smith [Anti-Sm])
  • Concurrent treatment with at least one of the following: steroids, antimalarials, immunosuppressives, or nonsteroidal anti-inflammatory drugs (NSAIDS)
LUPUS NEPHRITIS (LN) 
​Belimumab (Benlysta) for intravenous use is considered medically necessary and, therefore, covered when used for the treatment of individuals with lupus nephritis (LN) 18 years of age and older who meet all of the following criteria:
  • Active systemic lupus erythematosus
  • Biopsy-proven LN Class III, IV, and/or V and have active renal disease at screening
  • Concurrent standard treatment for LN (eg, corticosteroids along with one of the following regimens: mycophenolate for induction followed by mycophenolate for maintenance or cyclophosphamide for induction followed by azathioprine for maintenance)
EXPERIMENTAL/INVESTIGATIONAL

Belimumab (Benlysta) for intravenous use is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature in the following clinical circumstances:
  • In individuals with severe, active central nervous system lupus 
  • In combination with other biologics or B-cell targeted therapies
All other uses for belimumab (Benlysta) for intravenous use are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

BILLING REQUIREMENTS

For drugs that have more than one method of administration, application of the JA modifier is required to indicate the route of administration.
To report the intravenous route of administration, append the following modifier: JA Administered Intravenously

Inclusion of a code in this policy does not imply reimbursement. Eligibility, benefits, limitations, exclusions, utilization management/referral requirements, provider contracts, and Company policies apply.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, belimumab (Benlysta) for intravenous use is covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.

However, services that are identified in this policy as experimental/investigational are not eligible for coverage or reimbursement by the Company.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Belimumab (Benlysta) for intravenous use was approved by the FDA on March 9, 2011 for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy. Supplemental approvals for belimumab (Benlysta) for intravenous use have since been issued by the FDA. The efficacy of belimumab (Benlysta) for intravenous use has not been evaluated in individuals with severe active central nervous system lupus. Belimumab (Benlysta) for intravenous use has not been studied in combination with other biologics. Use of belimumab (Benlysta) for intravenous use is not recommended in these situations.

PEDIATRIC INDIVIDUALS
Intravenous administration of belimumab (Benlysta) is indicated in individuals aged five years and older with systemic lupus erythematosus; its safety and effectiveness have not been established in pediatric individuals younger than five years of age. The safety and effectiveness of intravenous administration of belimumab (Benlysta) have not been established in pediatric patients with active lupus nephritis younger than 18 years of age.

Description

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by periods of illness and remissions in which the immune system produces antibodies to cells within the body leading to widespread inflammation and tissue damage. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease. SLE has a variety of clinical manifestations, and it can affect joints, skin, brain, lungs, kidneys, and blood vessels. Individuals with SLE may experience fatigue, pain or swelling in joints, skin rashes, and fevers.

On March 9, 2011, the US Food and Drug Administration (FDA) approved belimumab (Benlysta) for intravenous (IV) use, an intravenously delivered agent, for use in individuals with active, autoantibody-positive lupus (systemic lupus erythematosus [SLE]) who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs (NSAIDs). It is the first inhibitor intended to target B-lymphocyte stimulator (BLyS) protein, which may reduce the number of abnormal B cells. BLyS is overexpressed in patients with SLE and other autoimmune diseases. After subsequent studies using the IV formulation, the FDA granted approval in pediatric individuals age five years and older. Additionally, a subcutaneous formulation of belimumab (Benlysta) for use in adults was also FDA approved.

LUPUS NEPHRITIS (LN)

Lupus nephritis (LN) is the most common organ-threatening manifestation of SLE and can result in significant morbidity and mortality. It adversely affects individuals with SLE in terms of individual and renal survival rates as well as quality of life and work disability. Improved outcomes in members with LN can result from treatment of both the underlying SLE as well as the renal disease. The presence of renal disease can be demonstrated with multiple methods including serum and urine laboratory tests. The presence of nephritis can be identified with a kidney biopsy. Standard therapy includes treatment with corticosteroids along with induction and maintenance medications.​ On December 16, 2020, the FDA approved belimumab (Benlysta) for IV use in individuals, age 18 and older, with active LN who are receiving standard therapy, which can include corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance.

PEER-REVIEWED LITERATURE

SUMMARY 
Systemic Lupus Erythematosus​ (SLE)

Two clinical studies involving 1,684 individuals with lupus demonstrated the safety and effectiveness of belimumab (Benlysta) for IV use. The studies diagnosed individuals with active lupus and randomized them to receive belimumab (Benlysta) for IV use plus standard therapy, or an inactive infused solution (placebo) plus standard therapy. The studies excluded anyone who had received prior B-cell targeted therapy or IV cyclophosphamide, and those who had active lupus involving the kidneys or central nervous system.

The individuals treated with belimumab (Benlysta) for IV use and standard therapies experienced less disease activity than those who received a placebo and standard-of-care medicines. Results suggested, but did not definitively establish, that some patients had a reduced likelihood of severe flares, and some reduced their steroid doses.

Subsequent safety and efficacy results for subjects treated up to seven years continue to support disease control and safety profile in individuals with active SLE taking belimumab (Benlysta) plus standard therapy.

Lupus Nephritis (LN)

​A clinical study involving 448 individuals with active proliferative and/or membranous LN demonstrated the safety and effectiveness of belimumab (Benlysta) for IV use. The individuals had a clincial diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven LN Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance.

The proportion of individuals achieving Primary Efficacy Renal Response (PERR) at week 104 was significantly higher in individuals receiving belimumab (Benlysta) plus standard therapy compared with placebo plus standard therapy (p=0.031). The major secondary endpoints also showed significant improvement with belimumab (Benlysta) plus standard therapy compared with placebo plus standard therapy. In descriptive subgroup analyses, the PERR and Complete Renal Response (CRR) rates were examined by induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V), and urine protein:creatinine ratio (uPCR) levels at baseline (<3 g/g or 3 g/g; post-hoc analysis). In descriptive subgroup analyses of time to renal-related event or death, results were consistent with the overall endpoint regardless of induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V; post-hoc analysis), and baseline proteinuria (<3 g/g or 3 g/g; post-hoc analysis). The treatment difference was primarily driven by the renal worsening and renal-related treatment failure components of the endpoint.​

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

Belimumab (Benlysta). American Hospital Formulary Service (AHFS). Drug Information. [Lexicomp Web site]. 03/02/2020. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/essential_ashp/5072084 [via subscription only]. Accessed January 25, 2021.

Belimumab (Benlysta). Elsevier’s Clinical Pharmacology Compendium. 12/31/2020. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed January 25, 2021.

Belimumab (Benlysta). Lexi-Drugs Compendium. 01/05/2021. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 25, 2021.

Belimumab (Benlysta). Micromedex® DrugDex® Compendium. [Micromedex® Solutions Web site]. 12/18/2020. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 25, 2021.

Bishton M, Spencer A, Dickinson M, et al. A single-arm, phase II study of the anti-Blys monoclonal antibody belimumab in symptomatic Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2013;13(5):575-578.

Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013;22(1):63-72. 

Furie R, Robin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117-1128.

Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther.2008;10(5):R109.

Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol. 2014;41(2):300-309. 

Hanly JG, O’Keeffe AG, Su L, et al. The frequency and outcome of lupus nephritis results from an international inception cohort study. Rheumatology. 2016;55:252-262.

Human Genome Sciences, Rockville MD. and GlaxoSmithKline, Research Triangle Park, NC. Benlysta® (belimumab) Prescribing Information. 12/16/2020. Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG.PDF. Accessed January 25, 2021.

Lateef A, Petri M. Biologics in the treatment of systemic lupus erythematosus. Curr Opin Rheumatol. 2010;22(5):504-509.

Lutalo PM, D'Cruz DP. Update on belimumab for the management of systemic lupus erythematosus. Expert Opin Biol Ther. 2014;14(11):1701-1708.

Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74(3):526-531. 

Mok CC, Kwok RC, Yip PS. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum. 2013;65(8):2154-2160.

Navarra S, Buzman R, Gallacher A, et al. Belimumab, a BLyS-specific inhibitor, reduces disease activity and flares, and predinosone use in patients with active SLE: efficacy and safety results from the phase 3 BLISS-52 study. Late Breaking Abstract B L1. Presented at the ACR/ARHP meeting. 2009.

Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lypus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731.

Novitas Solutions, Inc. Article (A53127) For Self-Administered Drug Exclusion List. [Novitas Medicare Services Web site]. Original: 10/01/2015, Revised: 12/02/2019. Available at:
https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53127&ver=88&name=331*1&UpdatePeriod=855&bc=AAAAEAAAAAAA&. Accessed January 25, 2021.

Novitas Solutions, Inc. Article (A53127) For Self-Administered Drug Exclusion List [Novitas Medicare Services Web site]. Original 10/01/2015, Revised: 01/01/2021. Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53127&ver=90&Date=01/24/2021&SearchType=Advanced&ContrId=&DocID=A53127&bc=JAAAAAIAAAAA&. Accessed January 25, 2021.

Singh JA, Noorbaloochi S, Tucker MD. Belimumab for systemic lupus erythematosus (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010668.

Stohl W, Merrill JT, McKay JD, et al. Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study. J Rheumatol. 2013;40(5):579-589.

Thanou-Stavrakil A, Sawalha H. An update on belimumab for the treatment of lupus. Biologics. 2011;5:33-43.

van Vollenhoven RF, Zamani O, Wallace DJ, et al. Belimumab, a BLyS-Specific inhibitor, reduces disease activity and severe flares in seropositive SLE patients: BLISS-76 study. Ann Rheum Dis. 2010;69(suppl 3):74.

Wallace DJ, Navarra S, Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus. 2013;22(2):144-154.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Belimumab (Benlysta). Approval letter and prescribing information. [FDA web site]. 12/16/2020. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed January 25, 2021.

Coding

CPT Procedure Code Number(s)
N/A

ICD - 10 Procedure Code Number(s)
N/A

ICD - 10 Diagnosis Code Number(s)

M32.0 Drug-induced systemic lupus erythematosus

M32.10 Systemic lupus erythematosus, organ or system involvement unspecified

M32.11 Endocarditis in systemic lupus erythematosus

M32.12 Pericarditis in systemic lupus erythematosus

M32.13 Lung involvement in systemic lupus erythematosus

M32.14 Glomerular disease in systemic lupus erythematosus

M32.15 Tubulo-interstitial nephropathy in systemic lupus erythematosus

M32.19 Other organ or system involvement in systemic lupus erythematosus

M32.8 Other forms of systemic lupus erythematosus

M32.9 Systemic lupus erythematosus, unspecified


HCPCS Level II Code Number(s)
J0490 Injection, Belimumab 10 mg

Revenue Code Number(s)
N/A

Modifiers


THE FOLLOWING MODIFIER IS USED WHEN REPORTING
Belimumab (Benlysta®) for Intravenous Use

JA Administered intravenously

Coding and Billing Requirements

For drugs that have more than one method of administration, application of the JA modifier is required to indicate the route of administration.
  • To report the intravenous route of administration, append the following modifier: JA Administered Intravenously
Inclusion of a code in this policy does not imply reimbursement. Eligibility, benefits, limitations, exclusions, utilization management/referral requirements, provider contracts, and Company policies apply.

Policy History

3/15/2021
3/15/2021
08.00.99
Medical Policy Bulletin
Commercial
No