BCBSNJ Medical Policy for - (Drugs) Policy Number

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Horizon BCBSNJ
Uniform Medical Policy Manual	Section:	Drugs
	Policy Number:	088
	Effective Date:	09/11/2020

	Original Policy Date:	04/26/2011
	Last Review Date:	09/08/2020
	Date Published to Web:	04/15/2019

Subject:
Belimumab (Benlysta)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Belimumab (Benlysta), a B-lymphocyte stimulator (BLyS)- specific inhibitor, was FDA approved for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy. Patients treated with Benlysta 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. A phase II dose ranging study of belimumab + standard treatment vs. standard treatment alone showed no significant difference between either arm. The reduction in SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index) from baseline was 19.5% in the combined belimumab group versus 17.2% in the placebo group. In another study of 867 patients, belimumab plus standard therapy was found to be more effective than standard therapy alone. Patients receiving belimumab 10 mg/kg were found to have a significantly higher SRI rate (Systemic Lupus Erythematosus Responder Index) when compared to standard therapy alone. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 10mg/kg (169 [58%] p=0.0024) than placebo (132 [46%]). Rates of adverse events were similar in the groups given belimumab 10 mg/kg and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. There were more deaths reported with belimumab than with the placebo during clinical trials. In addition, depression and suicide have been reported in belimumab studies. This drug should not be administered with live vaccines.

Subcutaneous dosing were evaluated in a randomized, double-blind, placebo controlled trial with 836 patients with SLE. Patients with severe active lupus nephritis and severe active CNS lupus were excluded. The trial evaluated belimumab 200 mg once weekly plus standard therapy compared with placebo once weekly plus standard therapy over 52 weeks in patients with active SLE. The primary endpoint was the SLE responder index-4 at week 52, the same used in the IV trials. The proportion of patients achieving SRI-4 response was statistically significant in patients receiving belimumab plus standard therapy compared with placebo plus standard therapy. 48% of placebo group responded versus 61 % of the bemlimumab group, P=0.0006.

In April 2019, the FDA approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children (aged 5 years and older) with systemic lupus erythematosus (SLE). The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was based on ‘PLUTO’ (Pediatric Lupus Trial of Belimumab Plus Background Standard Therapy), a multicenter, randomized, double-blind study (BEL114055) in 93 children with active SLE. The study comprised three phases: Part A (randomised double-blind 52-week treatment phase), Part B (long-term open-label safety phase) and Part C (long-term safety follow-up phase). The long-term follow-up phases of the study (Parts B and C) are planned for a total of up to 10 years. The proportion of children achieving a clinically meaningful improvement in disease activity, as assessed by the SLE responder index (SRI) response rate, was numerically higher in patients receiving belimumab plus standard therapy (52.8%) compared with placebo plus standard therapy (43.6%) at Week 52. The drug’s safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE. The proportion of patients experiencing more than one adverse event (AE) and a serious AE was 79.2% and 17.0% for the belimumab group compared to 82.5% and 35.0% for the placebo group, respectively. AEs that led to discontinuation were lupus nephritis, hepatitis A, hypertransaminasemia, acute pancreatitis, post herpetic neuralgia, retinal vasculitis and pancreatitis.

Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

The requirements of the Horizon BCBSNJ Belimumab (Benlysta) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Please refer to a separate policy on Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) under the Drug Section.

2. Belimumab (Benlysta) is medically necessary when all of the following are met:

The prescriber is a specialist in the area of the patient’s diagnosis (e.g. rheumatologist) or has consulted with a specialist in the area of the patient’s diagnosis AND
Member is at least 5 years of age; AND
Member has diagnosis of systemic lupus erythematosus (SLE) based on American College of Rheumatology (ACR) criteria (see Appendix A); AND
Member has ONE of the following:
- Member has active SLE with score of 6-12 Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)
- British Isles Lupus Assessment Group (BILAG) A organ domain score ≥1
- British Isles Lupus Assessment Group (BILAG) B organ domain score ≥2; AND
Member has a positive autoantibody test (e.g., anti-nuclear antibody [ANA] greater than laboratory reference range and/or anti-double-stranded DNA [anti-dsDNA] greater than 2 fold the laboratory reference range if tested by ELISA); AND
Member is currently receiving standard therapy including corticosteroids, antimalarials, immunosuppressives or nonsteroidal anti-inflammatory drugs for at least 30 days; AND
Member is not currently receiving any therapy for acute or chronic infection; AND
Member does not have any of the following exclusion criteria:
- Severe active lupus nephritis or severe active central nervous system lupus; AND
- Previously treated with any B cell targeted therapy including rituximab; AND
- Currently receiving other biologics or intravenous cyclophosphamide; AND
- currently receiving intravenous immunoglobulin (Ig) or prednisone (>100mg/day) or its equivalent corticosteroid dose within 3 months; AND
- historically positive test or test positive for HIV, hepatitis B, or hepatitis C infection; AND
- Given concurrently with live vaccines; AND
Member is NOT receiving subcutaneous administration of belimumab (Benlysta) and intravenous administration of belimumab (Benlysta) concomitantly; AND
If the subcutaneous form of the drug is requested, the requested drug will be administered in an office/outpatient setting by a healthcare professional or home infusion by a home-health nurse and is there is documentation that member will not be self-administering. Documentation must be provided stating the member is unable to self-administer due to one of the following reasons:

[

INFORMATIONAL NOTE

As per the FDA approved package insert, the safety and efficacy of Belimumab (Benlysta) in children has not been established.
Also based on the FDA approved package insert, live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established.
The SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index) tool is a cumulative and weighted index used to assess disease activity across 24 different disease descriptors in patients with SLE. A patient’s SELENA-SLEDAI total score is the sum of all marked SLE-related descriptors. A total score can fall between 0 and 105, with a higher score representing a more significant degree of disease activity. Activity categories have been defined on the basis of SLEDAI scores: no activity (SLEDAI= 0), mild activity (SLEDAI 1-5), moderate activity (SLEDAI 6-12), high activity (SLEDAI 13-19), very high activity (SLEDAI ≥20).
The British Isles lupus assessment group (BILAG) also is used to evaluate the occurrence of flares in patients with SLE. The BILAG is an organ-specific 86-question assessment based on the principle of the doctor’s intent to treat, which requires an assessment of improved (1), the same (2), worse (3), or new (4) over the last month. Within each organ system, multiple manifestations and laboratory tests are combined into a single score for that organ. The resulting scores for each organ can be A through E, where A is very active disease, B is moderate activity, C is mild stable disease, D is resolved activity, and E indicates the organ was never involved. Severe and moderate flare is defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores.]

3. When Belimumab (Benlysta) is medically necessary, initial therapy will be approved for a period of 6 months at the following FDA approved recommended doses

o 10 mg/kg every 2 weeks for the first 3 doses and every 4 weeks thereafter.

o 200 mg once weekly in the abdomen or thigh

[

INFORMATIONAL NOTE

As per the FDA approved package insert,

If transitioning from IV to SC administration, administer the first SC dose 1 to 4 weeks after the last IV dose

As per the FDA approved package insert,

ubcutaneous dosing of Benlysta has not been evaluated and is not approved for patients younger than 18 years of age

]

4. At the end of the 6 months, the need for continued therapy will be approved for 1 year and evaluated annually if:

Member continues to meet the initial approval criteria AND
Disease stability and/or improvement is documented as indicated by the following when compared to baseline:
Absence of unacceptable toxicity from the drug (e.g.: depression, suicidal thoughts, serious infections, malignancy, signs or symptoms of progressive multifocal leukoencephalopathy (PML), severe hypersensitivity reactions, etc.) AND
If the subcutaneous form of the drug is requested, the requested drug will be administered in an office/outpatient setting by a healthcare professional or home infusion by a home-health nurse and is there is documentation that member will not be self-administering. Documentation must be provided stating the member is unable to self-administer due to one of the following reasons:

5. Belimumab (Benlysta) is not medically necessary in combination use of intravenous and subcutaneous formulations.

6. Other uses of Belimumab (Benlysta), including but not limited to, sensitization prior to kidney transplant, symptomatic Waldenstroms Macroglobulinaemia, Multiple Sclerosis, idiopathic thrombocytopaenic purpura, Primary Sjogren’s Syndrome, Myasthenia Gravis, and Rheumatoid Arthritis are considered investigational

Appendix A: 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus

Criterion	Definition
Malar rash	Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Discoid rash	Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Photosensitivity	Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Oral ulcers	Oral or nasopharyngeal ulceration, usually painless, observed by physician
Non erosive arthritis	Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
Pleuritis or pericarditis	Pleuritis-convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion OR Pericarditis-documented by electrocardiogram or rub or evidence of pericardial effusion
Renal disorder	Persistent proteinuria >0.5 grams per day or >3 if quantitation not performed OR Cellular casts-may be red cell, hemoglobin, granular, tubular, or mixed
Neurologic disorder	Seizures-in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) OR Psychosis-in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
Hematologic disorder	Hemolytic anemia with reticulocytosis OR Leukopenia <4,000/mm3 on >2 occasions OR Lymphopenia <1,500/mm3 on >2 occasions OR Thrombocytopenia <100,000/mm3 in the absence of offending drugs
Immunologic disorder	Anti-DNA: antibody to native DNA in abnormal titer OR Anti-Sm: presence of antibody to Sm nuclear antigen OR Positive finding of antiphospholipid antibodies on: 1. Abnormal serum level of IgG or IgM anticardiolipin antibodies 2. Positive test result for lupus anticoagulant using a standard method 3. False-positive test result for at least 6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
Positive antinuclear antibody	Abnormal titer of antinuclear antibody by immunofluorescence or equivalent assay at any point in time and in the absence of drugs

Requires documentation of at least 4 of 11 criterion at any time during patient’s disease history to be considered as having SLE. This ACR classification criteria was used in clinical studies to identify patients with SLE.

Adopted from American College of Rheumatology: Revised Criteria for Classification of Systemic Lupus Erythematosus. 1997.

Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL specifically for this drug. Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them. Therefore, Medicare Advantage Products will cover Belimumab (Benlysta) by subcutaneous route when the Horizon policy criteria is met AND the drug is furnished and administered by a licensed medical provider as part of a physician service.

For additional information, refer to Local Coverage Article: Self-Administered Drug Exclusion List (A53127). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

For Belimumab (Benlysta) given intravenously, Medicare Advantage Products will follow the Horizon BCBSNJ medical policy.

**Note: Bullet 1 of the policy section referring to Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) does not apply for Medicare Advantage Products.

Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Belimumab (Benlysta)
Benlysta (Belimumab)

References:
1. GlaxoSmithKline Inc. Benylsta Package Insert. Research Triangle Park, NC 27709. January 2020.

2. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active system lupus erythematosus. Arthritis Rheumatism 2009;61(9):1168-1178

3. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial (BLISS 52). Lancet 2011;377:721-31

4. ClinicalTrials.gov. Belimumab. http://clinicaltrials.gov/ct2/results?term=belimumab

5. Finnish Medical Society Duodecim. Systemic Lupus Erythematosus. In: EBM Guidelines. Evidence-Based Medicine. Helsinki, Finland: Wiley Interscience. John Wiley & Sons; 2007 Feb 20.

6. Belimumab (Benlysta). Micromedex. DrugDex Evaluations. Updated 12/31/13. Accessed at http://www.thomsonhc.com. Accessed 02/20/14.

7. 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 22:63-72

8. Petri MA, Vollenhoven RF, Buyon J et al. Baseline Predictors of Systemic Lupus Erythematosus Flares. Arthritis Rheum 2013 Aug; 65;8:2143-2153

9. Furie R, Petri M, Zamani O et al. 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;12:3918-3930

10. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Arthritis Rheum. 2011 Dec;63(12):3918-30.

11. Health Genome Sciences Inc.; GlaxoSmithKline. A study of belimumab in subjects with systemic lupus erythematosus (BLISS-76). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Jul 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT00410384 NLM Identifier: NCT00410384.

12. Gordon C, Amissah-Arthur MB, Gayed M, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatol 2017 Oct 6. doi: 10.1093/rheumatology/kex286.

13. NICE. Belimumab for treating active autoantibody-positive systemic lupus erythematosus: Technology Appraisal Guidance [TAG397]. https://www.nice.org.uk/guidance/ta397/ Accessed November 2017.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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