* Autoantibody positive (i.e. antinuclear antibody or ANA titre 1:80 or anti-double stranded (ds) DNA antibody 30 IU/mL)

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1 Benlysta (belimumab) Policy Number: Last Review: 05/2018 Origination: 06/2011 Next Review: 05/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Benlysta (belimumab) when it is determined to be medically necessary because the criteria shown below are met. When Policy Topic is covered Benlysta (belimumab) requires prior authorization through the pharmacy services area. Drug must be sourced from an approved specialty infusion provider Benlysta is considered medically necessary in the treatment of the following conditions: Systemic lupus erythematosus (SLE)-adults *Autoantibody-positive who are currently receiving standard therapy alone or in combination for at least 30 days: - Immunosuppresants - NSAIDs - Hydroxychloroquine - High dose corticosteroids Belimumab IV is medical benefit and will be considered for coverage at a dosage of 10 mg/kg at weeks 0, 2, and 4 and then every 4 weeks thereafter as specified in the product information provided by the manufacturer. Benlysta is supplied in 120 and 400mg vials. Belimumab Sub-Q is pharmacy benefit and will be considered for coverage at a dosage of 200mg SQ once weekly as specified in the product information provided by the manufacturer. It is supplied in 200mg/ml syringes which may be self-injected. When switching from IV therapy, administer the first SQ dose 1-4 weeks after the last IV dose. * Autoantibody positive (i.e. antinuclear antibody or ANA titre 1:80 or anti-double stranded (ds) DNA antibody 30 IU/mL) When Policy Topic is not covered Benlysta (belimumab) is considered investigational when used for all other conditions, including, but not limited to: In combination with other biologics Severe active lupus nephritis Central nervous system lupus In combination with IV cyclophosphamide Safety and effectiveness in pediatrics have not been established * Should be used with caution in patients with chronic infections

2 Considerations This Blue Cross and Blue Shield of Kansas City policy statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Benlysta (belimumab) is the first inhibitor designed to target B-lymphocyte stimulator (BLyS) protein, which may reduce the number of abnormal B cells which is thought to be a problem in lupus. Benlysta should be diluted and administered as an IV infusion over a period of 1 hour. Premedication prior to administration, may prevent infusion and hypersensitivity reactions. Immediately discontinue Benlysta if a serious hypersensitivity reaction develops. It is approved by the FDA for active, autoantibodypositive, systemic lupus erythematosus (SLE) in adults who are receiving standard therapy. Rationale Systemic Lupus Erthymateous (SLE) is a chronic autoimmune disease affecting mostly women between the ages of 15 to 44. This disease affects more than 322,000 individuals in the US and 90% of this population is female. SLE generally presents during child bearing ages of years in women but may be diagnosed at any age. Black, Hispanic, Asian, and American Indian races have a higher incidence than white women. The disease commonly presents with skin rashes, fatigue, arthritis, and fevers and the disease s morbidity is demonstrated through renal manifestations, neuropsychiatric diseases, and musculoskeletal disorders. SLE patients generally have conditions predisposed by corticosteroids including cataracts, osteoporosis, diabetes, and increased infections. Lupus is generally described as the abnormalities in the function, maturation, and development of B cells. Most importantly, auto-reactive B cells release pathogenic autoantibodies which damage cells and tissues or may form immune complexes that lead to inflammation and tissue damage. After constant tissue damage, SLE may become fatal and most common causes of death are cardiovascular disease, infections, renal disease, and other complications. To treat SLE, Benlysta is a human recombinant monoclonal antibody that can bind and inhibit a B lymphocyte stimulator and therefore play a role in differentiation and regulation of B cells. Before the use of steroids and immunosuppressants, the 5 yr survival rate was less than 50%. In contrast, new agents have increased the 5 year survival rate to over 95%.

3 Appendix 1: American College of Rheumatology (ACR) Classification Criteria for Establishing the Diagnosis of Lupus Diagnosis of Lupus requires the presence of at least 4 of 11 criteria below: 1. Butterfly shaped facial rash, covers nose and spreads across the cheeks 2. Discoid rash- raised, scaly patches 3. Sun related rash 4. Painless mouth sores 5. Two or more swollen and painful joints 6. Swelling of the linings around the lungs or heart 7. Kidney disease 8. Neurological disorders such as seizures or psychosis 9. Low blood counts- thrombocytopenia, leucopenia, low red blood cells 10. Positive antinuclear antibody test 11. Other tests such as positive double stranded anti-dna test, positive Sm test, positivie antiphospholipid antibody test or false-positive syphilis test Use of Benlysta in other conditions Ongoing studies for further evaluation include use for rheumatoid arthritis, primary Sjogren s syndrome, symptomatic Waldenstrom s macroglobulinemia, and for desensitization in sensitized patients awaiting kidney transplant. Safety of Benlysta Benlysta has been linked to numerous reports of serious adverse reactions. These adverse effects can be found in the Warning and Precautions section of Benlysta s package insert. These have been observed with Benlysta in clinical trials: Mortality- 14 patient deaths occurred in three clinical trials of 2133 patients. No single cause of death predominated; however, mostly from infection, cardiovascular disease and suicide. Serious Infections- In the studies 6.0% Benlysta use compared to 5.2% of those receiving placebo reported serious infections. These include pneumonia, urinary tract infection, cellulitis, and bronchitis. Patients being treated for chronic infections should not begin Benlysta. Malignancies- Although shown to be equal occurring as placebo treatment, immunomodulators have an increase risk if the development of malignancies. Hypersensitivity Reactions, including anaphylaxis- Shown in 13% of patient on Benlysta and 11% on placebo. Premedication at this time is not required. Infusion reactions- Patients administered Benlysta or placebo had similar reactions. Limited data to determine premedication diminishes frequency or severity of infusion reactions. Depression- Patients on Benlysta were reported to have more depression than those taking placebo. Two suicides were reported while taking Benlysta. Patients receiving Benlysta should contact their physician if they experience new or worsening depression, mood changes or suicidal thoughts. Longer-term safety data has been published. In general, rates of serious adverse reactions in patients treated up to 7 years in open-label, extension studies was similar to those seen in the shorter-term, randomized controlled trials.

4 Clinical Studies Three randomized, placebo-controlled, double-blinded studies were completed to evaluate Benlysta s safety and efficacy. The studies included 2133 patients and patients with severe active lupus nephritis and CNS involvement were excluded. The patients were established on a treatment regimen consisting alone or in combination of corticosteroids, antimalarias, NSAIDs, and immunosuppressives. Trial 1 comprised of 449 patients on standard therapy and evaluated on dosing of Benlysta 1mg/kg, 4mg/kg, and 10mg/kg doses. The co-primary endpoints were the time to first flare in a 52 week period as well as percent change in SELENA-SLEDAI score at 24 weeks. The study did not show a difference between Benlysta groups and the placebo group; however, a serum antibody positive subgroup demonstrated a benefit. This led trials 2 and 3 to limit their target population to autoantibody positive SLE individuals. Trials 2 and 3 were similar in design to trial 1; however, these trials had a more extended duration 76 weeks and 52 weeks, respectively. Eligible patients had autoantibody positive tests and active SLE as measured by SELENA-SLEDAI score > 6. Patients were excluded due to IV cyclophosphamide use in previous 6 months or currently receiving therapy with biologic agent or B-cell targeted agent. Greater than 70% of patients were receiving standard SLE therapies. The primary endpoints were a reduction in SELENA-SLEDAI by 4, no new British Isles Lupus Assessment Group, and no worsening of Physicians Global Assessment (PGA). 10mg/kg was most effective treatment in both studies while 1mg/kg had similar results to placebo and thus is not recommended. In trial 2 at 76 weeks, Benlysta 10mg/kg did not have a significant SRI compared to placebo. References 1. Benlysta injection for intravenous infusion [package insert]. Rockville, MD: Human Genome Sciences; March, Data on file. Benlysta for intravenous infusion; BLA Briefing document for Arthritis Advisory Committee. November 16, Accessed March 18, Available at: sdrugsadvisorycommittee/ucm pdf. 3. 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. Lancet Feb 26;377(9767): van Vollenhoven RF, Zaamo P. 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(Suppl3): Thanou-Stavraki A, Sawalha AH. An update on belimumab for the treatment of lupus. Biologics. 2011;5: 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 systemic lupus erythematosus. Arthritis Rheum. 2009;61(9): Chatham W, Weinstein A, Petri M, et al. Five-year safety and efficacy experience with belimumab, a BLyS-specific inhibitor, in patients with systemic lupus erythematosus (SLE). Ann Rheum Dis. 2010;69(Suppl3): Ospedaliera A, della Misericordia SM. University of Udine. Efficacy and Safety of Belimumab in Primary Sjögren's Syndrome. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2011 Mar 15]. Available from: Identifier: NCT

5 9. Human Genome Sciences. Cancer Trials Australia. A study of belimumab in treating symptomatic Waldenstroms macroglobulinaemia. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2011 Mar 15]. Available from: Identifier: NCT Human Genome Sciences. University of Pennsylvania. Desensitization With Belimumab in Sensitized Patients Awaiting Kidney Transplant. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2011 Mar 15]. Available from: Identifier: NCT Wiglesworth AK, Ennis KM, Kockler DR. Belimumab: a BLyS-specific inhibitor for systemic lupus erythematosus. Ann Pharmacother. 2010;44(12): Lupus data/statistics. US Department of Health & Human Services Web site. Updated July 8, Accessed November 19, Available at: About Lupus: no two cases are alike. Lupus Research Institute Web site. Accessed March 18, Available at: Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis. 2008;67(2): Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010;69(12): FDA approves Benlysta to treat lupus. [press release] US Food and Drug Administration Web site. March 9, Accessed March 9, Billing Coding/Physician Documentation Information J0490 Injection, belimumab, 10mg (IV is considered medical benefit) Sub-Q, belimumab 200mg/ml (considered pharmacy benefit) Additional Policy Key Words Policy Implementation/Update Information 06/2011 New policy titled Benlysta (belimumab) 06/2012 Reviewed no changes made 06/2013 Reviewed no changes made 06/2014 Updated with specified JCode 06/ / / / /2018 Reviewed no changes made Reviewed no changes made Added specialty provider requirement Added Subcutaneous dosing information Reviewed no changes made State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The

6 medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.