Medical Policy

 

Subject: Belimumab (Benlysta®)
Document #: DRUG.00044 Publish Date:    02/28/2018
Status: Reviewed Last Review Date:    01/25/2018

Description/Scope

This document addresses the use of belimumab (Benlysta, Human Genome Sciences (HGS) and GlaxoSmithKline, Rockville, MD) for the treatment of individuals age 18 or older with active, antibody-positive systemic lupus erythematosus (SLE), and for other indications. Belimumab is an intravenously administered human monoclonal antibody drug that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation.

Position Statement

Medically Necessary:

Belimumab is considered medically necessary for individuals age 18 or older when all the following criteria are met prior to initiating therapy:

  1. Clinical diagnosis of SLE per the American College of Rheumatology (ACR) criteria; and
  2. Unequivocally positive ANA (anti-nuclear antibody) titre greater than or equal to 1:80 or anti-dsDNA (double stranded DNA antibody) greater than or equal to 30 IU/mL; and
  3. SLE is active as documented by a SELENA-SLEDAI score greater than or equal to 6 (see Appendix A) while on current treatment regimen; and
  4. There is no evidence of severe renal disease (proteinuria greater than 6 gm/day, serum creatinine greater than 2.5 mg/dl, or requiring renal dialysis); and
  5. There is no evidence of active central nervous system lupus (for example, psychosis or seizures); and
  6. SLE remains active while on corticosteroids, antimalarials, or immunosuppressants (alone or as combination therapy) for at least the last 30 days.

Continuing therapy with belimumab for treatment of SLE is considered medically necessary for individuals age 18 or older when all the following criteria are met:

  1. Clinical diagnosis of SLE per the ACR criteria; and
  2. There is documentation of previous improvement in disease activity following treatment with belimumab indicating a therapeutic response; and
  3. There is no evidence of severe renal disease (proteinuria greater than 6 gm/day, serum creatinine greater than 2.5 mg/dl, or requiring renal dialysis); and
  4. There is no evidence of active central nervous system lupus (for example, psychosis or seizures).

Investigational and Not Medically Necessary:

Belimumab is considered investigational and not medically necessary for active SLE when all of the criteria specified above are not met, or when any of the following contraindications are present:

Belimumab is considered investigational and not medically necessary for all other indications.

Rationale

Wallace and colleagues (2009), reported on a multicenter trial assessing the safety and efficacy of belimumab in combination with standard of care (SOC) in 449 adults with active SLE. Belimumab was given to 336 subjects and placebo administered to the remaining 113 subjects. Changes in these populations were compared by percent of change in Safety of Estrogen in Lupus Erythematosus National Assessment SLE Disease Activity Index (SELENA-SLEDAI) scores taken from the treatment group versus the placebo group. The author concluded:

In this phase II study, belimumab treatment combined with SOC therapy in SLE patients with active disease did not result in significant improvement compared with placebo as assessed by the co-primary endpoints of SELENA-SLEDAI score reduction at week 24 or reduction in time to first SLE flare over 52 weeks. Nevertheless, this trial provided evidence that belimumab was well tolerated and improved many secondary disease activity measures (SLE flares, PGA, SELENA-SLEDAI, SF-36 PCS) when added to SOC in a large (71.5%) subpopulation of serologically active patients. It generated a clinically meaningful hypothesis that provides the basis for the design of phase III confirmatory studies. The phase II study provided 4 valuable insights into the pharmacodynamics of belimumab, SLE disease activity, and trial design.

Belimumab (Benlysta) met its primary endpoint in two phase III trials in SLE. In 2010, belimumab was granted a priority review designation by the U.S. Food and Drug Administration (FDA) under the Prescription Drug User Free Act (PDUFA), and in March 2011 the manufacturer was granted approval to market belimumab in the United States. The data from one of the two pivotal trials were subsequently published by Navarra (2011). It should be noted that the primary outcome measure, the systemic lupus response index (SRI) was developed specifically for this study and was based in part on the results obtained from the Wallace (2009) phase II study. The SRI is a composite measure which has not been independently validated. The reliability and clinical significance of this metric remains unknown.

Navarra (2011) reported a phase III international study (Latin America, Asia-Pacific, and eastern Europe) using subjects randomized using a 1:1:1 ratio to belimumab 1 mg/kg (n=288), belimumab 10 mg/kg (n=290), or placebo (n=288); subjects were further stratified based on SELENA-SLEDAI score, proteinuria concentration and ethnic origin. The primary outcome response rate was assessed during 52 weeks using systemic lupus erythematosus response index (SRI), created to assess the improvement in disease activity without worsening of the overall disorder or development of substantial disease activity in new organ systems. The SRI response to belimumab was significant at both dosage levels [1 mg/kg (n=148) 51%, p=0.0129 and 10 mg/kg (n=167) 58%, p=0.0006]. With the SRI composite measure, a responder was defined as having a reduction of at least 4 points in the SELENA-SLEDAI score. Greater percentages of subjects on belimumab had a greater than or equal to 4 point reduction in this score [belimumab 1 mg/kg (53%), 10 mg/kg (58%) vs. placebo (46%)]. Individuals treated with both doses of belimumab reported no disease worsening compared to placebo, demonstrated by a reduction by 43%, 42%, & 55% in British Isles Lupus Assessment Group (BILAG) 1A flares or no more than one BILAG 2B organ domain flare at week 52. The Physician's Global Assessment (PGA) reported greater results in the belimumab group defined as improvement from baseline (greater than 0.3) at week 52, belimumab 1 mg/kg (59%), belimumab 10 mg/kg (64%), and placebo (49%). The study population consisted of a sub-group of 30 African American subjects divided into 3 groups: belimumab 1 mg/kg (n=8), 3%; belimumab 10 mg/kg (n=11), 4%; placebo (n=11), 4%; the FDA requested additional post-market study of this subgroup of subjects. Nearly 69% of subjects in the study were on prednisone greater than 7.5 mg a day at the onset of the study. The prolonged use of high doses of corticosteroids has been identified as a cause of long-term damage and mortality in individuals with SLE. Although belimumab has steroid-sparing effects, it is currently unknown how the long-term side effects of belimumab treatment compare to those of chronic prednisone. Currently there are ongoing trials (Furie, 2009; Jacobi 2010) evaluating the long-term benefits and potential long-term harms of belimumab.

A phase III multicenter study reported by Furie and colleagues (2011) assessed the long-term efficacy of subjects age 18 or older with active SLE (per ACR criteria) receiving standard therapy regimen (stable treatment regimen included prednisone [or equivalent] at 7.5-40 mg/day alone or prednisone 0-40 mg/day combined with antimalarial drugs, nonsteroidal anti-inflammatory drugs, and/or immunosuppressive therapies) in combination with belimumab or placebo. Individuals presenting with positive ANA or anti-dsDNA positive SLE with SELENA-SLEDAI score of greater than or equal to 6 were randomized using a 1:1:1 ratio to receive belimumab 10 mg/kg (n= 273), belimumab 1 mg/ kg (n=271), or placebo (n=275) intravenously. At week 52, belimumab 10 mg/kg met the primary efficacy endpoint with generated SLE Response Index (SRI) response rate (defined by a reduction of greater than or equal to 4 points in the SELENA-SLEDAI score, no new BILAG A organ domain score and no more than 1 BILAG B score, and no worsening [increase less than 0.3] in the physician's global assessment score versus baseline) of 43.2%, belimumab 1 mg/kg (40.6%), or placebo 33.5%. At baseline, a subgroup of subjects (n=376) received doses greater than 7.5 mg/day of prednisone (or equivalent); during weeks 40-52 the prednisone dose was reduced greater than or equal to 25% to less than or equal to 7.5 mg/day in the belimumab 10 mg/kg group (17.5%), belimumab 1 mg/kg group (19.2%), and placebo group (12.7%). According to authors, the secondary efficacy endpoint, SRI response rate at week 76, demonstrated slightly greater response for belimumab 10 mg (39.1%) compared with belimumab 1 mg (38.5%) and placebo (32.4%), although the study was designed and powered to evaluate the SRI response rate at 52 weeks which makes the results statistically insignificant. The risk of severe flares (using the modified SLE Flare Index) reported at 52 and 76 weeks was reduced, belimumab 10 mg/kg (23%) (p=0.13) and belimumab 1 mg/kg (34%) (p=0.023). Study results report three deaths in the belimumab groups; one to ovarian cancer, one due to cardiac arrest after onset of multi-organ severe SLE flare and one due to unknown causes. There were six reported cases of malignancy among the belimumab groups. The authors reported:

The rate of malignancies (excluding non-melanoma skin cancers) per 100 patients-year in all patients with SLE treated with belimumab as of December 31, 2009 (odds ratio 0.45 [95% confidence interval 0.27-0.72]) is consistent with that reported in the literature for patients with SLE (odds ratio 0.53 [95% confidence interval 0.45-0.59)].

Belimumab in combination with standard therapy showed improvement in the SRI response rate, although further studies are needed to determine the long term potential harm of belimumab.

Merrill and colleagues (2012) reported on a continuation phase II study which evaluated the safety and efficacy of belimumab plus standard therapy; the study evaluated long-term safety profile in participants with active SLE. A total of 364 active SLE participants completed the initial 52-week double-blind treatment period, receiving placebo or intravenous belimumab 1, 4 or 10 mg/kg, plus standard therapy (consisting of corticosteroids, antimalarial agents, and immunosuppressants, either alone or in combination). For the continuation study, 345 participants entered in a 24-week extension study; a total of 296 participants continued treatment with belimumab 10 mg/kg in the long-term continuation study. The safety data through 4 years of belimumab exposure (1165 cumulative patient/years) reported:

The most common adverse events included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year follow-up period. Rates of serious infection decreased from 5.9/100 patient/years to 3.4/100 patient/years, and no specific type of infection predominated.

Ongoing clinical trials are investigating the use of belimumab in the treatment of rheumatoid arthritis (Furie, 2008; Stohl, 2013), Sjögren's syndrome (Mariette, 2015) and the administration of belimumab subcutaneously (once per week) in the treatment of SLE. In conclusion, there is insufficient evidence in the published literature to support the safety and effectiveness of belimumab for these indications.

Background/Overview

Belimumab is the first new drug approved for the treatment of lupus in 5 decades. Belimumab is administered via intravenous infusion at weeks 0, 2 and 4, and then every 4 weeks thereafter.

According to the Centers for Disease Control and Prevention (2015) there are approximately 1.5 million individuals with various forms of lupus nationally; nearly 90% are women, with African American women 3 times more likely to have the disease. Systemic lupus erythematosus, often referred to as lupus, is a complex systemic form of the disease which attacks tissue and can affect joints, skin and other organs. This chronic life threatening autoimmune disease is currently treated with medicines such as aspirin, aristospan, corticosteroids, or plaquenil. Belimumab is a fully human monoclonal antibody which inhibits the biological activity of BLyS, otherwise known as B cell activation factor of the TNF family (BAFF), used in the treatment of active SLE.

Adverse Events and Warnings
The following are warnings and adverse events from the belimumab (Benlysta) Product Information Label (2016):

Precautions for use in specific populations:
The FDA approved labeling for belimumab (Benlysta) includes additional precautions for use in specific populations (Product Information Label, 2016):

Pregnancy
Pregnancy Category C. There are no adequate and well-controlled clinical studies using Benlysta in pregnant women. Immunoglobulin G (IgG) antibodies, including Benlysta can cross the placenta. Because animal reproduction studies are not always predictive of human response, Benlysta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with Benlysta and at least 4 months after the final treatment.

Nursing Mothers
It is not known whether Benlysta is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human milk, a decision should be made whether to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Pediatric Use
Safety and effectiveness of Benlysta have not been established in children.

Geriatric Use
Clinical studies of Benlysta did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

Race
In Trial 2 and Trial 3 (Benlysta 1 mg/kg and 10 mg/kg), response rates for the primary endpoint were lower for black subjects in the Benlysta group relative to black subjects in the placebo group. Use with caution in black/ African American patients.

Definitions

ACR classification criteria of SLE: The ACR requires 4 of these 11 criteria simultaneously or in succession for an individual to be classified as having SLE:

SLE. Criterion Definition/Examples
1. Malar rash Fixed erythema over the malar eminences, tending to spare nasolabial folds
2. Discoid rash Erythematous raised patches, may scar
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight
4. Oral ulcers Usually painless
5. Arthritis Non-erosive, involving one or more peripheral joints
6. Serositis a. Pleuritis, OR b. Pericarditis
7. Renal disorders a. Persistent proteinuria (>3+ or 500 mcg/day), OR b. Cellular casts in urine
8. Neurological disorder a. Seizures, OR b. Psychosis
9. Hematological disorder a. Hemolytic anemia, OR b. Leukopenia (<4000/cmm total), OR c. Lymphopenia (<1500/cmm or two or more occasions), OR d. Thrombocytopenia (<100,000/cmm)
10. Immunological disorder a. Anti-DNA antibody to native DNA in abnormal titer, OR b. Anti-SM antibody to SM nuclear antigen, OR c. Anti-phospholipid antibodies
11. Anti-nuclear antibody Abnormal titer of ANA excluding drug causes

Lupus nephritis: A kidney disorder that is a complication of systemic lupus erythematosus, disease often categorized on biopsy results.

Systemic lupus erythematosus (SLE): A systemic form of lupus attacking tissue with potential to affect joints, skin and other organs.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met:

HCPCS  
J0490 Injection, belimumab, 10 mg [Benlysta]
   
ICD-10 Diagnosis  
M32.0-M32.9 Systemic lupus erythematosus (SLE)

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009; 61(9):1143-1151.
  2. Furie RA, 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; 66(12):3918-3930.
  3. 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.
  4. 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.
  5. Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med. 2013; 368(16):1528-1535.
  6. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40(9):1725.
  7. Jacobi AM, Huang W, Wang T, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2010; 62(1):201-210.
  8. 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; 74:526-531.
  9. Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum. 2012; 64(10):3364-3373.
  10. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011; 377(9767):721-731.
  11. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005; 353(24):2550–2558.
  12. 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.
  13. 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):1168-1178.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Rheumatology (ACR). Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis & Rheumatism. 1999; 42(9):1785-1796.
  2. Belimumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 21, 2011. Accessed on December 14, 2016.
  3. Belimumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. December 8, 2016. Available at: http://www.micromedexsolutions.com. Accessed on December 14, 2016.
  4. Benlysta® (belimumab) [Product Information]. Rockville, MD. Human Genome Sciences, Inc. December 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125370s055lbl.pdf. Accessed on December 14, 2016.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Systemic lupus erythematosus (SLE). Updated April 23, 2015. Available at: http://www.cdc.gov/arthritis/basics/lupus.htm. Accessed on December 14, 2016.
  2. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Handout on health: Systemic Lupus Erythematosus. June 2016. Available at: http://www.niams.nih.gov/Health_Info/Lupus/default.asp. Accessed on December 14, 2016.
Index

Belimumab
Benlysta

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 01/25/2018 Medical Policy & Technology Assessment Committee (MPTAC) review.  The document header wording updated from “Current Effective Date” to “Publish Date.”
Reviewed 02/02/2017 MPTAC review. Update formatting in position statement section. Updated Rationale, Background, References and Websites sections.
Reviewed 02/04/2016 MPTAC review. Updated Rationale, Background, References, and Websites. Removed ICD-9 codes from Coding section.
Revised 02/05/2015 MPTAC review. Revised belimumab medically necessary statement to address criteria "prior to initiating therapy". Added medically necessary statement for continuing therapy with belimumab when criteria met. Updated References.
Reviewed 08/14/2014 MPTAC review. Description, Rationale, Background, References and Websites updated.
Revised 08/08/2013 MPTAC review. Clarified medically necessary standard therapy criteria for belimumab. Updated Rationale, Background, References and Websites.
Revised 08/09/2012 MPTAC review. Revised medically necessary criteria. Updated Rationale, References and Websites.
Reviewed 05/10/2012 MPTAC review. Updated Rationale, References and Websites.
  01/01/2012 Updated Coding section with 01/01/2012 HCPCS changes; removed code Q2044 deleted 12/31/2011.
Revised 08/18/2011 MPTAC review. Clarified medically necessary criteria requirements. Removed contraindication in Investigational and not medically necessary statement for females who are pregnant or nursing. Updated background and websites.
New 05/19/2011 MPTAC review. Initial document development.
     

Appendix A

SELENA-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) INSTRUMENT SCORE
Check box: if descriptor is present at the time of visit or in the preceding 10 days.
Check if

Wt Present Descriptor Definition

8

Seizure Recent onset (last 10 days). Exclude metabolic, infectious or drug cause, or seizure due to past irreversible CNS damage.

8

Psychosis Altered ability to function in normal activity due to severe disturbance in the perception of reality. Include hallucinations; incoherence; marked loose associations; impoverished thought content; marked illogical thinking; bizarre, disorganized or catatonic behavior. Exclude uremia and drug causes.

8

Organic brain syndrome Altered mental function with impaired orientation, memory or other intellectual function, with rapid onset and fluctuating clinical features. Include clouding of consciousness with reduced capacity to focus, and inability to sustain attention to environment, plus at least 2 of the following: perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or decreased psychomotor activity. Exclude metabolic, infectious or drug causes.

8

Visual disturbance Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, serous exudate or hemorrhages in the choroid, optic neuritis, scleritis or episcleritis. Exclude hypertension, infection or drug causes.

8

Cranial nerve disorder New onset of sensory or motor neuropathy involving cranial nerves. Include vertigo due to lupus.

8

Lupus headache Severe persistent headache: may be migrainous, but must be nonresponsive to narcotic analgesia.

8

CVA New onset of cerebrovascular accident(s). Exclude arteriosclerosis or hypertensive causes.

8

Vasculitis Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages, or biopsy or angiogram proof of vasculitis.

4

Arthritis More than 2 joints with pain and signs of inflammation (i.e., tenderness, swelling or effusion).

4

Myositis Proximal muscle aching/weakness, associated with elevated creatine phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis.

4

Urinary casts Heme-granular or red blood cell casts.

4

Hematuria >5 red blood cells/high power field. Exclude stone, infection or other cause.

4

Proteinuria New onset or recent increase of more than 0.5 gm/24 hours.

4

Pyuria >5 white blood cells/high power field. Exclude infection.

2

Rash Ongoing inflammatory lupus rash.

2

Alopecia Ongoing abnormal, patchy or diffuse loss of hair due to active lupus.

2

Mucosal ulcers Ongoing oral or nasal ulcerations due to active lupus.

2

Pleurisy Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural thickening due to lupus.

2

Pericarditis Classic and severe pericardial pain or rub or effusion, or electrocardiogram confirmation.

2

Low complement Decrease in CH50, C3 or C4 below the lower limit of normal for testing laboratory.

2

Increased DNA binding >25% binding by Farr assay or above normal range for testing laboratory.

1

Fever □ >38oC. Exclude infectious cause.

1

Thrombocytopenia <100,000 platelets/mm3 .

1

Leukopenia <3,000 white blood cells/mm3 . Exclude drug causes.

______ TOTAL SCORE (Sum of weights next to descriptors marked present)

 

Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005; 353(24):2550–2558.