Download Belimumab (Benlysta®)

MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
Original Issue Date (Created):
12/1/2011
Most Recent Review Date (Revised):
3/28/2017
Effective Date:
4/1/2017
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
I.
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
POLICY
Note: Safety and effectiveness of Benlysta have not been established in children.
Note: Benlysta should not be given via home infusion due to potential anaphylactic
reaction.
Note: The efficacy of Benlysta has not been evaluated in patients with severe active lupus
nephritis or severe active central nervous system lupus. Benlysta has not been studied in
pregnant or nursing mothers.
Note: The use of Benlysta is not recommended in combination with biologic therapies or
intravenous cyclophosphamide. Live vaccines should not be given concurrently with
Benlysta.
Initial Therapy
Belimumab (Benlysta®) may be considered medically necessary for the treatment of adult
patients with active autoantibody-positive systemic lupus who are receiving standard
therapy, and when the following criteria are met:
 Consulting rheumatologist recommends treatment with Belimumab (Benlysta)
 The patient has an inadequate response to standard treatments (e.g. prednisone,
Plaquenil, aspirin).
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
Maintenance Therapy
Belimumab (Benlysta®) maintenance therapy may be considered medically necessary
when therapy has demonstrated improvement in disease activity at 12 weeks and
maintenance of that improvement at each six-month re-evaluation.
Belimumab (Benlysta®) for all other indications than those listed above is considered
investigational. There is insufficient evidence to support a conclusion concerning the
health outcomes or benefits associated with treatment of this drug for other indications.
Cross-reference:
MP-2.103 Off-Label Use of Medications
II. PRODUCT VARIATIONS
Top
This policy is applicable to all programs and products administered by Capital BlueCross
unless otherwise indicated below.
FEP PPO*
* Refer to FEP Medical Policy Manual MP-10.07.30, Benlysta. The FEP Medical Policy
Manual can be found at: www.fepblue.org.
Note for Medicare Advantage:
1.FDA approved drugs used for indications other than what is indicated on the FDA approved product
label may be covered under Medicare if it is determined that the use is medically accepted, taking
into consideration the Medicare recognized national drug compendia, authoritative medical literature
and/or accepted standards of medical practice.” Refer to Medicare Benefit Policy Manual (100-2,
Chapter 15, Section 50.4.2- Unlabeled Use of Drug).
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
2. In accordance with CMS letter issued on September 17, 2012, entitled “Prohibition on Imposing
Mandatory Step Therapy for Access to Part B Drugs and Services”. Step therapy that is not
part of the FDA label does not apply to Medicare Advantage.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
III. DESCRIPTION/BACKGROUND
Top
Systemic lupus erythematosus (SLE) is the most common type of lupus which can lead to
symptoms of fever, swollen joints, anemia, and kidney failure. Symptoms of lupus vary
widely depending on the individual case and the form of lupus present. There are generally
four recognized forms or types of lupus: Cutaneous (skin) Lupus Erythematosus, Systemic
Lupus Erythematosus, Drug-induced Erythematosus and Neonatal Lupus. According to the
Lupus Foundation of America, SLE affects 1.5 million Americans, mostly women.
There is no single test to diagnose lupus. However, there are many laboratory tests which
can assist the physician in making a lupus diagnosis. Commonly used blood tests in the
diagnosis of SLE include the following:

Anti-nuclear antibody test (ANA) to determine if autoantibodies to cell nuclei are
present in the blood

Anti-DNA antibody test to determine if there are antibodies to the genetic material
in the cell

Anti-Sm antibody test to determine if there are antibodies to Sm, which is a
ribonucleoprotein found in the cell nucleus

Serum (blood) complement test to examine the total level of a group of proteins
which can be consumed in immune reactions

Complement proteins C3 and C4 test to examine specific levels

Antiphospholipid antibody
However, a positive ANA test, by itself, is not proof of lupus since the test may also be
positive in many other autoimmune diseases. Because the ANA is positive in so many
conditions, the results of the ANA test should be interpreted in light of the person's medical
history, and his or her clinical symptoms.
Principal Therapeutic Options
Until the development of belimumab (Benlysta®), there were only 3 drugs that were FDA
approved for the treatment of systemic lupus erythematosus (SLE): prednisone, aspirin, and
hydroxychloroquine. Other drugs commonly used in the treatment of SLE include
nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressive agents, such as
cyclophosphamide, methotrexate, azathioprine, and mycophenolate.
Belimumab is a human monoclonal antibody drug that specifically recognizes and inhibits
the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring
protein that is required for the development of B-lymphocyte cells into mature plasma B
cells. Plasma B cells produce antibodies, the body's first line of defense against infection.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to
contribute to the production of autoantibodies - antibodies that attack and destroy the
body's own healthy tissues. The presence of autoantibodies appears to correlate with
disease severity. Preclinical and clinical studies suggest that belimumab can reduce
autoantibody levels in SLE as well as lower the frequency of the flare-ups that plague lupus
patients.
Belimumab is administered intravenously 10 mg/kg over one hour at 2- week intervals for
the first 3 doses and then at 4-week intervals thereafter. Hypersensitivity reactions
including serious anaphylactic reactions have been reported. Benlysta should be
administered by healthcare providers prepared to manage anaphylaxis.
Serious and sometimes fatal infections have also been reported in patients receiving
immunosuppressive agents, including Benlysta. Belimumab (Benlysta®) has not been
studied in combination with other biologic therapies, including B-cell target therapies, or
intravenous cyclophosphamide. Therefore, use of Benlysta is not recommended in
combination with biologic therapies or intravenous cyclophosphamide. It is not known if
Benlysta is safe and effective in people with severe active lupus nephritis, or severe active
central nervous system lupus. Benlysta has not been studied in pregnant or nursing
mothers. The efficacy of Benylsta has not been evaluated in patients with severe active
lupus nephritis or severe active central nervous system lupus. Benylsta has not been studied
in combination with other biologics or intravenous cyclophosphamide . Use of Benylsta is
not recommended in these situations.
Belimumab (Benlysta®) is also being studied for patients with rheumatoid arthritis who
have failed prior therapy.
IV. RATIONALE
Top
The safety and effectiveness of Benlysta were evaluated in 3 randomized, double-blind,
placebo-controlled trials involving 2,133 patients with SLE according to the American
College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus
nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of
care SLE treatment regimen comprising any of the following (alone or in combination):
corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics
and intravenous cyclophosphamide were not permitted.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
Trial 1: Benlysta 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg Benlysta plus
standard of care compared with placebo plus standard of care over 52 weeks in patients with
SLE. Patients had to have a SELENA-SLEDAI score of >4 at baseline and a history of
autoantibodies (anti-nuclear antibody [ANA] and/or anti-double-stranded DNA [antidsDNA]), but 28% of the population was autoantibody negative at baseline.
The co-primary endpoints were Trials 2 and 3: Benlysta 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE
that were similar in design except duration - Trial 2 was 76 weeks duration and Trial 3 was 52
weeks duration. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score
≥6, and positive autoantibody test results at screening. Patients were excluded from the trial if
they had ever received treatment with a B-cell targeted agent or if they were currently receiving
other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6
months or during the trial. Trial 2 was conducted primarily in North America and Europe. Trial
3 was conducted in South America, Eastern Europe, Asia, and Australia.
Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%),
immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate, and
mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were
receiving 2 or more classes of SLE medications.
In Trial 2 and Trial 3, more than 50% of patients had 3 or more active organ systems at baseline.
The most common active organ systems at baseline based on SELENA-SLEDAI were
mucocutaneous (82% in both trials); immune (Trial 2: 74%, Trial 3: 85%); and musculoskeletal
(Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and
less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.
At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score
(≤9 vs. ≥10), proteinuria level (<2 g/24 hr vs. ≥2 g/24 hr), and race (African or IndigenousAmerican descent vs. other), and then randomly assigned to receive Benlysta 1 mg/kg, Benlysta
10 mg/kg, or placebo in addition to standard of care. The patients were administered trial
medication intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48
weeks in Trial 3 and for 72 weeks in Trial 2.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index or SRI) that
defined response as meeting each of the following criteria at Week 52 compared with baseline:
• ≥4-point reduction in the SELENA-SLEDAI score, and
• no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new
BILAG B organ domain scores, and
• no worsening (<0.30-point increase) in Physician’s Global Assessment (PGA) score.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
The SRI uses the SELENA-SLEDAI score as an objective measure of reduction in global
disease activity; the BILAG index to ensure no significant worsening in any specific organ
system; and the PGA to ensure that improvements in disease activity are not accompanied by
worsening of the patient’s condition overall.
In both Trials 2 and 3, the proportion of SLE patients achieving an SRI response, as defined for
the primary endpoint, was significantly higher in the group receiving Benlysta 10 mg/kg than in
the group receiving placebo. The effect on the SRI was not consistently significantly different
for patients receiving Benlysta 1 mg/kg relative to placebo in both trials. The 1-mg/kg dose is
not recommended. The trends in comparisons between the treatment groups for the rates of
response for the individual components of the endpoint were generally consistent with that of
the SRI (Table 3). At Week 76 in Trial 2, the SRI response rate with Benlysta 10 mg/kg was not
significantly different from that of placebo (39% and 32%, respectively).
Table 3. Clinical Response Rate in Patients with SLE after 52 Weeks of Treatment
Responsea
SLE Responder
Index
Placebo+
Standard of
Car e
(n = 275)
34%
Trial 2
BENLYSTA
1 mg/kg +
Standard of
Careb
(n = 271)
41%
(P = 0.104)
Odds Ratio
(95% CI) vs.
1.3 (0.9, 1.9)
placebo
Components of SLE Responder Index
Percent of
36%
43%
patients with
reduction in
SELENASLEDAI≥4
Percent of
65%
75%
patients with no
worsening by
BIlAG index
Percent of
63%
73%
patients with no
worsening by
PGA
Trial 3
BENLYSTA
1 mg/kg +
Standard of
Car eb
(n = 288)
51 %
BENLYSTA
10 mg/kg+
Standar d of
Car e
(n = 290)
58%
(P = 0.021)
(P = 0.013)
(P < 0.001)
1.5 ( 1.1, 2.2)
1.6 (1.1, 2.2)
1.8 (1.3, 2.6)
BENLYSTA
10 mg/kg +
St andar d of
Care
(n = 273)
43%
Placebo+
Standard of
Care
(n = 287)
44%
47%
46%
53%
58%
69%
73%
79%
81%
69%
69%
79%
80%
a Patients
dropping out of the trial early or experiencing certain increases in background medication
were considered as failures in these analyses. In both trials, a higher proportion of 16
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
placebo patients were considered as failures for this reason as compared with the groups
receiving Benlysta.
b The 1-mg/kg dose is not recommended. The reduction in disease activity seen in the SRI was
related primarily to improvement in the most commonly involved organ systems namely,
mucocutaneous, musculoskeletal, and immune.
Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI response
rate in patients of black race were performed. In Trial 2 and Trial 3 combined, the SRI response
rate in black patients (N = 148) in groups receiving Benlysta was less than that in the group
receiving placebo (22/50 or 44% for placebo, 15/48 or 31% for Benlysta 1 mg/kg, and 18/50 or
36% for Benlysta 10 mg/kg). In Trial 1, black patients (N = 106) in the groups receiving
Benlysta did not appear to have a different response than the rest of the trial population.
Although no definitive conclusions can be drawn from these subgroup analyses, caution should
be used when considering treatment with Benlysta in black/African-American SLE patients.
Effect on Concomitant Steroid Treatment: In Trial 2 and Trial 3, 46% and 69% of patients,
respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of
patients able to reduce their average prednisone dose by at least 25% to ≤7.5 mg/day during
Weeks 40 through 52 was not consistently significantly different for Benlysta relative to placebo
in both trials. In Trial 2, 17% of patients receiving Benlysta 10 mg/kg and 19% of patients
receiving Benlysta 1 mg/kg achieved this level of steroid reduction compared with 13% of
patients receiving placebo. In Trial 3, 19%, 21%, and 12% of patients receiving Benlysta 10
mg/kg, Benlysta 1 mg/kg, and placebo, respectively, achieved this level of steroid reduction.
Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as defined by
a modification of the SELENA Trial flare criteria which excluded severe flares triggered only
by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials 2 and 3.
The proportion of patients having at least 1 severe flare over 52 weeks was not consistently
significantly different for Benlysta relative to placebo in both trials. In Trial 2, 18% of patients
receiving Benlysta 10 mg/kg and 16% of patients receiving Benlysta 1 mg/kg had a severe flare
compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients
receiving Benlysta 10 mg/kg, Benlysta 1 mg/kg and placebo, respectively, had a severe flare.
V. DEFINITIONS
Top
MONOCLONAL ANTIBODY is a type of antibody, specific to a certain antigen, created in the
laboratory from hybridoma cells.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
VI. BENEFIT VARIATIONS
Top
The existence of this medical policy does not mean that this service is a covered benefit
under the member's contract. Benefit determinations should be based in all cases on the
applicable contract language. Medical policies do not constitute a description of benefits.
A member’s individual or group customer benefits govern which services are covered,
which are excluded, and which are subject to benefit limits and which require
preauthorization. Members and providers should consult the member’s benefit information
or contact Capital for benefit information.
VII. DISCLAIMER
Top
Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute
medical advice and are subject to change. Treating providers are solely responsible for medical advice and
treatment of members. Members should discuss any medical policy related to their coverage or condition
with their provider and consult their benefit information to determine if the service is covered. If there is a
discrepancy between this medical policy and a member’s benefit information, the benefit information will
govern. Capital considers the information contained in this medical policy to be proprietary and it may only
be disseminated as permitted by law.
VIII. CODING INFORMATION
Top
Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The
identification of a code in this section does not denote coverage as coverage is determined
by the terms of member benefit information. In addition, not all covered services are
eligible for separate reimbursement.
Covered when medically necessary:
HCPCS
Code
Description
J0490
Injection, Belimumab, 10 Mg
ICD-10-CM
Diagnosis
Codes
M32.0
M32.11
Description
Drug-induced systemic lupus erythematosus
Endocarditis in systemic lupus erythematosus
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
ICD-10-CM
Diagnosis
Codes
M32.12
M32.13
M32.14
M32.15
M32.19
M32.8
Description
Pericarditis in systemic lupus erythematosus
Lung involvement in systemic lupus erythematosus
Glomerular disease in systemic lupus erythematosus
Tubulo-interstitial nephropathy in systemic lupus erythematosus
Other organ or system involvement in systemic lupus erythematosus
Other forms of systemic lupus erythematosus
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses
IX. REFERENCES
Top
BCBSA Specialty Pharmacy Combined Capacity (SPCC) Report #16-2010. Belimumab
(Benlysta®).
Benlysta prescribing information. Human Genome Sciences Inc. Revised12/16. [Website]:
http://www.hgsi.com/images/Benlysta/pdf/benlysta_pi.pdf Accessed January 17, 2017.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual. Publication
100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective 10/01/03. [Website]:
http://www.cms.gov/manuals/Downloads/bp102c15.pdf Accessed. January 17, 2017.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual. Publication
100-02. Chapter 15. Sections 50, 50.4.1, 50.4.3. Drugs and Biologicals. Effective November
24, 2015.
[Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf Accessed January 17,
2017.
ClinicalTrials.gov. Benlysta completed clinical trial. Updated February 13, 2014. [Website]:
http://www.clinicaltrials.gov/ct2/show/NCT00424476?term=benlysta&rank=5 Accessed
January 17, 2017.
Gladman, DD. Overview of the clinical manifestations of systemic lupus erythematosus in adults.
In: UpToDate Online Journal [serial online]. Waltham, MA: UpToDate; updated September
10, 2015. Website]: www.uptodate.com . Accessed January 17, 2017.
Lupus Foundation of America, Inc. Understanding Lupus.2017. [Website]:
http://www.lupus.org/webmodules/webarticlesnet/templates/new_learnunderstanding.aspx?art
icleid=2231&zoneid=523 Accessed January 17, 2017.
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
2011 26;377(9767):721-31.
No author listed. Lupus Foundation: FDA Clears First Lupus Drug Since 1955. March 10, 2011.
Medical News Today [Website]: http://www.medicalnewstoday.com/articles/218811.php
Accessed January 17, 2017.
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MEDICAL POLICY
POLICY TITLE
BELIMUMAB (BENLYSTA®)
POLICY NUMBER
MP-2.155
Taber’s Cyclopedic Medical Dictionary 19th edition
X. POLICY HISTORY
MP-2.155
Top
CAC 7/26/11 New policy.
CAC 1/29/13 Consensus review. No change to policy statements. References
updated.
CAC 1/27/15 Consensus review. No change to the policy statements. References
updated. Rationale added. Deleted notation regarding preauthorization requirement.
All users should refer to officially posted preauthorization resources for
requirements. Medicare variation revised. Coding reviewed.
CAC 1/26/16 Consensus review. No changes to the policy statement. References
updated. Coding reviewed.
Admin update 1/1/17: Product variation section reformatted.
CAC 3/28/17 Consensus review. No changes to the policy statement. References
reviewed. Coding reviewed.
Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company®,
Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross BlueShield Association.
Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies.
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