Drug and Biologic Coverage Policy

Effective Date ...... 1/1/2021 Next Review Date ...... 1/1/2022 Coverage Policy Number ...... M0006

Abatacept Intravenous

Table of Contents Related Coverage Resources

Overview ...... 1 Immunomodulators – Oral and Subcutaneous Coverage Policy ...... 1 (Employer Group Benefit Plans) FDA Approved Indications ...... 2 Immunomodulators – Oral and Subcutaneous Recommended Dosing ...... 3 (Individual and Family Plans) General Background ...... 4 Coding/ Billing Information ...... 6 References ...... 7

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Overview

This coverage policy addresses the use of intravenous abatacept (Orencia®). The use of subcutaneous abatacept is addressed in separate coverage policies [Immunomodulators – Oral and Subcutaneous (Employer Group Benefit Plans) and Immunomodulators – Oral and Subcutaneous (Individual and Family Plans)]. Please refer to the related coverage policy link above.

Coverage Policy

Abatacept intravenous (Orencia®) is considered medically necessary when any of the following criteria are met: • Polyarticular Juvenile Idiopathic (PJIA) and BOTH of the following: o Individual is 6 years of age or older o Prescribed by, or in consultation with a rheumatologist or a prescriber who specializes in PJIA

• and BOTH of the following:

Page 1 of 7 Medical Benefit Injectable Clinical Criteria: M006 o Documented failure or inadequate response, contraindication per FDA label, intolerance, or not a candidate for ONE disease-modifying anti-rheumatic (DMARD) (for example, , , sulfasalazine)† † NOTE: An exception to this requirement can be made if the individual has already tried a biologic. These individuals are not required to “step back” and try a DMARD o Prescribed by or in consultation with a rheumatologist, dermatologist or a prescriber who specializes in psoriatic arthritis

• and BOTH of the following: o Documented failure or inadequate response, contraindication per FDA label, intolerance, or not a candidate for ONE disease-modifying anti-rheumatic drug (DMARD) (for example, methotrexate, leflunomide, sulfasalazine)† † NOTE: An exception to this requirement can be made if the individual has already tried a biologic. These individuals are not required to “step back” and try a conventional synthetic DMARD o Prescribed by or in consultation with a rheumatologist or a prescriber who specializes in rheumatoid arthritis

Coverage for abatacept intravenous (Orencia) varies across plans. Refer to the customer’s benefit plan document for coverage details.

Where coverage requires the use of preferred products, the following criteria apply.

For Employer Group Benefit Plans and Individual and Family Plans: Documented failure or inadequate response, contraindication per FDA label, intolerance, or not a candidate for TWO self-administered immunomodulators

Initial authorization is up to 12 months.

Abatacept intravenous (Orencia) is considered medically necessary for continued use when the individual has had a positive response to abatcept intravenous.

Reauthorization for up to 12 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Abatacept intravenous (Orencia) is considered experimental, investigational or unproven for ANY other use including the following: • Concomitant use with any other biologic including all non- (non-TNF) biologics, anti-TNF biologics, or oral immunomodulatory agents (for example, Otezla or Xeljanz/ Xeljanz XR) • Ankylosing Spondylitis (AS) • Inflammatory Bowel Disease (i.e., Crohn’s Disease [CD], Ulcerative Colitis [UC]) • Psoriasis

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

FDA Approved Indications

Adult Rheumatoid Arthritis (RA) Orencia is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Orencia may be used as monotherapy or concomitantly with disease-modifying antirheumatic (DMARDs) other than tumor necrosis factor (TNF) antagonists.

Page 2 of 7 Medical Benefit Injectable Clinical Criteria: M006 Juvenile Idiopathic Arthritis Orencia is indicated for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. Orencia may be used as monotherapy or concomitantly with methotrexate (MTX).

Adult Psoriatic Arthritis (PsA) Orencia is indicated for the treatment of adult patients with active psoriatic arthritis (PsA).

Important Limitations of Use Orencia should not be administered concomitantly with TNF antagonists. Orencia is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as .

Recommended Dosing

FDA Recommended Dosing Indication FDA Recommended Dosing Adult For adult patients with RA, Orencia may be administered as an intravenous infusion or as a Rheumatoid subcutaneous . Orencia may be used as monotherapy or concomitantly with DMARDs Arthritis other than TNF antagonists. (RA) Intravenous Dosing Regimen Orencia lyophilized should be reconstituted and administered after dilution as a 30- minute intravenous infusion utilizing the weight range based dosing specified in the package insert. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

Dose of Orencia for Intravenous Infusion in Adult RA Patients Body Weight Dose Number of Vials Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1000 mg 4

Each vial provides 250 mg of abatacept for administration.

Subcutaneous Dosing Regimen Orencia 125 mg in prefilled or in Orenica ClickJect should be administered by once weekly and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, Orencia should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion.

Patients transitioning from Orencia intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. Juvenile For patients with juvenile idiopathic arthritis (JIA), Orencia may be administered as an Idiopathic intravenous infusion (6 years of age and older) or a subcutaneous injection (2 years of age and Arthritis older). Intravenous dosing has not been studied in patients younger than 6 years of age.

Orencia may be used as monotherapy or concomitantly with methotrexate.

Intravenous Dosing Regimen Orencia should be administered as a 30-minute intravenous infusion based on body weight. Pediatric patients with: • body weight less than 75 kg should be administered Orencia at a dose of 10 mg/kg

Page 3 of 7 Medical Benefit Injectable Clinical Criteria: M006 Indication FDA Recommended Dosing • body weight of 75 kg or more should be administered Orencia following the adult intravenous dosing regimen (see Table 1), not to exceed a maximum dose of 1000 mg.

Following the initial administration, Orencia should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded.

Subcutaneous Dosing Regimen Orencia for subcutaneous injection should be initiated without an intravenous loading dose and be administered utilizing the weight range-based dosing as specified in Table 2.

Dose of Orencia for Subcutaneous Administration in Patients 2 Years of Age or Older with JIA Body Weight of Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg

The safety and efficacy of Orencia ClickJect autoinjector for subcutaneous injection has not been studied in patients under 18 years of age. Adult For adult patients with psoriatic arthritis, Orencia may be administered as an intravenous Psoriatic infusion (IV) or a subcutaneous (SC) injection. Orencia can be used with or without non- Arthritis biologic DMARDs.

Intravenous Dosing Regimen Orencia IV should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

Subcutaneous Dosing Regimen Orencia SC 125 mg should be administered by subcutaneous injection once weekly without the need for an intravenous loading dose.

Patients switching from Orencia intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

General Background

Disease Overview Activated T lymphocytes are implicated in the pathogenesis of inflammatory conditions and are found in the synovium of patients with inflammatory conditions such as RA and PsA. (Orencia Prescribing Information, 2019) Activated T cells trigger increased production of autoantibodies and proinflammatory cytokines, which contribute to joint erosion and chronic inflammation. Orencia IV inhibits T-cell activation, which is a key event in the autoimmune and inflammatory process of RA.

Professional Societies/Organizations Rheumatoid Arthritis American College of Rheumatology (ACR) Guidelines from the American College of Rheumatology (ACR) [2015] have TNFis and non-TNF biologics such as Orencia, administered with or without MTX, equally positioned as a recommended therapy following a trial of a conventional synthetic DMARD (e.g., MTX, leflunomide, , sulfasalazine). (Singh, 2016)

Juvenile Idiopathic Arthritis American College of Rheumatology (ACR)

Page 4 of 7 Medical Benefit Injectable Clinical Criteria: M006 Guidelines for JIA (ACR, 2019) list biologics among the treatment options for subsequent therapy in patients with polyarthritis. (Ringold, 2019) Initial therapy with a biologic may be considered for patients with risk factors and involvement of high-risk joints (e.g., cervical spine, wrist, or hip), high disease activity, and/or those judged to be at high risk of disabling joint damage. In patients with active sacroiliitis or enthesitis despite nonsteroidal anti-inflammatory drug (NSAID), a TNFi is recommended.

Psoriatic Arthritis American College of Rheumatology (ACR) Guidelines from ACR (2018) recommend TNFis over other biologics for use in treatment-naïve patients with PsA and in those who were previously treated with an oral therapy. (Singh, 2019) However, Orencia may be considered over other biologics in patients with recurrent or serious .

® The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely Initiative: The American College of Rheumatology Choosing Wisely® recommends a 3 month trial of methotrexate (or another conventional non-biologic DMARD) unless contraindicated or other exceptions (e.g., high disease activity and poor prognostic features) before initiating biologic therapy for rheumatoid arthritis.

Centers for Medicare & Medicaid Services - National Coverage Determinations (NCDs) There are no CMS National Coverage Determinations for abatacept intravenous.

Other Uses with Supportive Evidence AHFS Drug Information 2019 Edition does not support any off-label uses of abatacept.

Other Uses without Supportive Evidence Ankylosing Spondylitis (AS) In an open-label Phase II trial, Orencia was administered by IV infusion on Days 1, 15, 29, and every 28 days thereafter to patients with active AS. (Song, 2011) Patients received a fixed dosage of Orencia of approximately 10 mg/kg based on body weight. The primary endpoint was a 40% improvement in disease activity at Week 24 in the Assessment of SpondyloArthritis international Society criteria (ASAS 40). At Week 24, the ASAS 40 was 13.3% (n = 2/15) in TNF blocker-naïve patients compared with no responses in patients who had previously failed TNF blockers (n = 15). ASAS 20 response was 26.7% (n = 4/15) in TNF blocker-naïve patients compared with 20% (n = 3/15) in those who had previously failed TNF blockers. A major response was not shown with treatment to Orencia.

Concurrent Use with a Biologic or with a Targeted Synthetic DMARD Orencia IV should not be administered in combination with another biologic or with a targeted synthetic DMARD used for an inflammatory condition. Combination therapy is generally not recommended due to a higher rate of AEs with combinations and lack of data supportive of additional efficacy. (Furst, 2012, Prescribing Information, 2017) Note: This does NOT exclude the use of conventional synthetic DMARDs (e.g., MTX, leflunomide, hydroxychloroquine, and sulfasalazine) in combination with Orencia IV. Please note that this table is not all inclusive.

Brand (generic name) Mechanism of Action Cimzia ( for SC injection) Inhibition of TNF Enbrel ( for SC injection) Inhibition of TNF Erelzi™ (etanercept-szzs for SC injection) Inhibition of TNF Humira® ( for SC injection) Inhibition of TNF Amjevita™ (adalimumab-atto for SC injection) Inhibition of TNF Cyltezo® (adalimumab-adbm for SC injection) Inhibition of TNF Simponi® ( for SC injection) Inhibition of TNF Simponi® Aria™ (golimumab for IV infusion) Inhibition of TNF Remicade® ( for IV infusion) Inhibition of TNF Inflectra™ (infliximab-dyyb for IV infusion) Inhibition of TNF Renflexis® (infliximab-abda for IV infusion) Inhibition of TNF Actemra® ( for IV infusion) Inhibition of IL-6 Actemra® (tocilizumab for SC injection) Inhibition of IL-6

Page 5 of 7 Medical Benefit Injectable Clinical Criteria: M006 Kevzara™ (sarilumab for SC injection) Inhibition of IL-6 Orencia® (abatacept for IV infusion) T-cell costimulation modulator Orencia® (abatacept for SC injection) T-cell costimulation modulator Rituxan® ( for IV infusion) CD20-directed cytolytic Truxima® (rituximab-abbs IV injection) CD20-directed cytolytic antibody Kineret® (anakinra for subcutaneous SC injection) Inhibition of IL-1 Stelara® ( for SC injection) Inhibition of IL-12/23 Stelara® (ustekinumab for IV infusion) Inhibition of IL-12/23 Siliq™ (brodalumab SC injection) Inhibition of IL-17 Cosentyx™ ( for SC injection) Inhibition of IL-17A Taltz® (ixekizumab for SC injection) Inhibition of IL-17A Ilumya™ (tildrakizumab-asmn for SC injection) Inhibition of IL-23 Skyrizi™ (risankizumab SC injection) Inhibition of IL-23 Tremfya® (guselkumab for SC injection) Inhibition of IL-23 Entyvio™ ( IV infusion) receptor antagonist Otezla® ( tablets) Inhibition of PDE4 Xeljanz®, Xeljanz XR ( tablets, tofacitinib extended-release Inhibition of the JAK pathways tablets) SC – Subcutaneous; TNF – Tumor necrosis factor; IL – Interleukin; IV – Intravenous; PDE4 – Phosphodiesterase 4; JAK – Janus kinase.

Inflammatory Bowel Disease (i.e., Crohn’s Disease [CD], Ulcerative Colitis [UC]) In placebo-controlled trials evaluating the efficacy of Orencia IV for induction and maintenance in adults with active, moderate to severe CD (n = 451) and UC (n = 490), Orencia was no more effective than placebo. (Sandborn, 2012) Patients were randomized to Orencia 30, 10, or 3 mg/kg IV (according to body weight) or placebo and dosed at Weeks 0, 2, 4, and 8. A total of 90 patients with CD and 131 patients with UC who responded to Orencia IV induction were then randomized to Orencia 10 mg/kg IV or placebo every 4 weeks through Week 52. When used for induction of CD, 17.2%, 10.2%, and 15.5% of patients receiving Orencia 30 mg, 10 mg, and 3 mg/kg IV achieved a clinical response at Weeks 8 and 12 compared with 14.4% of patients receiving placebo (P = not significant [NS] for all comparisons). In patients with CD, response and remission at Week 52 was not significantly different between the Orencia IV and placebo treatment groups. When used as induction therapy in UC, 21.4%, 19.0%, and 20.3% of patients receiving Orencia 30 mg, 10 mg, and 3 mg/kg IV achieved a clinical response at Week 12 compared with 29.5% of patients receiving placebo (P = 0.043 for 10 mg/kg vs. placebo; other comparisons NS). At Week 52, 12.5% (n = 8/64) and 14.1% (n = 9/64) of patients with UC were in remission (P = NS) and 17.2% of patients in each treatment group (n = 11/64 for each group) had achieved a response.

Psoriasis (Note: Patients with concomitant plaque psoriasis and psoriatic arthritis may be reviewed under the psoriatic arthritis criteria above.) In a multicenter, Phase I, 26-week, open-label dose-escalation study, 43 patients with stable plaque psoriasis (10% to 49% body surface area involvement) received four doses of Orencia given as a 1-hour IV infusion on Days 1, 3, 16 and 29. (Abrams, 1999) The starting dose was 0.5 mg/kg. Four to six patients were accrued to each of eight dose levels: 0.5, 1, 2, 4, 8, 16, 25 and 50 mg/kg. A parallel control group was matched for age and overall disease severity. In all, 46% of patients on Orencia for IV infusion achieved a 50% or greater sustained improvement in clinical disease activity (Physician’s Global Assessment of disease activity) compared with baseline psoriasis evaluation. Progressively greater effects were observed with the highest doses. Further studies are needed to establish safety and efficacy in plaque psoriasis.

Coding/ Billing Information

Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.

Considered Medically Necessary when criteria in the applicable policy statements listed above are met:

Page 6 of 7 Medical Benefit Injectable Clinical Criteria: M006 HCPCS Description Codes J0129 Injection, abatacept, 10 mg (code may be used for Medicare when drug administered under direct supervision of a physician, not for use when drug is self-administered)

References

1. Abrams JR, Lebwohl MG, Guzzo CA, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest. 1999;103:1243-1252. 2. AHFS Drug Information 2020 Edition 3. Furst DE, Keystone EC, Braun J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2011. Ann Rheum Dis. 2012;71 Suppl 2:i2-i45. 4. Gottenberg JE, Brocq O, Perdriger A, et al. Non-TNF-targeted biologic vs a second anti-TNF drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: a randomized clinical trial. JAMA. 2016;316(11):1172-1180. 5. Orencia® for injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; March 2019. 6. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non- systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Rheumatol. 2019 Apr 25. [Epub ahead of print]. 7. Sandborn WJ, Colombel JF, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology. 2012;143(1):62-69.e4. 8. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 9. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the treatment of psoriatic arthritis. Arthritis Care Res (Hoboken). 2019;71(1):2-29. 10. Song IH, Heldmann F, Rudwaleit M, et al. Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study. Ann Rheum Dis. 2011;70(6):1108-1110. 11. Xeljanz® tablets [prescribing information]. New York, NY: Pfizer Inc; December 2017.

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