MEDICAL POLICY – 5.01.536 Nulojix® (belatacept) for Adults

Effective Date: Dec. 1, 2020 RELATED MEDICAL POLICIES: Last Revised: Nov. 3, 2020 11.01.523 Site of Service: Infusion Drugs and Biologic Agents Replaces: N/A

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POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

Nulojix® (belatacept) is a drug that suppresses the immune system to prevent the body from rejecting a transplanted kidney. It can be used for both right at the time of transplantation (induction) and long-term as a maintenance therapy. It was shown to be safe and effective in two large studies that compared it to other drugs used to prevent rejection after kidney transplant. In the study and based on the recommendation of the drug manufacturer, the drug needs to be given with other medications: all basiliximab, mycophenolate mofetil (MMF), and corticosteroids.

Note: The Introduction section is for your general knowledge and is not to be construed as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria

This policy does not apply to members who are currently admitted to an acute hospital setting.

We will review specific intravenous (IV) and injectable drugs for medical necessity for all ages. For those age 13 and older, we also will review the site of service for medical necessity. Site of service is defined as the location where the drug is administered, such as a hospital-based outpatient setting, an infusion center, a physician’s office, or at home.

Drugs subject to site of service review addressed in this policy are:

• Nulojix® (belatacept)

Click on the links below to be directed to the related medical necessity criteria:

Epstein-Barr Virus (EBV) seronegative or Prophylaxis of organ rejection, organs unknown serostatus other than kidney

Prophylaxis of organ rejection, kidney Site of Service

Site of Service Medical Necessity Administration Medically necessary sites IV infusion therapy of various medical or biologic agents will of service be covered in the most appropriate, safe and cost-effective • Physician’s office site: • Infusion center • These are the preferred medically necessary sites of service for • Home infusion specified drugs. Hospital-based outpatient IV infusion therapy of various medical or biologic agents will setting be covered in the most appropriate, safe and cost-effective • Outpatient hospital IV site. infusion department • Hospital-based outpatient This site is considered medically necessary for the first 90 days clinical level of care for the following: • The initial course of infusion of a pharmacologic or biologic agent OR

Page | 2 of 14 ∞ Site of Service Medical Necessity Administration • Re-initiation of an agent after 6 months or longer following discontinuation of therapy*

*Note: This does not include when standard dosing between infusions is 6 months or longer

This site is considered medically necessary when there is no outpatient infusion center within 50 miles of the patient’s home and there is no contracted home infusion agency that will travel to their home, or a hospital is the only place that offers infusions of this drug.

This site is considered medically necessary only when the patient has a clinical condition which puts him or her at increased risk of complications for infusions, including any ONE of the following: • Known cardiac condition (eg, symptomatic cardiac arrhythmia) or pulmonary condition (eg, significant respiratory disease, serious obstructive airway disease, %FVC ≤ 40%) that may increase the risk of an adverse reaction • Unstable renal function which decreases the ability to respond to fluids • Difficult or unstable vascular access • Acute mental status changes or cognitive conditions that impact the safety of infusion therapy • A known history of severe adverse drug reactions and/or anaphylaxis to prior treatment with a related or similar drug Hospital-based outpatient These sites are considered not medically necessary for infusion setting and injectable therapy services of various medical and biologic • Outpatient hospital IV agents when the site-of-service criteria in this policy are not infusion department met. • Hospital-based outpatient clinical level of care

Page | 3 of 14 ∞ Condition Medical Necessity Prophylaxis of organ Nulojix® (belatacept) is subject to review for site of service rejection in adult patients administration. receiving a kidney transplant Nulojix® (belatacept) may be considered medically necessary for the induction therapy (ie, immunosuppression immediately post-transplant) when used in combination with: • Basiliximab induction • Mycophenolate Mofetil (MMF) • Corticosteroids

Nulojix® (belatacept) may be considered medically necessary for maintenance therapy (ie, immunosuppression post- induction) when used in be combination with: • Mycophenolate Mofetil (MMF) • Corticosteroids

Patient must have seropositive test result for Epstein-Barr Virus (EBV).

Note: Patients should be monitored for new or worsening neurological, cognitive, or behavioral signs and symptoms.

Prophylaxis of organ Nulojix® (belatacept) is subject to review for site of service rejection in transplanted administration. organs other than kidney The use of Nulojix® (belatacept) is considered investigational.

Use in liver transplant patients is not recommended by the manufacturer due to increased risk of graft loss and death. EBV seronegative or Nulojix® (belatacept) is subject to review for site of service unknown serostatus administration.

Nulojix® (belatacept) is contraindicated for use in patients who are EBV seronegative or with unknown serostatus because the risk of PTLD (post-transplant lymphoproliferative disorder) is particularly increased in patients who are EBV seronegative.

Page | 4 of 14 ∞ Investigational The use of Nulojix® (belatacept) in patients under the age of 18 for any indication is considered investigational because there have been no studies to support use, safety, and efficacy in pediatric patients.

Length of Approval Approval Criteria Initial authorization Nulojix® (belatacept) may be approved up to 6 months. Re-authorization criteria Future re-authorization of Nulojix® (belatacept) may be approved up to 12 months as long as the drug-specific coverage criteria are met and chart notes demonstrate that the patient continues to show a positive clinical response to therapy.

Documentation Requirements The patient’s medical records submitted for review for all conditions should document that medical necessity criteria are met. The record should include the following: • Office visit notes that contain the type of transplant, EBV serostatus, concurrent medication use, relevant history and physical evaluation

Coding

Code Description HCPCS J0485 Injection, belatacept (Nulojix®), 1 mg

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Related Information

Page | 5 of 14 ∞ Nulojix® (belatacept) inhibits T lymphocyte proliferation by binding to CD80 and CD86 on antigen-presenting cells, which blocks CD28 co-stimulation of the T cell. It also inhibits the production of interleukin-2&4, interferon-, and TNF-α. Immunologic rejections are mostly mediated by activated T lymphocytes. In primate models, graft survival was extended and anti- donor antibodies were diminished. Nulojix® (belatacept) has also been studied and is considered off-label in islet cell transplantation in type 1 diabetic patients and liver transplant patients; the latter is warned against in labeling.

Nulojix® (belatacept) has the advantage of not requiring therapeutic drug monitoring, due to its predictable PK profile in trials among both healthy and kidney transplant patients. Bioavailability is 100%, the PK profile is linear and the exposure increased proportionately to doses of 1 go 20 mg/kg. In an extended phase 2 trial at 5 mg/kg, the measured Cmin was consistent from year 1 through 5 (Cmin range of 3.43-4.85 mcg/mL). A trend of higher clearance was found among patients with higher body weight. Subgroups determined to have no effect on clearance included age, gender, race, renal function, hepatic function, diabetes, and concomitant dialysis. Table 5 from the package insert (previous page) summarizes PK variability among healthy and post-transplant patients. The FDA approved dose is 10mg/kg on day 1, day 5, week 2, week 4, week 8, week 12, and 5 mg/kg every 4 weeks thereafter.

Renal Transplantation

Renal transplant is considered for most patients when the glomerular filtration rate (GFR) falls below 10 mL/min, while renal failure is considered permanent when the GFR reaches this level or a serum creatinine exceeds 8 mg/dL. After transplantation, the survival of the graft and patient continues to be a challenge, and many therapies are targeted to help prevent rejection of the graft by the host’s immune system. Both dialysis and renal replacement therapy are options once the patient reaches end stage renal disease (ESRD). ESRD is most frequently caused by diabetes mellitus, with hypertension, glomerulonephritis, and renal cystic disease following in rank. After transplantation, the primary causes of death are heart disease, sepsis, and stroke (in this order). Compared to the general population, kidney transplant patients have an increased risk of atherosclerosis and ischemic heart disease and a 50-fold increase in the risk of mortality.

Approximately 360 per million people in the US begin renal replacement therapy each year. While the median age of a new patient is 64 years old, the prevalence and incidence is more pronounced in men and more pronounced among African-American, Hispanic, and Native American than Caucasian or Asian populations. The waiting list in the US for kidney transplantation is exceeds 80,000, while only 10,000 kidneys become available each year Among

Page | 6 of 14 ∞ those on immunosuppressive drug regimens, it has been estimated that anywhere from 5 to 55% of patients do not take all of the medications as directed.

Transplant Rejection

Rejection of kidney grafts can be hyperacute, acute cellular, acute humoral, or chronic. Hyperacute rejection occurs within hours after transplantation and contains a marked accumulation of neutrophils within the capillaries, arterioles, and glomeruli, leading to thrombosis, necrosis, and requiring removal of the non-functional organ. Acute rejection occurs from days to years after transplantation and involves humor or cellular immune mechanisms.

Acute cellular rejection appears clinically to resemble renal failure and histologically will show CD4+ and CD8+ T lymphocytes which express activated T cell markers. Tubular damage results from accumulation of mononuclear cells and T cells can also cause endothelitis in the vascular endothelial cells. This rejection can benefit from immunosuppressive therapies.

Acute humoral rejection involves antidonor antibodies resulting in damaged blood vessels and can present as endothelial necrosis, neutrophil accumulation, deposition of immunoglobulins and fibrin, or thrombosis. B-Cell depleting agents are the typical therapy utilized. Chronic rejection is a large cause of graft loss and is seen with a progressive rise in serum creatinine over 4 to 6 months, often controlled with immunosuppressive therapy. It presents with interstitial fibrosis, tubular atrophy, and vascular changes including vascular lesions and resulting ischemia.

Treatment Alternatives

Immunosuppression involves a combination of targeted therapy. Cyclosporine, a calcineurin inhibitor (CNI) which blocks activation of cytokine transcription factors, was a foundation of therapy early in the last decade but has fallen out of favor to tacrolimus in recent guidelines. Others include azathioprine (inhibits leukocyte development), steroids (block inflammation), rapamycin and mycophenylate mofetil (inhibit lymphocyte proliferation), monoclonal anti-T-cell antibodies, and drugs interrupting T-cell co-stimulatory signaling. While immunosuppression can further survival, patients become more susceptible to infections and carcinomas. CNIs and corticosteroids can contribute to weight gain, hypertension, and post-transplant diabetes, which can increase the risk of mortality and graft failure. CNIs also have an increased rate of renal function decline, which can further these risks and drug interactions involving CYP3A4 are concerning for this class as well.

Page | 7 of 14 ∞

Preferred Existing Therapy

For initial maintenance of immunosuppressive therapy, the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends a combination including a CNI (with tacrolimus being first-line) and an anti-proliferative agent (mycophenolyte being first-line), with or without corticosteroids (to be discontinued after one week in patients with low immunological risk). If an mTORi is chosen, it is recommended to be used after surgical wounds are healed and graft function is established. In long-term maintenance, if there has been no acute rejection, the lowest doses of immunosuppressive agents should be reached within 2-4 months. Also, CNIs should be continued and if prednisone is used beyond one week post- transplant, it should be continued as well.

Tacrolimus has been recommended over cyclosporine due to less acute rejection and better graft survival. While mortality, malignancy, infection, delayed onset of graft function, and blood pressure differences between the two agents are not significant, tacrolimus has less incidence of NODAT and lower non-HDL cholesterol. ACR occurrence is typically a top predictor of poor long-term graft survival, but in CNI studies, a decrease in ACR frequency did not increase graft or patient survival rates.

Consideration of Age

In relation to infusion place of service, the age described in this policy for medical necessity of select intravenous and injectable therapy services is 13 years of age or older. The age criteria are based on the following: Pediatric patients are not small adults. Pediatric patients differ physiologically, developmentally, cognitively, and emotionally from adult patients, and vary by age groups from infancy to teen. Children often require smaller doses than adults, lower infusion rates, appropriately sized equipment, the right venipuncture site determined by therapy and age, and behavioral management during administration of care. Specialty infusion training is therefore necessary for pediatric IV insertions and therapy. Due to pediatrics unique physiology and psychology, site of service review is limited to patients above the age of 13.

The ages stated in this policy for which the drugs are considered medically necessary are based on the FDA labeling for this drug.

Page | 8 of 14 ∞

Evidence Review

In renal transplant patients, Nulojix® (belatacept) was shown to be non-inferior to cyclosporine (CsA) for patient and graft survival and had significantly higher GFRs, a result which held up in long term studies as well. Incidences of acute rejection episodes, defined differently in each study, were often significantly higher in the Nulojix (belatacept) patients, although without direct correlation to graft loss or death, and these events occurred early in therapy. Secondary outcomes were often focused on the common drawbacks to oral calcineurin inhibitors (CNIs), namely BP, lipid panels, and diabetic complications. For Nulojix (belatacept), blood pressures and reductions in non-HDL cholesterol were significantly better, while fewer incidences of new- onset diabetes occurred with Nulojix (belatacept) (significant to borderline significant depending on patient population), but long term follow up in one study extension showed these benefits were not preserved over time between agents. Some studies were complicated by patients being switched to tacrolimus, another more-favored CNI, yet were included in analysis, while other extensions were limited in size.

Nulojix® (belatacept) was introduced as an infused alternative to oral CNIs, which can contribute to weight gain, hypertension, post-transplant diabetes (increasing the risk of mortality and graft failure), and a decline in renal function. Belatacept was primarily compared to CsA in studies, as that was the predominant CNI used at the time of most trials’ instigation. CsA has fallen out of favor compared to tacrolimus in guidelines, due to greater graft survival and less acute rejection but there is limited evidence available (one small trial) comparing these two agents.

Nulojix® (belatacept) has a black box warning concerning post-transplant lymphoproliferative disorder (PTLD), which occurred in belatacept patients who were Epstein-Barr virus (EBV) negative or previously used T-cell depleting therapies. The warning also contains cautions of malignancies, which can be opportunistic due to immunosuppression, and progressive multifocal leukoencephalopathy (PML), which was rare, but reported in studies. While general and serious AEs were similar compared to both CsA and tacrolimus, with more discontinuation of study drug with the latter, malignancies were varied in nature and fairly balanced across all arms in the pivotal studies. Non-life or graft-threatening infusion-related reactions occurred among belatacept patients, and while infections in general were higher in likelihood among all agents compared, fungal infections tended to be higher in belatacept patients when compared to tacrolimus.

Page | 9 of 14 ∞ 2013 Update

A literature search of the MEDLINE database conducted from January through December 2012 did not identify any additional published studies that would prompt reconsideration of the policy statements.

In 2-year follow up from a Phase II RCT of belatacept vs. caleineurin inhibitors cyclosporine or tacrolimus (CNI), year 2 data showed a mean cGFR of 62.0 ml/min (belatacept) vs. 55.4 ml/min (CNI). The mean change in cGFR from baseline was +8.8 ml/min (belatacept) and +0.3 ml/min (CNI). Higher cGFR was observed in patients switched from either cyclosporine (+7.8 ml/min) or tacrolimus (+8.9 ml/min). The frequency of acute rejection in the LTE cohort was comparable between the belatacept and CNI groups by Year 2. All acute rejection episodes occurred during Year 1 in the belatacept patients and during Year 2 in the CNI group. There were more non- serious mucocutaneous fungal infections in the belatacept group. Switching to a belatacept- based regimen from a CNI-based regimen resulted in a continued trend toward improved renal function at 2 years after switching. The results support the previous hypothesis of a prolonged renal-sparing effect of belatacept, since it avoids some of the toxicities commonly observed with CNI.

Similarly, in the 3-year extension of the Phase III BENEFIT-EXT trial in patients receiving extended donor criteria kidneys (ECD) where poorer outcomes are normally expected, patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in Nulojix® (belatacept)-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than Nulojix® (belatacept)-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Page | 10 of 14 ∞ 2014 Update

A literature search conducted from 1/1/13 through 12/31/13 did not reveal new evidence that would require changes to this policy.

2017 Update

A literature search conducted from 1/1/14 through 9/30/17 did not reveal new evidence that would require changes to this policy. In 2016 Vincenti, et al. reported results of a 7 year follow up study of renal transplant patients maintained on Nulojix® (belatacept). The authors concluded that patient and graft survival and the mean eGFR were significantly higher with than with cyclosporine in the comparator arm of the study.

2018 Update

A literature search conducted from 10/1/17 through 9/28/18 did not reveal new evidence that would require changes to this policy.

2019 Update

Reviewed Nulojix® (belatacept) prescribing information and conducted a literature search from 10/1/18 through 11/30/19. No new information was identified that would require changes to this policy.

2020 Update

Reviewed Nulojix® (belatacept) prescribing information and conducted a literature search from 12/1/19 through 09/30/20. No new information was identified that would require changes to this policy.

References

Page | 11 of 14 ∞ 1. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010 Mar;10(3):535-46.

2. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. 2010 Mar;10(3):547-57.

3. Larsen CP, Grinyó J, Medina-Pestana J, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation. 2010 Dec 27;90(12):1528-35.

4. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005 Aug 25;353(8):770-81.

5. Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010 Sep;21(9):1587-96.

6. Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011 Jan;11(1):66-76.

7. Rostaing L, Massari P, Garcia VD et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study. Clin J Am Soc Nephrol. 2011 Feb;6(2):430-9. Epub 2010 Nov 4.

8. NULOJIX (Belatacept) Dossier. Bristol Meyers Squibb. Princeton, NJ. July 2011.

9. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation 2009; 9(Suppl 3): S1–S157.

10. Wein: Campbell-Walsh Urology,10th. ed. http://www.mdconsult.com.offcampus.lib.washington.edu/ books/page. do ?eid= 4-u1.0-B978-1-4160-6911-9..00043-8&isbn=978-1-4160-6911-9&sid=1243233649&uniqId=307156460-3#4- u1.0-B978-1-4160-6911-9..00043-8. Accessed November 19, 2020.

11. Vanrenterghem Y, Bresnahan B, Campistol Jet al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidneytransplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011May 15;91(9):976-83.

12. Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition,8th ed. Available at: http://www.mdconsult.com.offcampus.lib.washington.edu/books/page.do?eid=4-u1.0-B978-1-4377-0792-2..50011-0-- cesec87&isbn=978-1-4377-0792-2&sid=1243243565&uniqId=307156460-12#4-u1.0-B978-1-4377-0792-2..50011-0-- cesec92 Accessed November 19, 2020.

13. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2012 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration; 2014. Available at: https://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/2012_SRTR_ADR.pdf Accessed November 19, 2020.

14. Posselt AM, Szot GL, Frassetto LA, et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on Tcell adhesion or costimulation blockade. Transplantation. 2010;90(12):1595-1601.

15. Klintmalm GB, Feng S, Lake, JR, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-Year experience from a phase II study. Oral presentation at: Annual Meeting of the American Transplant Congress; April 30-May 4, 2011; Philadelphia.

16. NULOJIX (Belatacept) prescribing information. Bristol Meyers Squibb. Princeton, NJ. April 2018.

17. Bremer S, Vethe NT, Rootwelt H, et al. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. J Transl Med. 2009 Jul 27;7:64.

18. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy. 2011 Apr;31(4):394-407. Review. The role of belatacept in transplantation: results and implications of clinical trials in the context of other new biological immunosuppressant agents. Clin Transplant. 2012 Dec 2. doi: 10.1111/ctr.12044 . Transplantation. 2018 Sep;102(9):1440-1452.Heemann U, Viklicky O.

Page | 12 of 14 ∞ 19. Grinyo J, Alberu J, et al. Transpl Int. 2012 Oct;25(10):1059-64. Available online at: Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study.Available at: http://www.ncbi.nlm.nih.gov/pubmed/22816557 Accessed November 19 ,2020.

20. Pestana JO, Grinyo JM, et al. Three-year outcomes from BENEFIT-EXT: a Phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012 Mar;12(3):630-9. https://www.ncbi.nlm.nih.gov/pubmed/22300431 Accessed November 19, 2020.

21. Bassil N, Rostaing L, Mengelle C, et al. Prospective monitoring of cytomegalovirus, Epstein-Barr virus, BK virus, and JC virus infections on belatacept therapy after a kidney transplant. Exp Clin Transplant. 2014 Jun;12(3):212-9.

22. Vincenti F1, Rostaing L, Grinyo J, et al. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43.

23. Schwarz C, Mahr B, Muckenhuber M, Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results. Expert Rev Clin Immunol. 2018 Jul;14(7):583-592. doi: 10.1080/1744666X.2018.1485489. Epub 2018 Jun 25.Perez CP, Patel N, Mardis CR, Belatacept in Solid Organ Transplant: Review of Current Literature Across Transplant Types.

History

Date Comments 02/27/12 New Policy. Add to Prescription Drug section. Reviewed by P&T January 24, 2012.

02/13/13 Replace policy. Policy updated with literature review; no change in policy statements. HCPCS code J0485 added (new code 1/1/13); C9286 deleted effective 12/31/12.

03/25/14 Replace policy. Policy updated with literature review; no change to policy statement.

08/11/15 Annual Review. A literature search was conducted from 3/1/14-6/30/15. No new studies were found that would require changes to this policy. One new reference added. HCPCS codes J3490, J3590 and J7599 removed; these are non-specific codes – the specific code J0485 remains on the policy.

06/01/16 Annual Review, approved May 10, 2016. Inclusion of the “Site of Service” criteria to the existing policy. Format of the “Policy” section re-structured to include tabulated view of the medical necessity criteria.

08/19/16 Converted to new policy format; no changes in content or coverage.

11/01/16 Interim Review, approved October 11, 2016. Clarified age criteria language indicating that site of service review is applicable to only those age 13 and older; drug criteria review applies to all ages.

01/01/17 Interim Review, approved December 13, 2016. Added Consideration of Age Requirements to policy.

07/01/17 Formatting update; added hyperlinks to medical necessity criteria sections.

Page | 13 of 14 ∞ Date Comments 09/25/17 Interim Review, approved September 22, 2017, effective September 25, 2017. Policy statement added to indicate that Nulojix® (belatacept) beis investigational for use in pediatric patients because there have been no studies to support use in this group.

11/01/17 Annual Review, approved October 3, 2017. Clarified site of service exception criterion related to access: There is no outpatient infusion center within 50 miles of the patient’s home and there is no contracted home infusion agency that will travel to their home, or a hospital is the only place that offers infusions of this drug. Added 7-year results of a long term follow up study.

02/14/18 Interim Review, approved February 13, 2018. Update hospital based outpatient coverage from 30 days to 90 days.

11/01/18 Annual Review, approved October 26, 2018. No changes to policy statement. References added.

01/01/19 Minor update. Clarified Consideration of Age information.

06/01/19 Interim Review, approved May 23, 2019. Clarified Nulojix (belatacept) criteria when used for induction therapy versus maintenance therapy.

01/01/20 Annual Review, approved December 10, 2019. No changes to policy statement.

12/01/20 Annual Review, approved November 3, 2020. No changes to policy statement.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2020 Premera All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Page | 14 of 14 ∞

Discrimination is Against the Law Oromoo (Cushite): Beeksisni kun odeeffannoo barbaachisaa qaba. Beeksisti kun sagantaa Premera Blue Cross complies with applicable Federal civil rights laws and yookan karaa Premera Blue Cross tiin tajaajila keessan ilaalchisee does not discriminate on the basis of race, color, national origin, age, odeeffannoo barbaachisaa qabaachuu danda’a. Guyyaawwan murteessaa disability, or sex. Premera does not exclude people or treat them differently ta’an beeksisa kana keessatti ilaalaa. Tarii kaffaltiidhaan deeggaramuuf because of race, color, national origin, age, disability or sex. yookan tajaajila fayyaa keessaniif guyyaa dhumaa irratti wanti raawwattan jiraachuu danda’a. Kaffaltii irraa bilisa haala ta’een afaan keessaniin Premera: odeeffannoo argachuu fi deeggarsa argachuuf mirga ni qabaattu. • Provides free aids and services to people with disabilities to communicate Lakkoofsa bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa. effectively with us, such as: • Qualified sign language interpreters Français (French): • Written information in other formats (large print, audio, accessible Cet avis a d'importantes informations. Cet avis peut avoir d'importantes electronic formats, other formats) informations sur votre demande ou la couverture par l'intermédiaire de • Provides free language services to people whose primary language is not Premera Blue Cross. Le présent avis peut contenir des dates clés. Vous English, such as: devrez peut-être prendre des mesures par certains délais pour maintenir votre couverture de santé ou d'aide avec les coûts. Vous avez le droit • Qualified interpreters d'obtenir cette information et de l’aide dans votre langue à aucun coût. • Information written in other languages Appelez le 800-722-1471 (TTY: 800-842-5357).

If you need these services, contact the Civil Rights Coordinator. Kreyòl ayisyen (Creole):

Avi sila a gen Enfòmasyon Enpòtan ladann. Avi sila a kapab genyen If you believe that Premera has failed to provide these services or enfòmasyon enpòtan konsènan aplikasyon w lan oswa konsènan kouvèti discriminated in another way on the basis of race, color, national origin, age, asirans lan atravè Premera Blue Cross. Kapab genyen dat ki enpòtan nan disability, or sex, you can file a grievance with: avi sila a. Ou ka gen pou pran kèk aksyon avan sèten dat limit pou ka Civil Rights Coordinator - Complaints and Appeals kenbe kouvèti asirans sante w la oswa pou yo ka ede w avèk depans yo. PO Box 91102, Seattle, WA 98111 Se dwa w pou resevwa enfòmasyon sa a ak asistans nan lang ou pale a, Toll free 855-332-4535, Fax 425-918-5592, TTY 800-842-5357 san ou pa gen pou peye pou sa. Rele nan 800-722-1471 Email [email protected] (TTY: 800-842-5357).

You can file a grievance in person or by mail, fax, or email. If you need help Deutsche (German): filing a grievance, the Civil Rights Coordinator is available to help you. Diese Benachrichtigung enthält wichtige Informationen. Diese

Benachrichtigung enthält unter Umständen wichtige Informationen You can also file a civil rights complaint with the U.S. Department of Health bezüglich Ihres Antrags auf Krankenversicherungsschutz durch Premera and Human Services, Office for Civil Rights, electronically through the Blue Cross. Suchen Sie nach eventuellen wichtigen Terminen in dieser Office for Civil Rights Complaint Portal, available at Benachrichtigung. Sie könnten bis zu bestimmten Stichtagen handeln https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: müssen, um Ihren Krankenversicherungsschutz oder Hilfe mit den Kosten U.S. Department of Health and Human Services zu behalten. Sie haben das Recht, kostenlose Hilfe und Informationen in 200 Independence Avenue SW, Room 509F, HHH Building Ihrer Sprache zu erhalten. Rufen Sie an unter 800-722-1471 Washington, D.C. 20201, 1-800-368-1019, 800-537-7697 (TDD) (TTY: 800-842-5357). Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html. Hmoob (Hmong):

Tsab ntawv tshaj xo no muaj cov ntshiab lus tseem ceeb. Tej zaum Getting Help in Other Languages tsab ntawv tshaj xo no muaj cov ntsiab lus tseem ceeb txog koj daim ntawv thov kev pab los yog koj qhov kev pab cuam los ntawm Premera Blue This Notice has Important Information. This notice may have important Cross. Tej zaum muaj cov hnub tseem ceeb uas sau rau hauv daim ntawv information about your application or coverage through Premera Blue no. Tej zaum koj kuj yuav tau ua qee yam uas peb kom koj ua tsis pub Cross. There may be key dates in this notice. You may need to take action dhau cov caij nyoog uas teev tseg rau hauv daim ntawv no mas koj thiaj by certain deadlines to keep your health coverage or help with costs. You yuav tau txais kev pab cuam kho mob los yog kev pab them tej nqi kho mob have the right to get this information and help in your language at no cost. ntawd. Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau Call 800-722-1471 (TTY: 800-842-5357). ua koj hom lus pub dawb rau koj. Hu rau 800-722-1471 (TTY: 800-842-5357). አማሪኛ (Amharic): ይህ ማስታወቂያ አስፈላጊ መረጃ ይዟል። ይህ ማስታወቂያ ስለ ማመልከቻዎ ወይም የ Premera Blue Iloko (Ilocano): Cross ሽፋን አስፈላጊ መረጃ ሊኖረው ይችላል። በዚህ ማስታወቂያ ውስጥ ቁልፍ ቀኖች ሊኖሩ ይችላሉ። Daytoy a Pakdaar ket naglaon iti Napateg nga Impormasion. Daytoy a የጤናን ሽፋንዎን ለመጠበቅና በአከፋፈል እርዳታ ለማግኘት በተውሰኑ የጊዜ ገደቦች እርምጃ መውሰድ pakdaar mabalin nga adda ket naglaon iti napateg nga impormasion

ይገባዎት ይሆናል። ይህን መረጃ እንዲያገኙ እና ያለምንም ክፍያ በቋንቋዎ እርዳታ እንዲያገኙ መብት maipanggep iti apliksayonyo wenno coverage babaen iti Premera Blue አለዎት።በስልክ ቁጥር 800-722-1471 (TTY: 800-842-5357) ይደውሉ። Cross. Daytoy ket mabalin dagiti importante a petsa iti daytoy a pakdaar. Mabalin nga adda rumbeng nga aramidenyo nga addang sakbay dagiti Arabic): partikular a naituding nga aldaw tapno mapagtalinaedyo ti coverage ti) العربية salun-atyo wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti يحوي ھذا اإلشعار معلومات ھامة . قد يحوي ھذا اإلشعار معلومات مھمة بخصوص طلبك أو daytoy nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti التغطية التي تريد الحصول عليھا من خالل Premera Blue Cross. قد تكون ھناك تواريخ مھمة .(bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357 في ھذا اإلشعار . وقد تحتاج التخاذ إجراء في تواريخ معينة للحفاظ على تغطيتك الصحية أو للمساعدة في دفع التكاليف . يحق لك الحصول على ھذه المعلومات والمساعدة بلغتك دون تكبد أية تكلفة . اتصل :(Italiano (Italian بـ(TTY: 800-842-5357) 800-722-1471 Questo avviso contiene informazioni importanti. Questo avviso può contenere 中文 (Chinese): informazioni importanti sulla tua domanda o copertura attraverso Premera 本通知有重要的訊息。 本通知可能有關於您透過 Premera Blue Cross 提交的 Blue Cross. Potrebbero esserci date chiave in questo avviso. Potrebbe 申請或保險的重要訊息。本通知內可能有重要日期。您可能需要在截止日期 essere necessario un tuo intervento entro una scadenza determinata per 之前採取行動，以保留您的健康保險或者費用補貼。您有權利免費以您的母 consentirti di mantenere la tua copertura o sovvenzione. Hai il diritto di ottenere queste informazioni e assistenza nella tua lingua gratuitamente. 語得到本訊息和幫助。請撥電話 。 800-722-1471 (TTY: 800-842-5357) Chiama 800-722-1471 (TTY: 800-842-5357).

037338 (07-2016) 日本語 (Japanese): Română (Romanian): この通知には重要な情報が含まれています。この通知には、 Premera Blue Prezenta notificare conține informații importante. Această notificare Cross の申請または補償範囲に関する重要な情報が含まれている場合があ poate conține informații importante privind cererea sau acoperirea asigurării ります。この通知に記載されている可能性がある重要な日付をご確認くだ dumneavoastre de sănătate prin Premera Blue Cross. Pot exista date cheie în aceast notificare. Este posibil s fie nevoie s ac iona i pân la anumite さい。健康保険や有料サポートを維持するには、特定の期日までに行動を ă ă ă ț ț ă termene limită pentru a vă menține acoperirea asigurării de sănătate sau 取らなければならない場合があります。ご希望の言語による情報とサポー asistența privitoare la costuri. Aveți dreptul de a obține gratuit aceste トが無料で提供されます。800-722-1471 (TTY: 800-842-5357)までお電話 informații și ajutor în limba dumneavoastră. Sunați la 800-722-1471 ください。 (TTY: 800-842-5357).

한국어 (Korean): Pусский (Russian): 본 통지서에는 중요한 정보가 들어 있습니다 . 즉 이 통지서는 귀하의 신청에 Настоящее уведомление содержит важную информацию. Это 관하여 그리고 Premera Blue Cross 를 통한 커버리지에 관한 정보를 уведомление может содержать важную информацию о вашем Premera Blue Cross. 포함하고 있을 수 있습니다 . 본 통지서에는 핵심이 되는 날짜들이 있을 수 заявлении или страховом покрытии через В настоящем уведомлении могут быть указаны ключевые даты. Вам, 있습니다. 귀하는 귀하의 건강 커버리지를 계속 유지하거나 비용을 절감하기 возможно, потребуется принять меры к определенным предельным 위해서 일정한 마감일까지 조치를 취해야 할 필요가 있을 수 있습니다 . срокам для сохранения страхового покрытия или помощи с расходами. 귀하는 이러한 정보와 도움을 귀하의 언어로 비용 부담없이 얻을 수 있는 Вы имеете право на бесплатное получение этой информации и 권리가 있습니다 . 800-722-1471 (TTY: 800-842-5357) 로 전화하십시오 . помощь на вашем языке. Звоните по телефону 800-722-1471 (TTY: 800-842-5357). ລາວ (Lao): Fa’asamoa (Samoan): ້ ້ ້ ້ ແຈ້ງການນີ ມີ ຂໍ ມູ ນສໍ າຄັ ນ. ແຈ້ງການນີ ອາດຈະມີ ຂໍ ມູ ນສໍ າຄັ ນກ່ ຽວກັບຄໍ າຮ້ອງສະ Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau ໝັ ກ ຫືຼ ຄວາມຄຸ້ ມຄອງປະກັນໄພຂອງທ່ານຜ່ານ Premera Blue Cross. ອາດຈະມີ ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala ວັນທີ ສໍ າຄັ ນໃນແຈ້ງການນີ້ . ທ່ານອາດຈະຈໍ າເປັ ນຕ້ອງດໍ າເນີ ນການຕາມກໍ ານົ ດ atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua ເວລາສະເພາະເພື່ ອຮັກສາຄວາມຄຸ້ ມຄອງປະກັນສຸ ຂະພາບ ຫືຼ ຄວາມຊ່ວຍເຫືຼ ອເລື່ ອງ atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le ້ ້ ຄ່ າໃຊ້ຈ່າຍຂອງທ່ານໄວ້ . ທ່ານມີ ສິ ດໄດ້ ຮັບຂໍ ມູ ນນີ ແລະ ຄວາມຊ່ວຍເຫືຼ ອເປັ ນພາສາ aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai ຂອງທ່ານໂດຍບໍ່ ເສຍຄ່ າ. ໃຫ້ໂທຫາ 800-722-1471 (TTY: 800-842-5357). i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i 徶羶ែខមរ (Khmer): ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471 (TTY: 800-842-5357). េសចកតជី ូនដណំ ឹងេនះ掶នព័ត៌掶ន架៉ ងស޶នំ។ ់ េសចកតីជូនដំណឹងេនះរបែហល ᾶ掶នព័ត៌掶ន架៉ ងសំ޶ន់អពំ ីទរមង់ ែបបបទ ឬζរ殶៉ បរង់ របសអ់ នក㾶មរយៈ Español (Spanish): Premera Blue Cross ។ របែហលᾶ掶ន ζលបរ េចិ ឆទសំ޶ន់េ俅កន ុងេសចកតជី ូន Este Aviso contiene información importante. Es posible que este aviso contenga información importante acerca de su solicitud o cobertura a ដណំ ងេនះ។ឹ អនករបែហលᾶរតវζរបេញូ ច ញសមត徶ពថ ដលក់ ណតំៃថ ់ ងᾶកច厶់ ស់ través de Premera Blue Cross. Es posible que haya fechas clave en este 侶侶 េដើមបីនងរកឹ 羶ទកζរ䮶侶ុ 殶៉ បរង់ សខ徶ពរបសុ ់អនក ឬរ厶កជ់ ំនួយេចញៃថល។ aviso. Es posible que deba tomar alguna medida antes de determinadas អនក掶នសទិ ធទទិ ួលព័ត掶នេ៌ នះ និងជំនួយេ俅កន ុង徶羶របស់អនកេ⮶យមនអសិ fechas para mantener su cobertura médica o ayuda con los costos. Usted លយេឡុ ើយ។ សូ មទូរស័ពទ 800-722-1471 (TTY: 800-842-5357)។ tiene derecho a recibir esta información y ayuda en su idioma sin costo alguno. Llame al 800-722-1471 (TTY: 800-842-5357).

ਪ ੰ ਜਾਬੀ (Punjabi): Tagalog (Tagalog): ਇਸ ਨ ੋ ਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨ ੋ ਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ƒ ਤੁਹਾਡੀ Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon ਕਵਰਜੇ ਅਤ ੇ ਅਰਜੀ ਬਾਰ ੇ ਮਹ ੱ ਤਵਪਰਨੂ ਜਾਣਕਾਰੀ ਹ ੋ ਸਕਦੀ ਹ ੈ . ਇਸ ਨ ੋ ਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ . tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue ਹੋ ਸਕਦੀਆਂ ਹਨ ਜੇਕਰ ਤਸੀੁ ਜਸਹਤ ਕਵਰਜੇ ਿਰੱ ਖਣੀ ਹਵੋ ੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring ਇਛ ੱ ੁਕ ਹ ੋ ਤ拓 ਤਹਾਨ ੁ ੰ ੂ ਅ ੰ ਤਮ ਤਾਰੀਖ਼ ਤ ƒ ਪਿਹਲ拓 ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੱ ਕਣ ੁ ਦੀ ਲੋੜ ਹ ੋ ਸਕਦੀ ਹ ੈ ,ਤੁਹਾਨੰ ੂ mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang ਮਫ਼ਤੁ ਿਵੱ ਚ ਤ ੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵ ੱ ਚ ਜਾਣਕਾਰੀ ਅਤ ੇ ਮਦਦ ਪਾਪਤ㘰 ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na 800-722-1471 (TTY: 800-842-5357). walang gastos. May karapatan ka na makakuha ng ganitong impormasyon at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471 .(Farsi): (TTY: 800-842-5357) فارسی اين اعالميه حاوی اطالعات مھم ميباشد .اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم :(ไทย (Thai تقاضا و يا پ وشش بيمه ای شما از طريق Premera Blue Cross باشد . به تاريخ ھای مھم در ั ประกาศนมข้ี ี ้อมลส ู ําคญ ั ประกาศนอาจม ้ี ีข ้อมลท ู ่ีส ําคญเก ั ่ียวกบการการสม ัครหร ั ือขอบเขตประกน اين اعالميه توجه نماييد .شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه . สขภาพของคุณผ ุาน ่ Premera Blue Cross และอาจมีก ําหนดการในประกาศนี ้ คณอาจจะต ุ ้อง ھای درمانی تان، به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد شما حق اين را داريد که اين اطالعات و ک مک را به زبان خود به طور رايگان دريافت نماييد . برای کسب ี่ ดําเน ินการภายในกาหนดระยะเวลาท ํ ่ีแนนอนเพ ่ ่ือจะร ักษาการประกนส ัขภาพของค ุณหร ุ ือการช ่วยเหล ือท اطالعات با شماره 1471-722-800 (کاربران TTY تماس باشماره 5357-842-800) تماس มคี่้่าใชจาย คณม ุีิิ่ี้ัู้สทธทจะไดรบขอมลและความชวยเหล ่ ื้ีอนในภาษาของคณโดยไม ุ่มค ี่้่าใชจาย โทร برقرار نماييد . 800-722-1471 (TTY: 800-842-5357) Polskie (Polish): To og oszenie mo e zawiera wa ne informacje. To og oszenie mo e ł ż ć ż ł ż Український (Ukrainian): zawiera wa ne informacje odno nie Pa stwa wniosku lub zakresu ć ż ś ń Це повідомлення містить важливу інформацію. Це повідомлення świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na може містити важливу інформацію про Ваше звернення щодо kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie страхувального покриття через Premera Blue Cross. Зверніть увагу на przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub ключові дати, які можуть бути вказані у цьому повідомленні. Існує pomocy zwi zanej z kosztami. Macie Pa stwo prawo do bezp atnej ą ń ł імовірність того, що Вам треба буде здійснити певні кроки у конкретні informacji we własnym języku. Zadzwońcie pod 800-722-1471 кінцеві строки для того, щоб зберегти Ваше медичне страхування або (TTY: 800-842-5357). отримати фінансову допомогу. У Вас є право на отримання цієї

інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за Português (Portuguese): номером телефону 800-722-1471 (TTY: 800-842-5357). Este aviso contém informações importantes. Este aviso poderá conter informações importantes a respeito de sua aplicação ou cobertura por meio Tiếng Việt (Vietnamese): do Premera Blue Cross. Poderão existir datas importantes neste aviso. Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông Talvez seja necessário que você tome providências dentro de tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua determinados prazos para manter sua cobertura de saúde ou ajuda de chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông custos. Você tem o direito de obter esta informação e ajuda em seu idioma báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357). để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).