Drug and Biologic Coverage Policy

Effective Date ...... 1/1/2021 Next Review Date ...... 1/1/2022 Coverage Policy Number ...... M0008

Natalizumab for Crohn’s Disease

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 ...... 2 (Individual and Family Plans) General Background ...... 2 Natalizumab for Multiple Sclerosis Coding/Billing Information ...... 3 References ...... 4

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 natalizumab (Tysabri®) for Crohn’s disease. Natalizumab (Tysabri) is also indicated for multiple sclerosis. Use for this indication is addressed in a separate coverage policy (Natalizumab for Multiple Sclerosis). Please refer to the related coverage policy link above.

Coverage Policy Natalizumab (Tysabri®) is considered medically necessary when all of the following criteria are met: • Individual is 18 years of age or older. • Diagnosis of moderate to severe Crohn's disease • Documented failure or inadequate response, contraindication per FDA label, intolerance, or not a candidate for ONE anti-tumor necrosis factor biologic • Prescribed by or in consultation with a gastroenterologist or a prescriber who specializes in Crohn’s disease

Initial authorization is up to 12 months.

Natalizumab (Tysabri) is considered medically necessary for continued use when the individual has had a positive response to natalizumab (Tysabri). Page 1 of 4 Drug and Biologic Coverage Policy: M0008

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.

Natalizumab (Tysabri) is considered experimental, investigational or unproven for ANY other use including the following: • Concomitant use with an immunosuppressant agent (for example, 6-mercaptopurine, azathioprine, cyclosporine, methotrexate, an infliximab product, an adalimumab product, Cimzia, Entyvio and Stelara) • Ulcerative Colitis

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

FDA Approved Indications

FDA Approved Indication Crohn’s Disease (CD) Tysabri is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. Tysabri should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Warnings and Precautions (5.1)].

Multiple Sclerosis (MS) Tysabri is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. Tysabri increases the risk of PML. When initiating and continuing treatment with Tysabri, physicians should consider whether the expected benefit of Tysabri is sufficient to offset this risk. See important information regarding the risk of PML with Tysabri [see Warnings and Precautions (5.1)].

Recommended Dosing

FDA Recommended Dosing – Crohn’s Disease Only prescribers registered in the CD TOUCH® Prescribing Program may prescribe Tysabri for Crohn’s disease [see Warnings and Precautions (5.2)].

The recommended dose of Tysabri for Crohn’s disease is 300 mg intravenous infusion over one hour every four weeks. Tysabri should not be used with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α. Aminosalicylates may be continued during treatment with Tysabri.

If the patient with Crohn’s disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue Tysabri. For patients with Crohn’s disease who start Tysabri while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of Tysabri has occurred; if the patient with Crohn’s disease cannot be tapered off of oral corticosteroids within six months of starting Tysabri, discontinue Tysabri. Other than the initial six-month taper, prescribers should consider discontinuing Tysabri for patients who require additional steroid use that exceeds three months in a calendar year to control their Crohn’s disease.

General Background

Disease Overview Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract. (Torres, 2017) The prevalence has been increasing worldwide. (Lichtenstein, 2018) Common symptoms of Crohn’s disease include abdominal pain,

Page 2 of 4 Drug and Biologic Coverage Policy: M0008 diarrhea, fatigue, weight loss, fever, anemia, and recurrent fistulas. Adults with Crohn’s disease may be at risk of bone fractures, as well as thromboembolism. Other extraintestinal manifestations may occur (e.g., primary sclerosing cholangitis). Younger patients may experience growth failure. (Torres, 2017, Lichtenstein, 2018) The chronic intestinal inflammation over time leads to intestinal complications such as strictures, fistulas, and abscesses. Only 20% to 30% of patients with Crohn’s disease will have a nonprogressive or indolent course. Therefore, it is appropriate to identify therapies that will achieve adequate control for the patient. Many different therapies are available including corticosteroids, immunomodulators (e.g., azathiopurine, 6-mercaptopurine), and anti-TNF agents (e.g., infliximab products, adalimumab products, Cimzia® [certolizumab pegol injection for subcutaneous use]).

Professional Societies/Organizations Crohn’s Disease American College of Gastroenterology The American College of Gastroenterology (ACG) has guidelines on management of Crohn’s disease in adults (2018). Some of the recommendations are summarized for moderate to severe disease or moderate to high-risk disease. Oral corticosteroids are effective and can be used short-term to alleviate signs and symptoms of moderately to severely active Crohn’s disease. Thiopurines (azathiopurine, 6-mercaptopurine) are effective and should be considered for use for steroid-sparing Crohn’s disease. Azathioprine and 6-mercaptopurine are effective therapies and should be considered for patients with Crohn’s disease for maintenance of remission. Anti-TNF agents (e.g., infliximab products, adalimumab products, Cimzia® [certolizumab pegol injection for subcutaneous use]) should be used to treat Crohn’s disease that is resistant to treatment with corticosteroids. Anti-TNF agents should be given for Crohn’s disease refractory to thiopurines or methotrexate. For patients with moderately to severely active Crohn’s disease and objective evidence of active disease, anti-integrin therapy (with Entyvio® [vedolizumab injection for intravenous use) with or without an immunomodulator is more effective than placebo and should be considered for use for induction of symptomatic remission in patients with Crohn’s disease. Tysabri is more effective than placebo and should be considered to be used for induction of symptomatic response and remission in patients with active Crohn’s disease (strong recommendation; high level of evidence). Tysabri should be used for maintenance of Tysabri-induced remission of Crohn’s disease only if serum antibody to John Cunningham virus is negative. Stelara® (ustekinumab injection for subcutaneous or intravenous use) should be given for moderate to severe Crohn’s disease patients who failed treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors or who have had no prior exposure to anti-TNF inhibitors. (Lichtenstein, 2018)

® The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely Initiative No recommendations are available for natalizumab or Crohn’s disease.

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

Other Covered Uses AHFS Drug Information 2019 Edition does not support any off-label uses of natalizumab.

Other Uses without Supportive Evidence Concurrent Use with an Immunosuppressant Agent in Patients with Crohn’s Disease Note: Examples include 6-mercaptopurine, azathioprine, cyclosporine, methotrexate, an infliximab product, an adalimumab product, Cimzia, Entyvio and Stelara. Ordinarily, patients who are receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune function should not take Tysabri. (Tysabri Prescribing Information, 2019)

Ulcerative Colitis Efficacy data with use of Tysabri are limited. (Gordon, 2002)

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

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

HCPCS Description Codes J2323 Injection, natalizumab, 1 mg

References

1. Biogen Idec Inc. Tysabri (natalizumab) [product information]. Cambridge, MA: Biogen Idec Inc.; April 2018. 2. Gordon FH, Hamilton MI, Donoghue S, et al. A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther. 2002;16:699- 705. 3. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481-517.doi:10.1038/ajg.2018.27 4. McEvoy GK, ed. AHFS 2019 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc. 2019. 5. Torres J, Mehandru S, Solombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2017;389(10080):1741- 1755.

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