Description:
Natalizumab is an integrin receptor antagonist. It is approved by the Food and Drug Administration (FDA) for the following indications. 

• Multiple sclerosis (MS), relapsing forms. As monotherapy for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. The efficacy of natalizumab beyond two years is unknown. Because natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, natalizumab is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternative MS therapy. 

Safety and efficacy in patients with chronic progressive multiple sclerosis have not been studied. 

• Crohn’s disease. For reducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor (TNF)-α. Natalizumab should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate) or inhibitors of TNF-α. 

Natalizumab increases the risk of PML. As of Aug. 22, 2011, 150 cases of PML have been reported in patients who received natalizumab after it became available in July 2006 — 85 cases in Europe, 58 in the U.S., and 7 in the rest of the world. The risk of developing PML increases with longer treatment duration. There is limited experience with greater than 3 years of treatment. Natalizumab is available only through a restricted distribution program called the TOUCH^™ Prescribing Program. The goal of the TOUCH program is to minimize the risk of PML. Prescribers, patients, infusion centers, and pharmacies associated with the infusion centers are required to be registered.  Patients must be evaluated 3 and 6 months after the first infusion and then every 6 months. Every 6 months it must be determined whether patients should continue on treatment and treatment is re-authorized through the TOUCH program every 6 months. 

Natalizumab is available as a preservative-free solution in single use vials containing 300 mg of natalizumab in 15 mL (20 mg/mL). This concentrated solution must be diluted before intravenous (IV) administration in 100 mL of 0.9% sodium chloride injection. The 300 mg in 100 mL solution is infused over about one hour.  It should not be given IV push or by bolus injection. 

Policy:
Initiation of natalizumab is considered MEDICALLY NECESSARY when administered to member who are 18 years of age or older for the following conditions:

1. Relapsing forms of Multiple Sclerosis (MS) (i.e., relapsing-remitting MS [RRMS], secondary-progressive MS [SPMS], with relapsing disease, progressive-relapsing MS [PRMS], when ALL of the following criteria are met:
   • The member has tried/railed or has a contraindication to at least one of the following interferon beta-1a (Avonex and Rebif) or interferon beta-1b (Betaseron and Extavia); AND
   • The member has tried/failed or has a contraindication to glatiramer acetate (Copaxone); AND
   • Natalizumab will not be used concomitantly with ANY of the following:  interferon beta-1a/b; glatiramer acetate; mitoxantrone (Novatrone); dimethyl fumarate (Tecfidera); fingolimod (Gilenya); or teriflunomid (Aubagio); AND
   • The dose does not exceed 300 mg every 28 days
   • This drug should be prescribed by a neurologist.
2. Moderately to severely active Crohn’s Disease when ALL of the following criteria are met:
   • Member has tried/failed or has a contraindication to ONE or more conventional therapies (e.g., sulfasalazine, mesalamine products, amino-salicylate, corticosteroids, immunosuppressants [6-mercaptopurine], azathioprine, cyclosporine, methotrexate); AND
   • Member has tried/failed or has a contraindication to ONE or more tumor-necrosis factor (TNF)-antagonists (i.e., adalimumab [Humira]. Infliximab [Remicade], certolizumab [Cimzia]); AND
   • Natalizumab will be used as monotherapy; AND
   • The dose does not exceed 300 mg every 28 days.
   • This drug should be prescribed by or in consultation with a gastroenterologist.

Approval duration: 1 year
Continuation of natalizumab therapy is considered MEDICALLY NECESSARY when ALL of the following criteria are met:

• Member is diagnosed with EITHER of the following:
  • A relapsing form of multiple sclerosis (i.e., RRMS, SPMS, PRMS), OR
  • Moderately to severely active Crohn’s disease; AND
• Member has demonstrated a beneficial response to therapy; AND
• Member has been approved by another health plan or meets Blue Cross Blue Shield of South Carolina initial criteria for coverage; AND
• Natalizumab will be used as monotherapy; AND
• Member is 18 years of age or older; AND
• The dose does not exceed 300 mg every 28 days.

Natalizumab IV is considered NOT MEDICALLY NECESSARY when administered for all other indications as there is insufficient clinical evidence to support its use including but not limited to:

• Ulcerative colitis.
• Chronic progressive multiple sclerosis.
• Individuals with a medical condition that results in significantly compromised immune system function such as human immunodeficiency virus (HIV) infection, leukemia, lymphoma, organ transplant.
• Individuals on antineoplastic, immunosuppressive, or immunomodulating agents.

Contraindications

• Patients who have or have had PML (4)
• Patients who have had a hypersensitivity reaction to TYSABRI (4, 5, 3)

Rationale:
In 2008, the American Academy of Neurology published an assessment of the effectiveness and safety of natalizumab in the treatment of MS. Articles reporting results from controlled clinical trials in humans were included in the analytic process for the assessment. The authors concluded that natalizumab reduces measures of disease activity including clinical relapse rate, gadolinium-enhancement, and new and enlarging T2 lesions in patients with relapsing MS. Additionally, natalizumab therapy is associated with improved measures of disease severity such as the EDSS progression rate and the T2-hyperintense and T1-ypointense lesion burden seen on MRI in patients with relapsing MS. In the setting of SPMS, the efficacy of natalizumab remains unclear. The only available evidence for the use of natalizumab in forms of MS other than RRMS is derived from a moderately-sized Phase II study in patients with RRMS or SPMS. This study reported a benefit on measures of disease activity (both clinical and MRI) in the combined group, but did not analyze the two subgroups separately. The assessment discusses the increased risk of developing PML in natalizumab-treated patients. Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, the authors recommend that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have particularly aggressive initial disease course. This recommendation is analogous to the U.S. Food and Drug Administration’s (FDA) recommendation for natalizumab. Furthermore, the authors advice against combination therapy (e.g., natalizumab with interferon beta therapy), as there is no data to support combination therapy and it may increase the risk of PML.

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract and can manifest as focal or patchy inflammation confined to the bowel wall or result in complications such as fistulas or strictures. Similar to MS, a definitive cure for CD has not been established. The goals of CD therapy are to induce and maintain remission, improve quality of life and prevent complications that may occur. Treatment options are individualized and target disease location, behavior and severity. Tumor necrosis factor (TNF) alpha antagonists have been considered the mainstay in the management of CD. Natalizumab is the first non-TNF alpha antagonist approved for the treatment of CD. It represents an important option for individuals who are intolerant or have lost efficacy to all other treatments including immune modulators and TNF alpha inhibitors.

References:

1. Tysabri injection [package insert].  South San Francisco, CA:  Elan Pharmaceuticals, Inc.; (manufactured by Biogen Idec Inc.) August 2011. 
2. National MS Society.  Update on Tysabri and PML.  Updated August 22, 2011.  Available at: http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=2308  Accessed September 15, 2011. 
3. Expert Opinion Paper.  National Clinical Advisory Board of the National Multiple Sclerosis Society.  Patient Access to Tysabri^®.  2008.  Accessed on September 15, 2011. Available at: http://www.nationalmssociety.org/for-professionals/healthcare-professionals/publications/expert-opinion-papers/index.aspx 
4. Kappos L, Hartung HP, Havrdova E, et al.  Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring.  Lancet Neurol.  2007;6:431-441.
5. Boster A, Edan G, Frohman E, et al; Multiple Sclerosis Clinical Research Center, Department of Neurology, Wayne State University School of Medicine. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol. 2008;7:173-183.
6. Hyams JS, Wilson DC, Thomas A, et al; International Natalizumab CD305 Trial Group.  Natalizumab therapy for moderate to severe Crohn disease in adolescents.  J. Pediatr Gastroenterol. Nutr.  2007;44:185-191. 
7. Huppke P, Stark W, Zürcher C, et al.  Natalizumab use in pediatric multiple sclerosis.  Arch Neurol.  2008;65:1655-1658. 
8. 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. 
9. Gilenya capsules [package insert].  East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2011. 
10. Biogen Idec Medical Information.  PML incidence in patients receiving Tysabri (natalizumab).  Available at: https://medinfo.biogenidec.com  Accessed on September 16, 2011. 
11. Clifford DB, De Luca A, Simpson DM, et al.  Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases.  Lancet Neurol.  2010;9:438-446. 
12. Kleinschmidt-DeMasters BK, Tyler KL.  Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.  N Engl J Med.  2005;353:369-374. 
13. Langer-Gould A, Atlas SW, Green AJ, et al.  Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.  N Engl J Med.  2005;353:375-381.
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15. US Food and Drug Administration.  FDA Drug Safety Communication:  Safety update on Progressive Multifocal Leukoencephalopathy (PML) associated with the use of Tysabri (natalizumab).  Updated 04/22/2011  Available at: http://www.fda.gov/Drugs/DrugSafety/ucm252045.htm  Accessed 09/14/2011.
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21. Havrdova E, Galetta S, Hutchinson M, et al.  Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.  Lancet Neurol.  2009;8:254-260. 
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23. Oturai AB, Koch-Henriksen N, Petersen T, et al.  Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study.  Eur J Neurol.  2009;16:420-423. 
24. Polman CH, O’Connor PW, Havrdova E, et al, for the AFFIRM Investigators.  A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med.  2006;354:899-910. 
25. Putzki N, Yaldizli O, Bühler R, et al.  Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity:  results from a multicenter study in Switzerland.  Eur Neurol.  2010;63:101-106. 
26. Putzki N, Yaldizli O, Mäurer M, et al.  Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: results from a multi-center study in German speaking countries.  Eur J Neurol.  2010;17:31-37. 
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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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