Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Natalizumab (Tysabri®)

Policy #:08.00.64f

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

MULTIPLE SCLEROSIS (MS)
Natalizumab (Tysabri®) is considered medically necessary and, therefore, covered as monotherapy for the treatment of adults with relapsing forms of MS to delay the accumulation of physical disability and to reduce the frequency of clinical exacerbations when the following criterion is met:
  • The individual has had an inadequate response to, or is unable to tolerate, alternate MS therapies (e.g., interferon beta-1a [Avonex®, Rebif®], interferon beta-1b [Betaseron®], glatiramer acetate [Copaxone®]).

CROHN'S DISEASE (CD)
Natalizumab (Tysabri®) is considered medically necessary and, therefore, covered for the treatment of adults with moderately to severely active CD, who have evidence of inflammation, to induce and maintain clinical response and remission when all of the following criteria are met:
  • The individual has had an inadequate response to, or is unable to tolerate, conventional CD therapies and inhibitors of tumor necrosis factor-alpha (TNF-α).
  • Natalizumab (Tysabri®) will not be used in combination with immunosuppressants or TNF-α inhibitors.

ANTI-JCV ANTIBODY
Measurement of anti-JCV antibodies (John Cunningham Virus) with ELISA (enzyme-linked immunosorbent assay) is considered medically necessary and, therefore, covered when tested prior to initiation of natalizumab (Tysabri®) treatment and every six months thereafter, to assess the risk of developing progressive multifocal leukoencephalopathy (PML).

ANTI-NATALIZUMAB ANTIBODIES
Measurement of anti-natalizumab antibodies is considered medically necessary and, therefore, covered in an individual receiving treatment with natalizumab (Tysabri®) when persistent anti-natalizumab antibodies are suspected to have caused a documented hypersensitivity or when there has been an extended dose interruption of natalizumab (Tysabri®) therapy. This test should be repeated three months after an initial positive result is detected.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of natalizumab (Tysabri®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

INDICATION AND USAGE IN MULTIPLE SCLEROSIS

The safety and effectiveness of treatment with natalizumab (Tysabri®) beyond two years are unknown.

The safety and effectiveness of treatment with natalizumab (Tysabri®) in individuals with chronic progressive multiple sclerosis (MS) have not been studied.

A magnetic resonance imaging (MRI) scan should be obtained prior to initiating therapy with natalizumab (Tysabri®). The MRI scan may be helpful in differentiating subsequent MS symptoms from progressive multifocal leukoencephalopathy (PML).

INDICATION AND USAGE IN CROHN'S DISEASE

Natalizumab (Tysabri®) should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate) or inhibitors of TNF-α. Aminosalicylates may be continued during treatment with natalizumab (Tysabri®).

If the individual with Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue natalizumab (Tysabri®).

For individuals with Crohn's disease who start natalizumab while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of natalizumab (Tysabri®) has occurred; if the individual with Crohn's disease cannot be tapered off oral corticosteroids within six months of starting natalizumab (Tysabri®), discontinue natalizumab (Tysabri®).

Other than the initial six-month taper, prescribers should consider discontinuing natalizumab (Tysabri®) for individuals who require additional steroid use that exceeds three months in a calendar year to control their Crohn's disease.

PEDIATRIC USE

Safety and effectiveness of natalizumab (Tysabri®) in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. Natalizumab (Tysabri®) is not indicated for use in pediatric patients.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, natalizumab (Tysabri®) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Natalizumab (Tysabri®) was initially approved by the FDA in November 2004 but was withdrawn by the manufacturer in February 2005 after three individuals in the drug's clinical trials developed progressive multifocal leukoencephalopathy (PML), a serious and rare viral infection of the brain. On June 5, 2006, the FDA approved an application for resumed marketing of natalizumab (Tysabri®), subject to a special restricted distribution program. Natalizumab (Tysabri®) is indicated as monotherapy for the treatment of individuals with relapsing forms of multiple sclerosis. Supplemental approval for use in Crohn's disease was issued on January 14, 2008.

Description

Natalizumab (Tysabri®) is a recombinant humanized monoclonal antibody administered by intravenous infusion. It is approved by the US Food and Drug Administration (FDA) for use in adults with relapsing forms of multiple sclerosis (MS) as monotherapy and in Crohn's disease (CD). The specific mechanism(s) by which natalizumab (Tysabri®) exerts its effects in relapsing forms of MS and CD have not been fully defined.

MULTIPLE SCLEROSIS (MS), RELAPSING FORMS

In relapsing forms of MS, natalizumab (Tysabri®) delays the accumulation of physical disability and reduces the frequency of clinical exacerbations. It is generally recommended for adults who have had an inadequate response to, or are unable to tolerate, alternate MS therapies.

In MS, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors that are present on the endothelial cells of the vessel wall. The clinical effect of natalizumab (Tysabri®) in MS may be secondary to blockade of the molecular interaction of the α4ß1 integrin that is expressed by inflammatory cells with vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells and with CS-L and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of MS demonstrate the reduction of leukocyte migration into the brain parenchyma and the reduction of plaque formation detected by magnetic resonance imaging following repeated administration of natalizumab (Tysabri®). The clinical significance of these animal data is unknown.

PEER-REVIEWED LITERATURE
Summary

Natalizumab (Tysabri®) was evaluated in two randomized, double-blind, placebo-controlled trials with over 2,000 study participants who had relapsing forms of MS, at least one clinical relapse during the past year, and a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. In Study one, 942 individuals who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months, were randomized to receive natalizumab (Tysabri®) (n=627) or placebo (n=315) every 4 weeks for up to 28 months. In Study two, 1171 individuals who had experienced one or more relapses while on interferon beta-1a during the year prior to study entry, were randomized to receive natalizumab (Tysabri®) (n=589) or placebo (n=582) every 4 weeks for up to 28 months. Interferon beta-1a treatment was continued during the study. In both studies, the time to onset of sustained increase in disability (defined as at least 1 point increase on the EDSS from baseline EDSS 1.0 or greater that was sustained for 12 weeks or at least 1.5 point increase on the EDSS from baseline EDSS=0 sustained for 12 weeks) was longer in the natalizumab (Tysabri®) group than the placebo group. The proportion of individuals with increased disability and the annualized relapse rates were lower in the natalizumab (Tysabri®) group than the placebo group.

CROHN'S DISEASE (CD)

Natalizumab (Tysabri®) may also be used to induce and maintain clinical response and remission in adults with moderately to severely active 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-alpha (TNF-α). For individuals with CD, natalizumab (Tysabri®) should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate) or TNF-α inhibitors.

In CD, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in individuals with CD, which suggests that it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab (Tysabri®) in CD may, therefore, be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of inflammatory bowel disease (IBD) and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear.

PEER-REVIEWED LITERATURE
Summary

The safety and effectiveness of natalizumab (Tysabri®) were evaluated in three randomized, double-blind, placebo-controlled clinical trials in 1,414 adults with moderately to severely active CD (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450). Concomitant inhibitors of TNF-α were not permitted. Combination therapy with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, methotrexate) is not recommended, although it was allowed in the clinical trials. Induction of clinical response (defined as greater than or equal to a 70-point decrease in CDAI from baseline) was evaluated in two studies, and maintenance therapy was evaluated in the third study (n=331).

In Study one, 896 individuals were randomized to receive three monthly infusions or either natalizumab (Tysabri®) or placebo. At week 10 the clinical results were not significant: in a post hoc analysis of a subset of 653 individuals with elevated baseline C-reactive protein (CRP), the natalizumab (Tysabri®) group (57%) had statistically more subjects in response than the placebo group (45%). In Study two, 509 individuals with elevated serum CRP were randomized to receive natalizumab (Tysabri®) or placebo in three monthly infusions. Clinical response and clinical remission (defined as CDAI score greater than 150) were measured at Week 8 and Week 12. The natalizumab (Tysabri®) group had a statistically better clinical response and clinical remission than the placebo group.

Maintenance therapy was evaluated in 331 individuals from Study 1 that had a clinical response to natalizumab (Tysabri®) at both Weeks 10 and 12. They were randomized to either continue treatment with natalizumab (Tysabri®) or placebo. Maintenance of response was assessed at Month 9 and Month 15. At Month 9, the natalizumab (Tysabri®) group had a statistically significant better clinical response and clinical remission than the placebo group.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) AND THE TOUCH™ PRESCRIBING PROGRAM

Natalizumab (Tysabri®) was initially approved by the FDA in November 2004 but was withdrawn by the manufacturer in February 2005 after three individuals in the drug's clinical trials developed progressive
multifocal leukoencephalopathy (PML), a serious and rare viral infection of the brain caused by a common virus known as the John Cunningham Virus (JC virus or JCV). This virus stays dormant in most individuals, but may become active in immunocompromised individuals. Among other factors, the presence of anti-JCV antibodies (anti-JCV antibody positive) increases the risk of developing PML. (Note: According to peer-reviewed literature, there is no threshold level for anti-JCV antibodies. The presence of anti-JCV antibodies put an individual at risk for developing PML.) Due to this increased risk, consideration should be made to test for anti-JCV antibody status prior to treatment, or during treatment if antibody status is unknown. Those who are anti-JCV antibody negative are still at risk for developing PML, due to the potential for a new JCV infection or a false negative test result. Therefore, individuals with a negative anti-JCV antibody test result may need to be retested every six months.

For individuals who test positive for anti-JCV antibodies, a decision must be made between the individual and the healthcare provider to assess the perceived risks and benefits of continuing therapy, taking into account the total number of risk factors the individual has. Those who choose to continue therapy should do so cautiously with more frequent monitoring (e.g., office visits, magnetic resonance imaging [MRIs]).

An early diagnosis of PML has been documented in asymptomatic individuals during periodic MRI monitoring for radiographic signs consistent with PML. Consider monitoring patients at high risk for PML more frequently.

The FDA allowed a clinical trial of natalizumab (Tysabri®) to resume in February 2006, after confirming that there were no additional cases of PML. On June 5, 2006, the FDA approved an application for resumed marketing of natalizumab (Tysabri®), subject to a special restricted distribution program called the TOUCH™ Prescribing Program.

Due to the risk of PML, natalizumab (Tysabri®) is available only through this program and can only be administered to individuals who are enrolled in and meet all of the conditions of the program. Under the TOUCH™ Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers that are registered with the program can prescribe, distribute, or infuse the drug. There have been 201 cases of PML, reported to the FDA, of approximately 96,582 individuals treated with Tysabri worldwide through January 1, 2012.

ANTI-NATALIZUMAB ANTIBODIES

Anti-natalizumab antibodies may form at any time during natalizumab (Tysabri®) therapy. These antibodies may cause a substandard clinical response. In addition, there may be an increased risk of serious hypersensitivity reactions after an extended dose interruption compared to individuals who received regularly scheduled treatment. Consideration should be given to testing for the presence of antibodies in individuals who wish to recommence therapy following a dose interruption. (Note: According to peer-reviewed literature, there is no threshold level for anti-natalizumab antibodies.)

If the presence of persistent antibodies is suspected due to a substandard clinical response or if the individual is resuming treatment after a dose interruption, antibody testing should be performed. Once an initial positive result is detected, repeat testing three months later is recommended to confirm that antibodies are persistent. Providers should consider the overall benefits and risks of natalizumab in persons with persistent antibodies.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


Calabresi PA, Giovannoni G, Confavreux C, et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007;69(14):1391-403. Epub 2007 Aug 29.

Elsevier's Clinical Pharmacology Compendium. Natalizumab. [Clinical Key Web site]. 03/03/2015. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 6, 2018.

Fernández O. Best practice in the use of natalizumab in multiple sclerosis. Ther Adv Neurol Disord. 2013;6(2):69-79.

Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68(3):295-303.

Lexi-Drugs Compendium. Natalizumab. [Lexicomp Online Web site]. 02/17/2018. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 6, 2018.

Natalizumab (Tysabri®) [prescribing information]. Cambridge, MA: Biogen Inc; 08/2017. Available at: https://www.tysabri.com/ . Accessed March 6, 2018.

Natalizumab (Tysabri®). American Hospital Formulary Service (AHFS). AHFS Drug Information 2018. [Lexi-Drug Web site]. 12/13/2012. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 6, 2018.

Natalizumab (Tysabri®). Micromedex® Healthcare Series. [Micromedex® 2.0 Web site]. 02/05/2018. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed March 6, 2018.

Oliver-Martos B, Orpez-Zafra T, Urbaneja P, Maldonado-Sanchez R, Leyva L, Fernández O. Early development of anti-natalizumab antibodies in MS patients. J Neurol. 2013;260(9):2343-7. Epub 2013 Jun 14.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Approved Risk Evaluation and Mitigation Strategies (REMS). Tysabri® (natalizumab). [FDA Web site]. Last Updated 10/14/2016. Available at:https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=63 . Accessed March 6, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: Tysabri® (natalizumab). [FDA Web site]. 08/16/17. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed March 6, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Postmarket Drug Safety Information for Patients and Providers Information on Natalizumab (marketed as Tysabri). [FDA Web site]. Site Updated 07/17/2015. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107198.htm . Accessed March 6, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab) safety announcement. [FDA website]. Announcement from January 20, 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm. Accessed March 29, 2016.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

MEDICALLY NECESSARY


MEASUREMENT OF ANTI-NATALIZUMAB ANTIBODY
83516, 83518

MEASUREMENT OF ANTI-JCV ANTIBODY
86711



Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

MEDICALLY NECESSARY

G35 Multiple sclerosis

K50.00 Crohn's disease of small intestine without complications

K50.011 Crohn's disease of small intestine with rectal bleeding

K50.012 Crohn's disease of small intestine with intestinal obstruction

K50.013 Crohn's disease of small intestine with fistula

K50.014 Crohn's disease of small intestine with abscess

K50.018 Crohn's disease of small intestine with other complication

K50.019 Crohn's disease of small intestine with unspecified complications

K50.10 Crohn's disease of large intestine without complications

K50.111 Crohn's disease of large intestine with rectal bleeding

K50.112 Crohn's disease of large intestine with intestinal obstruction

K50.113 Crohn's disease of large intestine with fistula

K50.114 Crohn's disease of large intestine with abscess

K50.118 Crohn's disease of large intestine with other complication

K50.119 Crohn's disease of large intestine with unspecified complications

K50.80 Crohn's disease of both small and large intestine without complications

K50.811 Crohn's disease of both small and large intestine with rectal bleeding

K50.812 Crohn's disease of both small and large intestine with intestinal obstruction

K50.813 Crohn's disease of both small and large intestine with fistula

K50.814 Crohn's disease of both small and large intestine with abscess

K50.818 Crohn's disease of both small and large intestine with other complication

K50.819 Crohn's disease of both small and large intestine with unspecified complications

K50.90 Crohn's disease, unspecified, without complications

K50.911 Crohn's disease, unspecified, with rectal bleeding

K50.912 Crohn's disease, unspecified, with intestinal obstruction

K50.913 Crohn's disease, unspecified, with fistula

K50.914 Crohn's disease, unspecified, with abscess

K50.918 Crohn's disease, unspecified, with other complication

K50.919 Crohn's disease, unspecified, with unspecified complications



HCPCS Level II Code Number(s)



MEDICALLY NECESSARY

J2323 Injection, natalizumab, 1 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

08.00.64f
04/25/2018This policy has undergone a routine review, and no revision have been made.
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.
Version Effective Date: 05/04/2016
Version Issued Date: 05/04/2016
Version Reissued Date: 04/25/2018

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