Currentsierra health and lifePolicy 2025D0026R

Tysabri (natalizumab) — coverage criteria for relapsing forms of multiple sclerosis and moderately to severely active Crohn's disease

Coverage criteria and clinical background for natalizumab (Tysabri) use in relapsing forms of multiple sclerosis and moderately to severely active Crohn's disease, including initial and continuation authorization requirements and applicable billing/diagnosis codes. Affects providers requesting coverage for natalizumab under the payer's medical/drug benefit.

Policy Summary

Payersierra health and life

PolicyTysabri (natalizumab) — coverage criteria for relapsing forms of multiple sclerosis and moderately to severely active Crohn's disease

Policy CodePolicy 2025D0026R

Change TypeNo material change

Effective DateOct 1, 2025

Next Review Date

Key ActionObtain prior authorization confirming TOUCH program enrollment and documentation of indication, prior therapy history (for Crohn's), and adherence to FDA‑labeled dosing; approvals are limited to ≤12 months.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

12 monthsauthorization duration (max)

J2323HCPCS

6 moanti-JCV testing interval (CD)

11/1,000PML risk (high-risk profile)

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria for Natalizumab (Tysabri)

Relapsing forms of Multiple Sclerosis (Initial and Continuation)

Covered when ALL of the following are met

Diagnosis of relapsing forms of multiple sclerosis (e.g., clinically isolated syndrome, relapsing-remitting disease, active secondary-progressive disease)

Monotherapy: Patient is not receiving Tysabri in combination with disease-modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers (examples: interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide; rituximab, belimumab, ofatumumab; alemtuzumab, mitoxantrone)

Lists examples of prohibited concomitant therapies

Dosing: Tysabri is dosed according to the U.S. FDA labeled dosing

Authorization length: Initial or continuation authorization is for no more than 12 months<=12 months

Continuation-specific: For continuation: patient has previously received Tysabri and documentation of positive clinical response to Tysabri therapy is provided

Crohn's Disease (Initial and Continuation)

Covered when ALL of the following are met

Diagnosis of moderately to severely active Crohn's disease

Prior therapy: History of inadequate response or intolerance to conventional Crohn's disease therapies and inhibitors of TNFα (conventional therapies may include aminosalicylates such as mesalamine or sulfasalazine, corticosteroids, immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate; TNF inhibitors include infliximab, adalimumab, certolizumab pegol)

Conventional therapies and TNFα inhibitors must be documented as failed or not tolerated

No concomitant immunosuppressants: Patient is not receiving concomitant immunosuppressants or TNF‑inhibitors (examples: 6-mercaptopurine, azathioprine, cyclosporine, methotrexate; etanercept, infliximab, adalimumab, certolizumab pegol)

Lists examples of prohibited concomitant therapies

Dosing:

Coverage Criteria — General

Covered when ALL of the following are met

Indication: Patient has relapsing forms of multiple sclerosis OR moderately to severely active Crohn's disease with evidence of inflammation

FDA indications referenced

Prior therapy for Crohn's disease: For Crohn's disease: inadequate response to or intolerance of conventional therapies and inhibitors of TNFα must be documented

Per ACG guideline and FDA labeling; anti-JCV testing considerations apply for maintenance

Avoid contraindicated combinations: Not coadministered with immunosuppressants or TNFα inhibitors (examples: 6-mercaptopurine, azathioprine, cyclosporine, methotrexate)

Per FDA label

Risk program enrollment:

Natalizumab (Tysabri) is not supported for indications outside its approved uses; specifically, its use for diseases or conditions other than the labeled indications — including multiple sclerosis subtypes other than relapsing forms — is considered unproven. Robust randomized controlled trial data demonstrating meaningful superiority in efficacy to justify the drug’s known safety risks are lacking for those other uses.

Natalizumab must not be coadministered with systemic immunosuppressants or tumor necrosis factor alpha (TNFα) inhibitors. The FDA label and the policy both state that Tysabri should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate) or TNFα inhibitors (examples include etanercept, adalimumab, certolizumab pegol, infliximab); requests for combination therapy will be denied.

Use of natalizumab for multiple sclerosis types other than relapsing forms (for example, primary progressive MS without relapses) is considered not supported by adequate evidence. The policy specifies that natalizumab’s benefit-risk profile has been established for relapsing forms of MS only; evidence is insufficient to support coverage for non-relapsing MS subtypes.

Because natalizumab is associated with the risk of progressive multifocal leukoencephalopathy (PML), clinicians should carefully weigh risks and benefits before initiating or continuing therapy in patients at increased PML risk. Known considerations include anti‑JCV antibody positivity, longer treatment duration (particularly beyond two years), and prior immunosuppressant exposure; when these factors are present, documented consideration of the risk–benefit profile is expected prior to approval.

Billing, Authorization Duration, and Diagnosis Codes

Covered HCPCSHCPCSCovered

J2323

Injection, natalizumab, 1 mg.

MS Diagnosis CodesICD-10

G35.A	Relapsing-remitting multiple sclerosis.
G35.B0	Primary progressive multiple sclerosis, unspecified.
G35.B1	Active primary progressive multiple sclerosis.
G35.B2	Non-active primary progressive multiple sclerosis.
G35.C0	Secondary progressive multiple sclerosis, unspecified.
G35.C1	Active secondary progressive multiple sclerosis.
G35.C2	Non-active secondary progressive multiple sclerosis.
G35.D	Multiple sclerosis, unspecified.

Crohn's Disease Diagnosis CodesICD-10

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.

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Authorization duration

Maximum authorization lengthInitial or continuation authorization is for no more than 12 months

Dosing requirementTysabri must be dosed according to the U.S. FDA labeled dosing

Renewal notesAuthorizations (initial or continuation) should not exceed a 12-month period and require documentation of clinical response for continuation

Known PML risk factors

Presence of anti‑JCV antibodiesTesting positive for anti‑JC virus (JCV) antibodies is a recognized risk factor for PML

Longer duration of treatmentLonger duration of Tysabri treatment, especially beyond 2 years, increases PML risk

Prior immunosuppressant usePrior treatment with immunosuppressant medications (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil) increases PML risk

Provider Requirements, Prior Authorization, and Denial Triggers

Prior Authorization

Prior Authorization Required

Prior authorization is required for initiation and continuation of Tysabri (natalizumab). Approvals are limited to the durations specified in the coverage criteria (initial and continuation authorizations up to 12 months).

Prior authorization required for initiation and continuation
Authorizations limited to a maximum of 12 months per approval

Documentation Required

Required Documentation

Prescribers must document diagnosis, prior treatment history, and supporting clinical details. Documentation should include: confirmation of the specific diagnosis (relapsing forms of MS or moderately to severely active Crohn's disease), prior therapies tried and reason for failure or intolerance, dosing consistent with FDA labeling, evidence of positive clinical response for continuation requests, and any baseline evaluations performed (e.g., MRI when applicable).

Include diagnosis and clinical course
List prior therapies and reason for inadequate response or intolerance
Document dosing per FDA label
For continuation: document prior receipt of Tysabri and positive clinical response

Step Therapy

Step Therapy for Crohn's Disease

For Crohn's disease, step therapy requires documentation of inadequate response or intolerance to conventional Crohn's therapies and to inhibitors of TNFα prior to approval of Tysabri.

Conventional therapies include aminosalicylates (e.g., mesalamine, sulfasalazine), corticosteroids, and immunomodulators (e.g., azathioprine, 6‑mercaptopurine, methotrexate)
TNFα inhibitors include agents such as infliximab, adalimumab, certolizumab pegol

Documentation Required

Prior Therapy Requirement for Crohn's Disease

Specifically, for moderately to severely active Crohn's disease, Tysabri is covered only after the patient has had an inadequate response to or intolerance of conventional Crohn's disease therapies and inhibitors of TNFα. The request must state which prior agents were tried, the duration of therapy, and the reason for failure or intolerance.

Require evidence of prior inadequate response or intolerance to both conventional therapies and TNFα inhibitors
Provide prior agent names, treatment durations, and reasons for discontinuation

Drug Definitions, Safety Risks, and Program Definitions

Natalizumab is a recombinant humanized IgG4 monoclonal antibody that binds the α4 integrin subunit on leukocytes (targeting α4β1 and α4β7 integrins) and inhibits leukocyte adhesion and transmigration. Its precise mechanism of clinical benefit in multiple sclerosis and Crohn’s disease is not fully defined. Clinically important safety considerations include an increased risk of progressive multifocal leukoencephalopathy (PML), which has informed requirements such as patient enrollment in the TOUCH Prescribing Program and periodic anti‑JCV antibody assessment.

Natalizumab (Tysabri) — key drug definition

Drug class and nameNatalizumab (Tysabri) — a recombinant humanized IgG4 κ monoclonal antibody targeting the α4 integrin subunit

Mechanism summaryBinds the α4‑subunit of α4β1 and α4β7 integrins on leukocytes to inhibit α4‑mediated adhesion and leukocyte transmigration

Manufacture detailProduced in murine myeloma cells (recombinant humanized monoclonal antibody)

Progressive multifocal leukoencephalopathy (PML) risk

Nature of riskProgressive multifocal leukoencephalopathy (PML) is a rare but serious, potentially fatal brain infection associated with Tysabri use

UnpredictabilityThere are currently no tests that can reliably predict who will develop PML; clinical benefit must be weighed against risk

Epidemiology and safety communicationsFDA safety communications report confirmed cases (31 confirmed as of Jan 21, 2010) and link increased risk with number of infusions and prior immunosuppressant use

TOUCH Prescribing Program — definition and enrollment requirements

Program purposeTOUCH Prescribing Program is a risk minimization program that registers prescribers, infusion centers, and pharmacies and requires patient enrollment for Tysabri dispensing/infusion

Enrollment requirementsPatients must be enrolled in TOUCH, read the Medication Guide, understand risks, and complete and sign the Patient‑Prescriber Enrollment Form

Site certificationPharmacies and infusion centers must be specially certified to dispense or infuse Tysabri; prescribers and sites are registered under MS TOUCH or CD TOUCH components

Anti‑JCV antibody testing — assay and recommended interval

Assay exampleAnti‑JCV antibody status may be determined using an analytically and clinically validated anti‑JCV antibody detection test (e.g., Stratify JCV Antibody ELISA, FDA cleared Jan 20, 2012)

Clinical useAnti‑JCV antibody testing identifies a risk factor for PML and should inform risk–benefit decisions for initiating or continuing Tysabri

Monitoring intervalRecommended periodic rechecking of anti‑JCV antibody status (example: every 6 months for Crohn's disease maintenance) to inform ongoing risk assessment