CurrentUnitedHealthcarePolicy 2025D0026R

Tysabri (natalizumab) — Coverage Criteria

Defines UnitedHealthcare medical benefit drug policy coverage criteria for natalizumab (Tysabri) for relapsing forms of multiple sclerosis and moderate to severe Crohn's disease, including initial and continuation authorization requirements for commercial members.

Policy Summary

PayerUnitedHealthcare

PolicyTysabri (natalizumab) — Coverage Criteria

Policy CodePolicy 2025D0026R

Change TypeTechnical update — codes/policy housekeeping

Effective DateOct 1, 2025

Next Review Date

Key ActionObtain prior authorization and confirm TOUCH Prescribing Program enrollment; initial and continuation authorizations are limited to no more than 12 months.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

12 monthsinitial auth period

J2323HCPCS

increases with infusionsPML risk

requiredTOUCH program

CD inductionACG endorsement

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.

Initial Therapy - Relapsing MS

Covered when ALL of the following are met:

Relapsing Forms of MS - Initial: 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 any of the following (used as monotherapy): disease-modifying therapies (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide), lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone), or B‑cell targeted therapies (e.g., rituximab, belimumab, ofatumumab)

Dosing and duration: Tysabri is dosed according to the U.S. FDA labeled dosing; initial authorization is for no more than 12 months12 months

Continuation Therapy - Relapsing MS

Covered when ALL of the following are met:

Prior receipt: Patient has previously received treatment with Tysabri

Clinical response: Documentation of positive clinical response to Tysabri therapy

Monotherapy: Patient is not receiving Tysabri in combination with any of the following (used as monotherapy): B‑cell targeted therapies (e.g., rituximab, belimumab, ofatumumab), disease-modifying therapies (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide), or lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone)

Dosing and duration: Tysabri is dosed according to the U.S. FDA labeled dosing; authorization is for no more than 12 months12 months

Initial Therapy - Crohn's Disease

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 TNF‑alpha

Conventional therapies may include aminosalicylates, corticosteroids, and immunomodulators (e.g., azathioprine, 6‑mercaptopurine, methotrexate)

Concomitant therapy avoidance: Patient is not receiving concomitant treatment with immunosuppressants (e.g., 6‑MP, azathioprine, cyclosporine, methotrexate) or TNF‑inhibitors

Dosing and duration: Tysabri is dosed according to the U.S. FDA labeled dosing; initial authorization is for no more than 12 months12 months

Continuation Therapy - Crohn's Disease

Covered when ALL of the following are met:

Prior receipt: Patient has previously received treatment with Tysabri

Clinical response: Documentation of positive clinical response to Tysabri therapy

Concomitant therapy avoidance: Patient is not receiving concomitant treatment with immunosuppressants (e.g., 6‑MP, azathioprine, cyclosporine, methotrexate) or TNF‑inhibitors

Dosing and duration: Tysabri is dosed according to the U.S. FDA labeled dosing; authorization is for no more than 12 months12 months

Not Proven / Unproven Indications

Other conditions: Natalizumab is unproven for treatment of other conditions or diseases, including types of multiple sclerosis other than relapsing forms; randomized controlled trials are needed

Covered indications with safety conditions

Covered when ALL of the following are met

Indication and prior therapy: For Crohn's disease: induction and maintenance in adults with moderately to severely active disease with evidence of inflammation who had inadequate response to or are intolerant of conventional CD therapies and TNF inhibitors (per FDA and ACG guidance). For MS: relapsing forms of multiple sclerosis as indicated by the FDA.

Source: FDA label; ACG guideline

Risk minimization enrollment: Patient and prescribing/infusion entities must be enrolled in the TOUCH Prescribing Program and meet program requirements.

TOUCH required by FDA

JCV testing and monitoring: Anti‑JCV antibody testing should be performed and repeated every 6 months for Crohn's disease; positive anti‑JCV status requires reassessment of benefit versus risk and may influence continuation decisions.repeat every 6 months

ACG recommendation; FDA identified anti‑JCV as a PML risk factor

Use of natalizumab for conditions other than relapsing forms of multiple sclerosis or moderate to severe Crohn's disease is considered unproven. Randomized controlled trials of adequate size are needed to determine whether natalizumab provides sufficient superiority in clinical efficacy to justify the inherent safety risks associated with its use.

Natalizumab should not be used in combination with other immunosuppressants (for example, 6‑mercaptopurine, azathioprine, cyclosporine, methotrexate) or with tumor necrosis factor (TNF) inhibitors when treating Crohn's disease. Such combinations are explicitly discouraged by the FDA and are included as exclusionary considerations in this policy.

Natalizumab is considered unproven for treatment of conditions or multiple sclerosis subtypes other than relapsing forms (for example, primary progressive MS). High‑quality randomized trials are required to establish efficacy and safety before coverage for other indications would be supported.

Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection associated with natalizumab use; the risk of PML increases with the number of infusions received and has resulted in patient deaths. Because alternatives without a PML association exist, natalizumab is generally reserved for patients meeting the specific coverage criteria and is unlikely to be routinely used in patients who have failed other available therapies. When prescribed, clinicians must weigh benefits against PML risk and comply with required safety measures (for example, baseline MRI and enrollment in the TOUCH risk‑management program).

Applicable Codes and Authorization Duration

Applicable HCPCSHCPCSCovered

J2323

Injection, natalizumab, 1 mg.

Applicable ICD-10 Codes - Multiple SclerosisICD-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.

Applicable ICD-10 Codes - Crohn's DiseaseICD-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.

1–10 of 28

1/3

Applicable ICD-10 Diagnosis Codes (updated)ICD-10

G35.A	added ICD-10 diagnosis code (policy update)
G35.B0	added ICD-10 diagnosis code (policy update)
G35.B1	added ICD-10 diagnosis code (policy update)
G35.B2	added ICD-10 diagnosis code (policy update)
G35.C0	added ICD-10 diagnosis code (policy update)
G35.C1	added ICD-10 diagnosis code (policy update)
G35.C2	added ICD-10 diagnosis code (policy update)
G35.D	added ICD-10 diagnosis code (policy update)

Authorization duration — initial and continuation

Initial authorization periodInitial authorizations are limited to no more than 12 months

Continuation authorization periodContinuation authorizations are limited to no more than 12 months

Dosing alignmentAll authorizations require dosing according to the U.S. FDA–labeled dosing for Tysabri (natalizumab)

Provider Actions, Authorization and Documentation

Prior Authorization

Prior authorization and duration

Prior Authorization Required. Prior authorization is required for natalizumab (Tysabri). Initial authorizations are limited to no more than 12 months and dosing must follow the U.S. FDA‑labeled dosing. Continuation authorizations are also limited to ≤ 12 months.

Initial and continuation authorizations limited to ≤ 12 months
Dosing must follow U.S. FDA label

Prior Authorization

TOUCH enrollment and indication confirmation

Confirm patient enrollment in the TOUCH Prescribing Program and indicate the appropriate TOUCH component (MS TOUCH or CD TOUCH). Ensure the prescribing site and infusion center/pharmacy are TOUCH‑certified. For Crohn’s disease, confirm indication aligns with TOUCH CD requirements.

Document patient enrollment in TOUCH and that the patient read the Medication Guide
Document that prescriber, infusion center, and pharmacy are TOUCH‑certified
For CD, confirm CD TOUCH enrollment when applicable

Denial Risk

Combination therapy, dosing, and duration contraindications

Natalizumab must be used as monotherapy. Denial risk if used in combination with prohibited agents. Do not authorize when patient is receiving B‑cell targeted therapies, other disease‑modifying therapies, lymphocyte trafficking blockers, immunosuppressants, or TNF‑inhibitors concurrently.

Prohibited concomitant therapies include: B‑cell targeted agents (rituximab, belimumab, ofatumumab)
Disease‑modifying therapies (interferon betas, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide)
Lymphocyte trafficking blockers (alemtuzumab, mitoxantrone)
Immunosuppressants and TNF‑inhibitors (6‑MP, azathioprine, cyclosporine, methotrexate, infliximab, adalimumab, certolizumab pegol, etanercept)

Documentation Required

Documentation of prior treatment and response

For continuation requests, document prior receipt of natalizumab and objective evidence of positive clinical response. For initial requests for Crohn’s disease, document prior inadequate response or intolerance to conventional CD therapies and to TNF‑alpha inhibitors, and provide reasons these therapies were ineffective or not tolerated.

Continuation: evidence of prior natalizumab use and positive clinical response
Initial CD: documentation of inadequate response or intolerance to conventional therapies (aminosalicylates, corticosteroids, immunomodulators)
Initial CD: documentation of inadequate response or intolerance to TNF‑inhibitors (eg, infliximab, adalimumab, certolizumab pegol)

Documentation Required

Enrollment and baseline testing documentation

Document baseline testing and monitoring per TOUCH and FDA guidance prior to and during therapy. This includes baseline and repeat anti‑JC virus (JCV) antibody testing (repeat every ~6 months), discussion of PML risk and documentation that the patient reviewed the Medication Guide, and consideration of baseline brain MRI when clinically indicated.

Document anti‑JCV antibody testing and dates; repeat anti‑JCV testing at least every 6 months
Document discussion of PML risk and that the patient read/signed the Medication Guide
Document baseline brain MRI when clinically indicated for Crohn’s disease or to distinguish pre‑existing lesions in MS

Step Therapy

Step therapy for Crohn's disease

Step therapy for Crohn’s disease: require documentation of prior inadequate response or intolerance to conventional Crohn’s therapies and failure or intolerance of at least one TNF‑alpha inhibitor before natalizumab is authorized. Follow FDA label and ACG guidance for use as induction and maintenance in moderately to severely active Crohn’s disease when JCV antibody is negative.

Require trial/failure or intolerance of conventional therapies (aminosalicylates, corticosteroids, immunomodulators)
Require trial/failure or intolerance of TNF‑alpha inhibitor(s) (eg, infliximab, adalimumab, certolizumab)
Authorize natalizumab for CD only if benefits outweigh PML risk and JCV antibody status has been addressed

Definitions

PML — definition and relevance to natalizumab therapy

DefinitionProgressive multifocal leukoencephalopathy (PML) — a rare, serious demyelinating brain infection associated with natalizumab use

Relevance to natalizumabFDA safety communications identify PML as an important risk associated with Tysabri and the drug label was revised to summarize PML rates by number of infusions (duration of exposure)

Risk factorsKnown PML risk factors include presence of anti‑JCV antibodies, prior treatment with immunosuppressants, and longer duration of Tysabri treatment (especially beyond 2 years)

Program-level implicationPML risk considerations are a basis for TOUCH enrolment and ongoing monitoring requirements for patients receiving natalizumab

PML — shorthand / alternate definition

ShorthandPML — Progressive multifocal leukoencephalopathy

Alternate termProgressive multifocal leukoencephalopathy (PML) — serious opportunistic demyelinating brain infection

Anti‑JCV antibody — definition and test

DefinitionAnti‑JCV antibody — serologic marker indicating exposure to John Cunningham (JCV) virus assessed to stratify PML risk

Test exampleStratify JCV Antibody ELISA — anti‑JCV antibody detection test cleared by FDA (cleared January 20, 2012)

Clinical useA positive anti‑JCV antibody test is an identified risk factor for PML and should prompt reassessment of benefit versus risk for continued natalizumab therapy

OpenPayer

Tysabri (natalizumab) — Coverage Criteria

Coverage Criteria for Natalizumab (Tysabri)

Applicable Codes and Authorization Duration

Provider Actions, Authorization and Documentation

Background and Clinical Evidence

Definitions

Revision History