CurrentUnitedHealthcarePolicy 2026D0026S

Natalizumab (Tyruko & Tysabri) Medical Benefit Drug Policy

UnitedHealthcare medical benefit drug policy that defines medical necessity criteria, preferred product rules, diagnosis-specific coverage (relapsing forms of multiple sclerosis and moderate to severe Crohn's disease), applicable HCPCS/J-codes and ICD-10 diagnosis codes, and policy history for natalizumab products including Tyruko and Tysabri.

Policy Summary

PayerUnitedHealthcare

PolicyNatalizumab (Tyruko & Tysabri) Medical Benefit Drug Policy

Policy CodePolicy 2026D0026S

Change TypeTitle change; added preferred product criteria; added Q5134

Effective DateJan 1, 2026

Next Review Date

Key ActionFollow authorization limits and dosing: obtain initial/continuation authorizations for no more than 12 months and dose natalizumab per the FDA labeled dosing.

POLICY UPDATE CHANGES

Title changed from 'Tysabri (Natalizumab) Coverage Rationale' to 'Natalizumab (Tyruko & Tysabri) Medical Benefit Drug Policy' effective 01/01/2026.

Added language to specify referenced natalizumab products (Tyruko, Tysabri, any approved biosimilar) and that Tyruko will be considered non-preferred until review.

Added Preferred Product Criteria requiring trial of Tysabri ≥14 weeks or intolerance to Tysabri plus provider attestation for coverage of non-preferred products.

Added HCPCS code Q5134 for Tyruko (natalizumab-sztn).

Replaced references to 'Tysabri' with 'natalizumab' in Diagnosis-Specific Criteria.

Added CMS section noting no NCD or LCDs exist for natalizumab and Medicare Part B applicability.

1Preferred product (Tysabri)

1Non-preferred (Tyruko) requires criteria

Q5134,J2323Key HCPCS/J-codes

Coverage Summary

UnitedHealthcare medical benefit drug policy covers natalizumab for specified indications with medical necessity criteria. The policy defines coverage for relapsing forms of multiple sclerosis and for induction and maintenance of response in moderate to severe Crohn's disease, and it includes applicable HCPCS/J-codes and ICD-10 diagnosis codes.

The policy applies to multiple natalizumab products: Tysabri (natalizumab), Tyruko (natalizumab-sztn), and any FDA-approved natalizumab biosimilar. Tysabri is the preferred natalizumab product. Coverage of Tyruko and other non-preferred natalizumab products is contingent on meeting the Preferred Product Criteria and the Diagnosis-Specific Criteria; non-preferred biosimilars will be considered non-preferred until reviewed by UnitedHealthcare. Coverage criteria for Tyruko are applicable upon product launch.

Policy metadata

Policy number2026D0026S

Effective dateJanuary 1, 2026

Last review01/01/2026

Next review

PayerUnitedHealthcare

Coverage stanceCovered with criteria (covered_with_criteria)

Preferred Product / Non-preferred Product Criteria

Preferred Product Criteria (Tyruko or other non-preferred natalizumab)

Treatment with Tyruko or other non-preferred natalizumab product is medically necessary when BOTH of the following are met:

ALL of the following

One of the following
- Option A
  - Documentation of a trial of at least 14 weeks of Tysabri resulting in minimal clinical response to therapy and residual disease activity
  - Provider attests that in their clinical opinion, the clinical response would be expected to be superior with Tyruko or other natalizumab biosimilar product than experienced with Tysabri
- Option B

Relapsing Forms of Multiple Sclerosis — Initial Therapy

Diagnosis-Specific Criteria: Relapsing Forms of Multiple Sclerosis - Initial Therapy

Natalizumab is medically necessary for relapsing forms of MS when ALL of the following are met:

Initial Therapy

Diagnosis of relapsing forms of multiple sclerosis (e.g., clinically isolated syndrome, relapsing-remitting disease, active secondary-progressive disease)
Monotherapy requirement
- Disease modifying therapy (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, or teriflunomide)
- B cell targeted therapy (e.g., rituximab, belimumab, ofatumumab)

Relapsing Forms of Multiple Sclerosis — Continuation of Therapy

Diagnosis-Specific Criteria: Relapsing Forms of Multiple Sclerosis - Continuation of Therapy

Continuation is medically necessary when ALL of the following are met:

Continuation of Therapy

Prior treatment: Patient has previously received treatment with natalizumab
Clinical response: Documentation of positive clinical response to natalizumab therapy
Monotherapy requirement
- Disease modifying therapy (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, or teriflunomide)

Crohn's Disease — Initial Therapy

Diagnosis-Specific Criteria: Crohn's Disease - Initial Therapy

Natalizumab is medically necessary for moderately to severely active Crohn's disease when ALL of the following are met:

Initial Therapy

Diagnosis of moderately to severely active Crohn's disease
Prior therapies: History of inadequate response or intolerance to conventional Crohn's disease therapies and inhibitors of TNFα
Conventional Crohn's disease therapies may include aminosalicylates (such as mesalamine and sulfasalazine), corticosteroids, immunomodulators (such as azathioprine, 6-mercaptopurine, and methotrexate) and TNF-inhibitors (e.g., infliximab, adalimumab, certolizumab pegol)
Monotherapy requirement: Patient is not receiving concomitant treatment with immunosuppressants or TNF-inhibitors

Crohn's Disease — Continuation of Therapy

Diagnosis-Specific Criteria: Crohn's Disease - Continuation of Therapy

Continuation is medically necessary when ALL of the following are met:

Continuation of Therapy

Prior treatment: Patient has previously received treatment with natalizumab
Clinical response: Documentation of positive clinical response to natalizumab therapy
Monotherapy requirement: Patient is not receiving concomitant treatment with immunosuppressants or TNF-inhibitors
Same list as initial

Not Medically Necessary / Unproven Uses

Natalizumab is unproven for other conditions including types of MS other than relapsing forms

Use of natalizumab for disease states or indications other than relapsing forms of MS or moderate-severe Crohn's disease is considered unproven

Applicable Codes

Drug HCPCS/J-codesHCPCSCovered

J2323	Injection, natalizumab, 1 mg
Q5134	Injection, natalizumab-sztn (Tyruko), biosimilar, 1 mg

Applicable ICD-10 Diagnosis Codes (Multiple Sclerosis & Crohn's Disease)ICD-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
K50.00	Crohn's disease of small intestine without complications
K50.011	Crohn's disease of small intestine with rectal bleeding

1–10 of 36

1/4

Clinical Evidence

5 RCTs, n=1771Crohn's induction RCTs showing natalizumab superior to placebo; PML risk noted

TOP study (observational): In the TOP open-label, multinational 10-year prospective study (n = 4821) the 5-year interim analysis reported 18 cases of progressive multifocal leukoencephalopathy (PML), a decrease in mean annualized relapse rate from 1.99 prior to baseline to 0.31 on natalizumab therapy (p < 0.0001), and mean EDSS scores remained unchanged up to 5 years. The report concluded natalizumab’s overall safety profile was consistent with known effects and confirmed low relapse rates and stabilized disability in RRMS patients.

Cochrane MS network meta-analysis: A 2015 Cochrane network meta-analysis ranked therapies for preventing relapses in relapsing-remitting MS and found that natalizumab ranked highly for preventing relapses with an estimated RR versus placebo of 0.56 (95% CI 0.47 to 0.66) and was supported by high quality evidence for effect on relapses in the first 24 months.

Cochrane Crohn's 2018 RCT evidence: A 2018 Cochrane review included five RCTs (1771 participants) showing that one, two, or three infusions of natalizumab were superior to placebo for induction of remission and clinical response at 4, 8, and 12 weeks (results reported with GRADE ratings of moderate to high quality for various endpoints). The review noted that natalizumab is associated with development of PML, that studies were not powered to detect rare but serious adverse events such as PML, and that PML risk remains a concern affecting clinical use.

Background

Natalizumab is a recombinant humanized monoclonal IgG4 κ antibody that binds the α4 subunit of α4β1 and α4β7 integrins on leukocytes (except neutrophils), inhibiting α4-mediated adhesion to receptors such as VCAM-1 and MAdCAM-1 and preventing transmigration of leukocytes across endothelium; the precise mechanisms in MS and Crohn's disease are not fully defined.

The FDA-approved indications include use as monotherapy for relapsing forms of multiple sclerosis (clinically isolated syndrome, relapsing-remitting disease, active secondary progressive disease) and for inducing and maintaining clinical response and remission in moderately to severely active Crohn's disease in adults who have had an inadequate response to, or are intolerant of, conventional therapies and TNFα inhibitors. Natalizumab should not be used in combination with immunosuppressants or TNFα inhibitors in Crohn's disease and is available only through the TOUCH Prescribing Program.

Use of natalizumab is associated with risk of progressive multifocal leukoencephalopathy (PML). FDA safety communications identify PML risk factors including presence of anti-JCV antibodies, longer duration of therapy (especially beyond 2 years), and prior immunosuppressant use; patients with all three risk factors have an estimated risk of PML of 11/1,000 users.

Natalizumab: Refers to all natalizumab products (Tysabri, Tyruko, and FDA-approved biosimilars) for the purposes of this policy.

Provider Actions & Documentation Requirements

Prior Authorization

Authorization duration and dosing requirement

Initial and continuation authorizations are limited to no more than 12 months. Natalizumab must be dosed according to the U.S. FDA labeled dosing.

J2323
Q5134

Prior Authorization

Preferred product requirement

Tysabri is the preferred natalizumab product. Coverage of Tyruko or other non-preferred natalizumab products requires meeting the Preferred Product Criteria: a documented trial of Tysabri for at least 14 weeks with minimal clinical response plus provider attestation of expected superiority of the non-preferred product, or documentation of intolerance/contraindication to Tysabri plus provider attestation that the same issue would not be expected with the non-preferred product.

Revision History

2026-01-01revised (is_material=true)Latest

Title changed from 'Tysabri (Natalizumab) Coverage Rationale' to 'Natalizumab (Tyruko & Tysabri) Medical Benefit Drug Policy'.

2026-01-01added (is_material=true)

Policy updated to refer to multiple natalizumab products: Tyruko (natalizumab-sztn), Tysabri (natalizumab), and any FDA‑approved natalizumab biosimilar product; coverage criteria for Tyruko applicable upon product launch and biosimilars considered non-preferred until review.

2026-01-01added (is_material=true)

Policy Summary

PayerUnitedHealthcare

PolicyNatalizumab (Tyruko & Tysabri) Medical Benefit Drug Policy

Policy CodePolicy 2026D0026S

Change TypeTitle change; added preferred product criteria; added Q5134

Effective DateJan 1, 2026

Next Review Date

Key ActionFollow authorization limits and dosing: obtain initial/continuation authorizations for no more than 12 months and dose natalizumab per the FDA labeled dosing.

On This Page

Documentation of intolerance, contraindication, or adverse event to Tysabri

Provider attests that the same intolerance, contraindication, or adverse event would not be expected to occur with Tyruko or other natalizumab biosimilar product

Patient has not had a loss of a favorable response after established maintenance therapy with Tysabri or other natalizumab product

Requirement to continue coverage of non-preferred product

Prior Authorization

Preferred product requirement

Tysabri is the preferred natalizumab product. Coverage of Tyruko or other non-preferred natalizumab products is allowed only when the Preferred Product Criteria are met (trial of Tysabri for ≥14 weeks with minimal clinical response and provider attestation of expected superior response with the non-preferred product, or documented intolerance/contraindication to Tysabri with provider attestation that the same issue would not occur with the non-preferred product).

J2323
Q5134

Documentation Required

Provider attestation for non-preferred product

The provider must attest that either the non-preferred natalizumab product would be expected to provide superior clinical response compared with Tysabri, or that an intolerance/contraindication/adverse event to Tysabri would not be expected to occur with the non-preferred product. This attestation is required to support coverage of a non-preferred natalizumab product.

Lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone)

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

Authorization duration: Initial authorization is for no more than 12 months12 months

Documentation Required

Monotherapy documentation

Provider must document that natalizumab is being used as monotherapy—i.e., it is not being given in combination with disease-modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers listed in the policy.

Disease-modifying therapies (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide)
B‑cell targeted therapies (e.g., rituximab, belimumab, ofatumumab)
Lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone)

Prior Authorization

Authorization duration and dosing requirement

Initial and continuation authorizations are limited to no more than 12 months. Natalizumab must be dosed according to the U.S. FDA labeled dosing.

J2323
Q5134

B cell targeted therapy (e.g., rituximab, belimumab, ofatumumab)

Lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone)

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

Authorization duration: Authorization is for no more than 12 months12 months

Documentation Required

Clinical response documentation for continuation

For continuation of therapy, the provider must document a positive clinical response to natalizumab therapy to support ongoing coverage.

Immunosuppressants e.g., 6-MP, azathioprine, cyclosporine, or methotrexate; TNF-inhibitors e.g., infliximab, adalimumab, certolizumab pegol

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

Authorization duration: Initial authorization is for no more than 12 months12 months

Documentation Required

Monotherapy documentation

For Crohn's disease, provider must document that natalizumab is being used as monotherapy and is not being given concomitantly with specified immunosuppressants or TNF‑inhibitors per policy.

6‑mercaptopurine (6‑MP)
Azathioprine
Cyclosporine
Methotrexate
Infliximab
Adalimumab
Certolizumab

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

Authorization duration: Authorization is for no more than 12 months12 months

Documentation Required

Documentation requirements

Documentation requirements include: confirmation that natalizumab is used as monotherapy (not combined with the listed DMTs, B‑cell therapies, lymphocyte trafficking blockers, or for Crohn's disease, immunosuppressants/TNF‑inhibitors); documentation of positive clinical response for continuation of therapy; and, when requesting a non-preferred natalizumab product, the provider attestation that the non-preferred product is expected to be superior or that intolerance/contraindication to Tysabri would not occur with the non-preferred product.

Examples of therapies to avoid concomitant use: interferon beta agents; glatiramer acetate; fingolimod; cladribine; siponimod; teriflunomide; rituximab; belimumab; ofatumumab; alemtuzumab; mitoxantrone
For Crohn's disease, examples include: 6‑MP, azathioprine, cyclosporine, methotrexate, infliximab, adalimumab, certolizumab
Affected HCPCS/J‑codes: J2323, Q5134

Preferred product language added: Tysabri designated preferred; coverage of Tyruko or other non-preferred natalizumab contingent on Preferred Product Criteria and Diagnosis-Specific Criteria; members on non-preferred products required to change to Tysabri unless criteria met.

2026-01-01added (is_material=true)

Preferred Product Criteria added requiring either: trial of Tysabri ≥14 weeks with minimal clinical response plus provider attestation that response would be superior with Tyruko/other biosimilar, or documentation of intolerance/contraindication to Tysabri plus provider attestation that same would not occur with Tyruko/other biosimilar; requires no loss of favorable response after established maintenance with Tysabri or other natalizumab product to continue non-preferred product.

2026-01-01added (is_material=true)

HCPCS code Q5134 (Injection, natalizumab-sztn [Tyruko], biosimilar, 1 mg) added to Applicable Codes.

2026-01-01revised (is_material=false)

References to 'Tysabri' replaced with the generalized term 'natalizumab' in Diagnosis-Specific Criteria to refer to all natalizumab products.

2026-01-01added (is_material=false)

CMS/Medicare informational section added noting no Medicare NCD or LCDs exist for natalizumab and Medicare Part B applicability guidance.