CurrentUnitedHealthcarePolicy 2026D0026S

Natalizumab

UnitedHealthcare medical benefit drug policy defining coverage, preferred product criteria, diagnosis-specific medical necessity criteria, applicable HCPCS/J-codes and ICD-10 diagnosis codes, and administrative/billing considerations for natalizumab products including Tysabri and Tyruko (natalizumab-sztn).

Policy Summary

PayerUnitedHealthcare

PolicyNatalizumab

Policy CodePolicy 2026D0026S

Change TypeAdded preferred product and biosimilar guidance; codes updated

Effective DateJan 1, 2026

Next Review Date

Key ActionPrior authorization required; ensure documentation of diagnosis, prior therapies and response, and meet Preferred Product Criteria for Tyruko or other non-preferred natalizumab products.

SourceLink

POLICY UPDATE CHANGES

Policy now refers to Tyruko (natalizumab-sztn), Tysabri (natalizumab), and any FDA-approved natalizumab biosimilar product not listed.

Preferred product designation: Tysabri is preferred; Tyruko and other non-preferred products require Preferred Product Criteria for coverage.

HCPCS code Q5134 (Injection, natalizumab-sztn (Tyruko), biosimilar, 1 mg) added to applicable codes.

Replaced references to 'Tysabri' with 'natalizumab' in Diagnosis-Specific Criteria (policy-wide terminology change).

Added CMS section and updated background and references.

Title changed from 'Tysabri (Natalizumab) Coverage Rationale' to 'Natalizumab'.

2Primary Covered Indications

Coverage Summary

Scope: UnitedHealthcare medical benefit drug policy for natalizumab products (Tysabri, Tyruko/natalizumab-sztn, and other FDA-approved natalizumab biosimilars) defining covered indications, preferred product designation, diagnosis-specific medical necessity criteria, applicable HCPCS/J-codes and ICD-10 diagnosis codes, and administrative/billing considerations. Effective/last review date: January 1, 2026 (policy number 2026D0026S).

Coverage stance: Covered with criteria. High-level preferred product designation: Tysabri is the preferred natalizumab product; Tyruko and other non-preferred biosimilars are considered non-preferred until review and require meeting Preferred Product Criteria for coverage.

Preferred Product Criteria (Tyruko / Non-preferred natalizumab)

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
- Trial of Tysabri with minimal response
  - 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
- Intolerance/contraindication to Tysabri
  - Documentation of intolerance, contraindication, or adverse event to Tysabri
  - Provider attests that in their clinical opinion, the same intolerance, contraindication, or adverse event would not be expected to occur with Tyruko or other natalizumab biosimilar product
Maintenance requirement: Patient has not had a loss of a favorable response after established maintenance therapy with Tysabri or other natalizumab product
Must be met to continue coverage of non-preferred product

Prior Authorization

Prior authorization required for natalizumab products

Coverage of natalizumab products requires prior authorization. Applicable HCPCS/J-codes: J2323 and Q5134. Note: Coverage of non-preferred products (e.g., Tyruko or other non-preferred natalizumab biosimilars) requires meeting the Preferred Product Criteria prior to approval.

Affected codes: J2323, Q5134
Non-preferred product requires meeting Preferred Product Criteria prior to approval

Documentation Required

Documentation of prior therapies and response

Providers must document the member's diagnosis and prior treatments. For requests for non-preferred products, documentation must include either a trial of Tysabri of at least 14 weeks with minimal clinical response and residual disease activity (with provider attestation that the non-preferred product would be expected to produce superior response) or documentation of intolerance/contraindication/adverse event to Tysabri (with provider attestation that the same would not be expected with the non-preferred product). For continuation requests, document prior treatment with natalizumab and a positive clinical response to therapy.

Required: diagnosis
Required: prior treatments — for non-preferred product: trial of Tysabri ≥14 weeks with minimal response OR history of intolerance/contraindication to Tysabri with provider attestation
For Crohn's: history of inadequate response or intolerance to conventional and TNFα therapies (per Crohn's criteria)
For continuation: documentation of positive clinical response to natalizumab

Relapsing Forms of Multiple Sclerosis — Initial Therapy Criteria

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:

ALL of the following

Diagnosis of relapsing forms of multiple sclerosis (e.g., clinically isolated syndrome, relapsing-remitting disease, active secondary-progressive disease)
Monotherapy requirement: Patient is not receiving natalizumab in combination with any of the following (used as monotherapy): disease modifying therapy (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, or teriflunomide); 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

Relapsing Forms of Multiple Sclerosis — Continuation Therapy Criteria

Diagnosis-Specific Criteria — Relapsing Forms of Multiple Sclerosis (Continuation of Therapy)

Continued natalizumab therapy is medically necessary when ALL of the following are met:

ALL of the following

Prior treatment: Patient has previously received treatment with natalizumab
Positive clinical response: Documentation of positive clinical response to natalizumab therapy
Monotherapy requirement: Patient is not receiving natalizumab in combination with any of the following (used as monotherapy): disease modifying therapy (e.g., interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, or teriflunomide); B cell targeted therapy (e.g., rituximab, belimumab, ofatumumab); lymphocyte trafficking blockers (e.g., alemtuzumab, mitoxantrone)

Crohn's Disease — Initial Therapy Criteria

Diagnosis-Specific Criteria — Crohn's Disease (Initial Therapy)

Natalizumab is medically necessary for moderate to severe Crohn's disease when ALL of the following are met:

ALL of the following

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 therapies may include aminosalicylates, corticosteroids, immunomodulators such as azathioprine, 6-mercaptopurine, methotrexate, and TNF-inhibitors e.g., infliximab, adalimumab, certolizumab pegol)
Concomitant therapy exclusion: Patient is not receiving concomitant treatment with immunosuppressants (e.g., 6-MP, azathioprine, cyclosporine, or methotrexate) or TNF-inhibitors (e.g., etanercept, infliximab, adalimumab, certolizumab pegol)

Crohn's Disease — Continuation Therapy Criteria

Diagnosis-Specific Criteria — Crohn's Disease (Continuation of Therapy)

Continued natalizumab therapy for Crohn's disease is medically necessary when ALL of the following are met:

ALL of the following

Prior treatment: Patient has previously received treatment with natalizumab
Positive clinical response: Documentation of positive clinical response to natalizumab therapy
Concomitant therapy exclusion: Patient is not receiving concomitant treatment with immunosuppressants (e.g., 6-MP, azathioprine, cyclosporine, or methotrexate) or TNF-inhibitors (e.g., Enbrel (etanercept), adalimumab, certolizumab pegol (Cimzia), or infliximab)

Not Medically Necessary / Unproven Uses

Not Medically Necessary / Unproven

Natalizumab is unproven for other conditions beyond the specified indications:

ALL of the following

Unproven use: Natalizumab is unproven for the treatment of other conditions or diseases, including types of MS other than relapsing forms
Evidence requirement: Statistically robust randomized controlled trials are needed to justify use in other conditions

Applicable Codes

HCPCS / J-codes (drug administration)HCPCSCovered

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

ICD-10 Diagnosis Codes (Covered Indications)ICD-10Covered

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.

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Billing Rule

Dosing/reporting and new biosimilar HCPCS

Billing/reporting: J2323 and Q5134 should be reported per mg as applicable. Note: HCPCS code Q5134 was added for the natalizumab biosimilar (Tyruko).

Report J2323 and Q5134 per mg as applicable
Q5134 = natalizumab-sztn (Tyruko) — new biosimilar HCPCS code

Provider Actions & Administrative Requirements

Provider actions: Prior authorization is required for natalizumab products (codes J2323 and Q5134) and coverage is contingent on meeting the policy’s medical necessity criteria and duration limits (initial or continuation authorizations of no more than 12 months). Non-preferred products (e.g., Tyruko) require meeting the Preferred Product Criteria prior to approval.

Documentation requirements: Providers must document diagnosis, prior therapies, and clinical response. For non-preferred products, documentation must include either a trial of at least 14 weeks of Tysabri with minimal clinical response and provider attestation of expected superiority with the biosimilar, or documentation of intolerance/contraindication/adverse event to Tysabri with provider attestation that the same issue would not be expected with the biosimilar. Members already on non-preferred products will be required to change to Tysabri unless Preferred Product Criteria are met.

Dosing and program enrollment: Natalizumab must be dosed according to the U.S. FDA labeled dosing for approvals (per-label dosing for J2323 and Q5134). Tysabri may only be prescribed and dispensed through the TOUCH Prescribing Program; prescribers, infusion centers, and patients must be enrolled and meet program requirements.

Denial Risk

Non-preferred product coverage and member transition

Denial risk/change impact: Members currently on non-preferred natalizumab products (e.g., Tyruko or other non-listed biosimilars) will be required to transition to the preferred product Tysabri unless they meet the Preferred Product Criteria. The policy explicitly adds Tyruko (natalizumab-sztn) and states any FDA-approved natalizumab biosimilar not listed will be considered non-preferred until reviewed.

Clinical Evidence

0.56Relapse prevention RR vs placebo (RRMS, up to 24 months)

0.31Mean annualized relapse rate on natalizumab at 5 years (TOP interim)

18PML cases reported in TOP (11-44 infusions) — serious safety risk

Long-term observational evidence: Large observational programs (STRATA and TOP) report sustained low relapse rates and stabilized EDSS over multiple years of natalizumab treatment, with observed cases of PML consistent with natalizumab’s known safety profile.

Randomized trial / meta-analysis evidence in RRMS: Network and Cochrane analyses rank natalizumab among the most effective therapies for preventing relapses in relapsing-remitting multiple sclerosis through the first 24 months of treatment (natalizumab RR versus placebo ~ 0.56 for relapse outcome in one network meta-analysis with high-quality evidence for relapse prevention up to 24 months).

Crohn’s disease RCT evidence and safety concerns: Multiple RCTs and Cochrane review/meta-analyses show natalizumab is superior to placebo for induction of remission and clinical response in moderately to severely active Crohn’s disease, but the association with progressive multifocal leukoencephalopathy (PML) and the inability to reliably predict PML risk limit its use.

Safety program note: Because of the PML risk, Tysabri is available only through the FDA-required TOUCH Prescribing Program to manage and mitigate this safety concern.

Background

Mechanism of action: Natalizumab is a humanized IgG4 monoclonal antibody that binds the α4-subunit of α4β1 and α4β7 integrins on leukocytes, inhibiting α4-mediated adhesion and preventing leukocyte transmigration into inflamed tissue; the exact mechanism in MS and Crohn's disease is not fully defined.

FDA indications: Tysabri (natalizumab) is FDA-indicated as monotherapy for relapsing forms of multiple sclerosis (including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease) and for induction and maintenance of clinical response and remission in adults with moderately to severely active Crohn's disease 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 for these indications, and dosing must follow the U.S. FDA labeled dosing.

PML risk and TOUCH program: Natalizumab is associated with risk of progressive multifocal leukoencephalopathy (PML); Tysabri increases PML risk with longer exposure and other risk factors. Because of this risk, Tysabri is available only through the FDA-mandated TOUCH Prescribing Program, which requires enrollment of prescribers, infusion centers, and patients and compliance with program requirements.

Definitions: 'Natalizumab' refers to all natalizumab products (Tysabri, Tyruko, and other FDA-approved biosimilars). A 'Preferred product' designation is applied to Tysabri; non-preferred products (e.g., Tyruko) require additional Preferred Product Criteria for coverage.

Revision History

2026-01-01policy_effectiveLatest

Policy effective date and administrative/title change: title changed from 'Tysabri (Natalizumab) Coverage Rationale' to 'Natalizumab' and policy effective January 1, 2026.

2026-01-01terminology_standardizationLatest

Policy-wide terminology standardized: 'Natalizumab' will be used to refer to all natalizumab products (replacing references to 'Tysabri' in Diagnosis-Specific Criteria).

2026-01-01

Billing Rule

Dosing per FDA label

Natalizumab must be dosed according to the U.S. FDA labeled dosing. HCPCS codes J2323 and Q5134 are reported per mg as applicable. Authorizations (initial or continuation) are limited to a duration of up to 12 months.

J2323 and Q5134 reported per mg as applicable
Authorization duration limit: up to 12 months

Documentation Required

TOUCH program enrollment for Tysabri

Tysabri is available only through the TOUCH Prescribing Program. Prescribers, infusion centers/pharmacies associated with infusion centers, and patients must be enrolled in and meet all TOUCH program requirements prior to prescribing/dispensing Tysabri.

Prescribers, infusion centers, and patients must be enrolled in the TOUCH program

2026-01-01criteria_additionLatest

Preferred Product Criteria added for coverage of Tyruko or other non-preferred natalizumab products, including requirements such as a trial of at least 14 weeks of Tysabri with minimal response or documentation of intolerance/contraindication to Tysabri, plus provider attestation and maintenance response conditions.