Colorado Rocky Mountain Health Plans Natalizumab Coverage

Coverage and Medical Necessity Criteria

Relapsing forms of multiple sclerosis - Initial Therapy

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

MS initial therapy criteria: Diagnosis of relapsing forms of multiple sclerosis (e.g., clinically isolated syndrome, relapsing-remitting disease, active secondary-progressive disease); patient is not receiving natalizumab in combination with disease-modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers (natalizumab used as monotherapy); natalizumab is dosed according to the U.S. FDA labeled dosing; initial authorization is for no more than 12 months.

Relapsing forms of multiple sclerosis - Continuation Therapy

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

MS continuation criteria: Patient has previously received natalizumab with documentation of positive clinical response to therapy; patient is not receiving natalizumab in combination with disease-modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers (natalizumab used as monotherapy); natalizumab is dosed according to the U.S. FDA labeled dosing; authorization is for no more than 12 months.

Crohn's disease - Initial and Continuation Therapy

Natalizumab is medically necessary for inducing and maintaining clinical response and remission in moderate to severe Crohn's disease when ALL of the following are met:

CD initial criteria: Diagnosis of moderately to severely active Crohn's disease; history of inadequate response or intolerance to conventional Crohn's disease therapies and TNFα inhibitors; patient is not receiving concomitant treatment with immunosuppressants or TNF‑inhibitors; natalizumab is dosed according to the U.S. FDA labeled dosing; initial authorization is for no more than 12 months.

CD continuation criteria: Patient has previously received natalizumab with documentation of positive clinical response to therapy; patient is not receiving concomitant treatment with immunosuppressants or TNF‑inhibitors; natalizumab is dosed according to the U.S. FDA labeled dosing; authorization is for no more than 12 months.

Unproven/Not supported indications

Other indications: Use of natalizumab for conditions other than relapsing forms of multiple sclerosis and Crohn's disease is considered unproven; randomized controlled trials are needed to establish efficacy relative to other treatments given known clinical risks (including PML).

Coverage criteria (indication + safety/administrative requirements)

Covered when ALL of the following are met (per FDA label, guideline and evidence summaries):

Indication: Diagnosis of relapsing forms of multiple sclerosis OR moderately to severely active Crohn's disease with evidence of inflammation (per FDA indications).

FDA indications referenced

Prior therapy for Crohn's: For Crohn's disease: history of inadequate response to, or intolerance of, conventional therapies and inhibitors of TNF‑alpha prior to initiating natalizumab.

ACG and Cochrane evidence support induction in selected patients

Risk mitigation and administrative requirements: Enrollment in the TOUCH Prescribing Program with documentation of patient enrollment and site/provider certification; availability of a certified infusion/dispensing site; baseline brain MRI recommended for MS; baseline anti‑JCV antibody testing and periodic retesting per guideline (every 6 months noted for Crohn's disease).

TOUCH program and anti‑JCV testing per FDA/ACG

Product preference and diagnosis-contingent coverage

Coverage for natalizumab products is contingent on diagnosis-specific criteria and product-preference rules.

Preferred product (Tysabri) coverage: Coverage for Tysabri is contingent on meeting the Diagnosis‑Specific Criteria section of this policy.

Non-preferred product (Tyruko or other biosimilars) coverage: Treatment with Tyruko or another non-preferred natalizumab product is medically necessary only when BOTH: (1) documentation of a trial of at least 14 weeks of Tysabri with minimal clinical response and provider attestation that the non-preferred product would be expected to provide superior clinical response, OR documentation of intolerance/contraindication/adverse event to Tysabri with provider attestation that the same issue would not be expected with the non-preferred product; AND (2) the patient has not had loss of a favorable response after established maintenance therapy with Tysabri or another natalizumab product.14 weeks

Preferred Product Criteria; policy history

Applicability to benefit plans: Any natalizumab product approval is contingent on meeting the Diagnosis‑Specific Criteria in this policy and member‑specific benefit plan terms.

Use of natalizumab for conditions other than relapsing forms of multiple sclerosis and Crohn's disease is considered unproven. Randomized controlled trials with sufficient power are needed to establish superiority in other indications given the known clinical risks associated with natalizumab.

Natalizumab (Tysabri) should not be used in combination with immunosuppressants or inhibitors of TNFα (examples cited include 6‑mercaptopurine, azathioprine, cyclosporine, and methotrexate). Concurrent use with other disease‑modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers is excluded by the policy and can trigger denial of medical necessity.

Coverage determinations must be made in the context of the member-specific benefit plan and any applicable federal or state mandates; the member's benefit document governs in the event of a conflict. Verify plan terms and applicable regulatory requirements before authorizing natalizumab.

Because natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), clinicians should weigh this risk when selecting therapy. For some patients, particularly those with alternative agents not associated with PML, those alternatives are generally preferred over natalizumab; PML risk factors (e.g., anti‑JCV antibody status, prior immunosuppressant exposure, and longer treatment duration) may prompt additional review or limit use.

Non‑preferred natalizumab products (for example, Tyruko or other biosimilars) are considered non-preferred pending UnitedHealthcare review and are subject to the policy's Preferred Product Criteria. Coverage of non‑preferred products requires documentation meeting those criteria and adherence to the Diagnosis‑Specific Criteria in this policy.

Initial Therapy Requirements

Initial Therapy — initial therapy criteria for MS and Crohn's disease including diagnosis, monotherapy, and dosing per label

Initial therapy criteria for MS and Crohn's disease require diagnosis, monotherapy, and dosing consistent with labeled/clinical trial induction regimens:

Diagnosis requirement: Appropriate FDA‑indicated diagnosis: relapsing forms of MS for MS patients; moderately to severely active Crohn's disease with evidence of inflammation for CD patients (with prior inadequate response/intolerance to conventional and anti‑TNF therapies for CD).

Monotherapy requirement: Natalizumab must be used as monotherapy — not in combination with other disease‑modifying therapies, B‑cell targeted therapies, lymphocyte trafficking blockers, immunosuppressants, or TNF‑inhibitors as specified for the indication.

Concurrent therapy exclusion referenced

Dosing and induction: Dosing must follow the U.S. FDA labeled dosing; induction regimens in Crohn's trials commonly used natalizumab 300 mg IV at weeks 0, 4, and 8 (label dosing for MS is 300 mg IV every 4 weeks).

Continuation and Maintenance Criteria

Continuation Therapy — continuation criteria mirroring initial therapy with requirement for positive clinical response and monotherapy

Continuation therapy is medically necessary when ALL of the following are met (mirrors initial therapy plus response requirement):

General continuation: Previously received natalizumab with documented positive clinical response; patient remains on monotherapy (no prohibited concomitant therapies); natalizumab is dosed per U.S. FDA labeling; authorization for continuation is for no more than 12 months.

Non-preferred product continuation: Patient has not had loss of a favorable response after established maintenance therapy with Tysabri or another natalizumab product (required when non-preferred product approval is sought as continuation).

Policy history Preferred Product Criteria

MS continuation therapy considerations

MS-specific continuation considerations:

Prior Authorization, Documentation, and Provider Steps

Prior Authorization

Authorization duration & dosing

Initial authorization and renewals are limited to a maximum duration of 12 months. Natalizumab must be dosed according to the U.S. FDA–labeled dosing for the requested indication.

Documentation Required

Indication, TOUCH enrollment, and anti‑JCV testing

Coverage is granted only for FDA‑indicated diagnoses (e.g., relapsing forms of multiple sclerosis; moderately to severely active Crohn's disease with evidence of inflammation). For any request for Tysabri, the member and prescriber must be enrolled in the TOUCH Prescribing Program (MS TOUCH® or CD TOUCH®) and the Patient‑Prescriber Enrollment Form must be completed. For Crohn's disease, document baseline and follow‑up anti‑JCV (anti‑John Cunningham virus) antibody testing per guidance; anti‑JCV antibody status and repeat testing every 6 months should inform ongoing treatment decisions.

Applicable Codes and Coding Notes

Applicable HCPCS CodesHCPCS

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

Applicable ICD-10 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.
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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Applicable ICD-10 Codes for Crohn's diseaseICD-10

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

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Applicable HCPCS CodesHCPCS

Q5134

HCPCS code added (natalizumab biosimilar/related)

Crohn's Disease Activity Index (CDAI) — moderate–severe range

Typical CDAI range for moderate–severe Crohn's diseaseCDAI 220–450

Clinical features associated with this rangeFailed treatment for mild–moderate disease or prominent symptoms (fever, significant weight loss, abdominal pain/tenderness, intermittent nausea/vomiting, significant anemia)

Endoscopic disease severityTypically moderate to severely active endoscopic mucosal disease

Tysabri trial duration — preferred-product criteria

Minimum documented Tysabri trial duration required for non-preferred product pathway>= 14 weeks of Tysabri with minimal clinical response (documentation required)

Step Therapy and Product Switching Rules

Step	Requirement
1	Members currently receiving a non-preferred natalizumab product (e.g., Tyruko) will be required to change therapy to the preferred product Tysabri to continue coverage unless they meet the Preferred Product Criteria for continued use of the non-preferred product.

Step	Requirement
1	Reserve natalizumab for patients with moderately to severely active Crohn's disease who have had an inadequate response to, or are intolerant of, conventional Crohn's therapies and inhibitors of TNF-alpha; consider PML risk and availability of alternative agents not associated with PML before using natalizumab.

Step	Requirement
1	For requests to continue or initiate a non-preferred natalizumab product, the provider must document either: (a) a trial of at least 14 weeks of Tysabri with minimal clinical response plus a provider attestation that the non-preferred product would be expected to be superior, or (b) documentation of intolerance, contraindication, or adverse event to Tysabri with provider attestation that the same issue would not be expected to occur with the non-preferred natalizumab product.

Step

Requirement

For requests to continue or initiate a non-preferred natalizumab product, the provider must document either: (a) a trial of at least 14 weeks of Tysabri with minimal clinical response plus a provider attestation that the non-preferred product would be expected to be superior, or (b) documentation of intolerance, contraindication, or adverse event to Tysabri with provider attestation that the same issue would not be expected to occur with the non-preferred natalizumab product.

Dispensing, Infusion Site, and Benefit Setting

Note

Billing Rule

Dispense/infuse only at TOUCH‑certified sites

Dispensing and infusion must occur at TOUCH‑certified infusion centers or at pharmacies associated with certified infusion centers; prescribers and infusion/dispensing sites must be registered in the TOUCH program.

Pharmacies and infusion centers must be specially certified to dispense or infuse Tysabri.
Prescribers and patients must use the appropriate TOUCH program (MS TOUCH or CD TOUCH).

Billing Rule

Medical‑benefit setting; verify plan for site‑of‑care

This is a Medical Benefit Drug Policy that applies in medical benefit settings; check the member‑specific benefit plan for any site‑of‑care determinations that may modify coverage.

Preferred Product, Biosimilars, and Formulary Status

Billing Rule

Tysabri designated preferred; biosimilars non‑preferred

Tysabri (natalizumab) is designated as the preferred natalizumab product; Tyruko and other biosimilars are non‑preferred and require meeting the Preferred Product Criteria for coverage.

Coverage for Tysabri is contingent on meeting the Diagnosis‑Specific Criteria.
Tyruko is non‑preferred and subject to Preferred Product Criteria, which take effect upon product launch.

Billing Rule

Non‑preferred status and contingent coverage

Non‑preferred natalizumab products are considered non‑preferred until reviewed by UnitedHealthcare Medical Necessity Plans; coverage of non‑preferred products is contingent on meeting Preferred Product and Diagnosis‑Specific Criteria.

Billing Rule

Tyruko coverage rules apply immediately on launch

Coverage criteria for Tyruko will apply immediately upon product launch; Tyruko is treated as a non‑preferred natalizumab product and requires meeting the Preferred Product Criteria for coverage.

Background and Rationale

Natalizumab is a humanized IgG4 monoclonal antibody that binds the α4 subunit of the α4β1 and α4β7 integrins on leukocytes, thereby blocking leukocyte adhesion and transmigration into inflamed tissues. This mechanism of inhibiting leukocyte trafficking underlies its use as a disease‑modifying therapy in relapsing forms of multiple sclerosis and as a biologic for selected patients with Crohn's disease.

Key Definitions

Natalizumab — policy definition

Definition'Natalizumab' refers to all natalizumab products including Tysabri, Tyruko, and any FDA‑approved natalizumab biosimilars

Policy usageThe term is used throughout the policy to encompass reference, coverage criteria, and product-preference rules for all natalizumab formulations

Examples of included productsTysabri (natalizumab), Tyruko (natalizumab-sztn), and other FDA-approved biosimilars not listed by name

PML — definition and natalizumab risk factors

DefinitionProgressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection associated with reactivation of John Cunningham (JC) virus, occurring in immunosuppressed patients

Association with natalizumab

OpenPayer

Natalizumab (Tyruko & Tysabri) Coverage Criteria

Coverage and Medical Necessity Criteria

Initial Therapy Requirements

Continuation and Maintenance Criteria

Prior Authorization, Documentation, and Provider Steps

Applicable Codes and Coding Notes

Step Therapy and Product Switching Rules

Dispensing, Infusion Site, and Benefit Setting

Preferred Product, Biosimilars, and Formulary Status

Background and Rationale

Key Definitions