Colorado Rocky Mountain Health Plans natalizumab Coverage Update

Coverage Criteria

Relapsing forms of MS — Initial Therapy

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

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

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

Examples listed in policy

Relapsing MS - Dosing & Authorization: Natalizumab is dosed according to FDA‑labeled dosing12 months

Initial authorization is for no more than 12 months

Relapsing forms of MS — Continuation Therapy

Continuation of natalizumab therapy for relapsing MS is medically necessary when ALL of the following are met:

Continuation - Prior Natalizumab: Patient has previously received treatment with natalizumab

Continuation - Clinical Response: Documentation of positive clinical response to natalizumab therapy

Continuation - Monotherapy: Patient is not receiving natalizumab in combination with disease‑modifying therapies, B‑cell targeted therapies, or lymphocyte trafficking blockers; natalizumab must be used as monotherapy

Examples listed in policy

Continuation - Dosing & Authorization: Natalizumab is dosed according to FDA‑labeled dosing12 months

Crohn's disease — Initial Therapy

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

Crohn's - Diagnosis: Diagnosis of moderately to severely active Crohn's disease with evidence of inflammation

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

Per FDA indication and ACG guidance

Crohn's - No concomitant immunosuppressants: Patient is not receiving concomitant immunosuppressants (e.g., 6‑MP, azathioprine, cyclosporine, methotrexate) or TNF‑inhibitors; natalizumab should not be used in combination with these agents

Examples listed in policy and FDA labeling

Crohn's disease — Continuation Therapy

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

Crohn's Continuation - Prior Natalizumab: Patient has previously received natalizumab

Crohn's Continuation - Clinical Response: Documentation of positive clinical response to natalizumab therapy

Crohn's Continuation - No concomitant immunosuppressants: Patient is not receiving concomitant immunosuppressants or TNF‑inhibitors (e.g., 6‑MP, azathioprine, cyclosporine, methotrexate, infliximab, adalimumab, certolizumab)

Crohn's Continuation - Dosing & Authorization: Natalizumab is dosed according to FDA‑labeled dosing12 months

Unproven indications

Not covered / unproven

Other uses: Natalizumab is unproven for the treatment of conditions other than relapsing forms of MS and Crohn's disease (including MS types other than relapsing forms); use for other indications is not considered medically necessary absent robust RCT evidence

Coverage with clinical and safety criteria

Covered when ALL of the following are met

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

FDA‑labeled indications

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

Per FDA and ACG guidance

TOUCH enrollment and certified site: Patient enrolled in the TOUCH Prescribing Program; prescribing clinician, infusion center, and pharmacy are registered/certified

Required by FDA REMS‑like program

Safety considerations: Assessment of anti‑JCV antibody status and discussion of PML risk; for Crohn's disease, repeat anti‑JCV antibody testing every 6 months during maintenance and stop treatment if positive

Use of natalizumab in combination with other disease-modifying therapies, B-cell targeted therapies, or lymphocyte trafficking blockers is excluded. The policy requires natalizumab to be used as monotherapy for relapsing forms of multiple sclerosis; examples of excluded concomitant agents include interferon beta preparations, glatiramer acetate, fingolimod, cladribine, siponimod, teriflunomide, rituximab, belimumab, ofatumumab, alemtuzumab, and mitoxantrone. Documentation of monotherapy status is required for prior authorization and continued coverage.

Per FDA labeling and the policy, Tysabri (natalizumab) must not be used in combination with immunosuppressants or TNFα inhibitors. Examples of immunosuppressants and TNFα inhibitors cited in the policy include 6-mercaptopurine, azathioprine, cyclosporine, methotrexate, etanercept, infliximab, adalimumab, and certolizumab pegol. Use in combination with these agents may be denied and must be avoided due to increased safety risk.

Natalizumab is considered unproven and not medically necessary for indications other than relapsing forms of multiple sclerosis and moderately to severely active Crohn's disease. The policy states that natalizumab is unproven for treatment of other conditions, including MS types other than relapsing forms, and that robust randomized controlled trial evidence would be required to support additional indications.

Treatment with natalizumab should be avoided when the risk of progressive multifocal leukoencephalopathy (PML) is judged to outweigh likely clinical benefit. The FDA and policy advise clinicians to consider whether the expected benefit is sufficient to offset the known PML risk, noting that risk increases with prior immunosuppressant exposure, cumulative duration of therapy, and anti‑JC virus antibody positivity. Documented rationale is expected when PML risk factors are present and continuing therapy is proposed.

Initial Therapy

Initial Therapy — Initial therapy criteria by indication

Initial therapy criteria by indication.

MS initial: Diagnosis of relapsing forms of MS; natalizumab used as monotherapy (no concomitant excluded therapies); dosed per FDA labeling; initial authorization up to 12 months12 months

Crohn's initial: Diagnosis of moderately to severely active Crohn's disease; history of inadequate response/intolerance to conventional therapies and TNF‑inhibitors; not receiving concomitant immunosuppressants or TNF‑inhibitors; dosed per FDA labeling; initial authorization up to 12 months12 months

Initial therapy for Crohn's disease (trial regimens)

Induction regimen and evidence summary for Crohn's disease.

Continuation Therapy

Continuation Therapy — Continuation therapy requires previous natalizumab use and documentation of positive clinical response; must be monotherapy and dosed per...

Continuation therapy requires previous natalizumab use and documentation of positive clinical response; must be monotherapy and dosed per FDA labeling with authorization up to 12 months.

Continuation node: Previously received natalizumab; documentation of positive clinical response; patient is not receiving excluded concomitant therapies (see monotherapy exclusions); natalizumab dosed per FDA‑labeled dosing12 months

Authorization for no more than 12 months

Maintenance / switching guidance

Continuation/maintenance considerations

Maintenance in Crohn's disease: Maintain only if patient is anti‑JCV antibody negative; repeat anti‑JCV antibody testing every 6 months during maintenance and stop treatment if result becomes positive

Step Therapy Requirements

Requirement	Details
Step requirement
Patient must have a history of inadequate response or intolerance to conventional Crohn's disease therapies and inhibitors of TNFα prior to initiating natalizumab. Conventional therapies may include aminosalicylates (e.g., mesalamine, sulfasalazine), corticosteroids, and immunomodulators (e.g., azathioprine, 6-mercaptopurine, methotrexate).

Expectation	Documentation to Provide
Prior use of conventional therapies
Documentation that the member received and had inadequate response or intolerance to conventional Crohn's therapies (e.g., aminosalicylates, corticosteroids, immunomodulators) before natalizumab initiation.

Provider Actions & Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required. Requests must include documentation that the patient meets indication-specific criteria per this policy (relapsing forms of multiple sclerosis or moderately to severely active Crohn's disease) and that dosing follows the FDA-labeled regimen. Initial authorizations are limited to no more than 12 months.

Prior authorization required for initial and continuation therapy
Initial authorization: ≤ 12 months

Prior Authorization

Prior Authorization — Indication, TOUCH Enrollment, and Certified Site Required

Prior authorization must confirm the FDA-indicated diagnosis and applicable prior-therapy requirements. For Crohn's disease, documentation must show inadequate response or intolerance to conventional therapies and to inhibitors of TNFα prior to natalizumab initiation. For continuation requests, documentation must show prior receipt of natalizumab and a positive clinical response. Enrollment in the TOUCH Prescribing Program is mandatory and the dispensing pharmacy or infusion center must be certified.

Confirm FDA-indicated diagnosis (relapsing forms of MS or moderately to severely active Crohn's disease)

Coding

Medication HCPCS / biosimilar codesHCPCS

J2323	Injection, natalizumab, 1 mg.
Q5134	Injection, natalizumab-sztn (tyruko), biosimilar, 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 codes (partial list)ICD-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.

Drug references / NDCs (documented package inserts)NDC

NDC (Tysabri package insert referenced)	Tysabri (natalizumab) product information — see package insert
NDC (Tyruko)	Tyruko reference in package inserts (biosimilar reference)

Known PML risk strata

Anti‑JCV antibody statusPresence of anti‑JC virus (JCV) antibodies increases PML risk; testing should be used to stratify risk

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

Treatment durationLonger duration of natalizumab exposure — especially beyond 2 years — is associated with increased PML risk

Combined risk estimatePatients with all three known risk factors have an estimated PML risk of 11 per 1,000 users (per FDA)

Site of Care Requirements

Billing Rule

Site-of-care requirement — certified infusion center or pharmacy

Natalizumab must be administered only at infusion centers or pharmacies that are registered/certified in the TOUCH Prescribing Program.

Confirm infusion center or pharmacy certification with TOUCH prior to scheduling infusion.

Biosimilar / Product References

Billing Rule

Products referenced — Tysabri and Tyruko covered when criteria met

The policy references both Tysabri (natalizumab) and Tyruko (natalizumab-sztn); both products are covered when policy criteria are met.

HCPCS codes listed include J2323 (natalizumab) and Q5134 (natalizumab-sztn, Tyruko).

Note

Biosimilar reference — package insert cited, no explicit preference stated

The document references the biosimilar package insert (Tyruko) but does not state an explicit preference or substitution rule; follow the policy coverage criteria for either product.

Refer to listed HCPCS/NDC and package insert information when billing or dispensing; no explicit biosimilar preference is stated in this document.

Definitions

Relapsing forms of MS — definition

Included diagnosesClinically isolated syndrome; relapsing‑remitting multiple sclerosis; active secondary‑progressive multiple sclerosis

Therapy contextRelapsing forms are the FDA‑indicated MS populations for natalizumab treatment

Monotherapy requirementPolicy requires natalizumab be used as monotherapy (no concomitant DMTs, B‑cell therapies, or lymphocyte‑trafficking blockers)

PML

DefinitionProgressive multifocal leukoencephalopathy (PML) — a rare but serious brain infection and known adverse event associated with natalizumab use

Unpredictable riskPML risk cannot be reliably predicted for every patient; FDA communications summarize evolving risk data

Background

Natalizumab is a humanized IgG4 monoclonal antibody that binds the α4 subunit of the α4β1 and α4β7 integrins on leukocytes to inhibit leukocyte adhesion and transmigration. The precise mechanisms by which natalizumab exerts therapeutic effects in multiple sclerosis and Crohn's disease are not fully defined, and use carries a known risk of progressive multifocal leukoencephalopathy (PML), which has been associated with prior immunosuppressant use, treatment duration, and anti‑JCV antibody status.

OpenPayer

Natalizumab (Tyruko & Tysabri) — Medical Benefit Drug Policy (coverage criteria)