CurrentPremera BluecrossPolicy 5.01.644

Medical Pharmacologic Treatment of Multiple Sclerosis

Defines medical necessity and site-of-service review requirements for specific intravenous and injectable disease-modifying therapies for multiple sclerosis, and documents documentation, coding, and age/prescriber requirements affecting providers and members.

Policy Summary

PayerPremera Bluecross

PolicyMedical Pharmacologic Treatment of Multiple Sclerosis

Policy CodePolicy 5.01.644

Change TypeMaterial updates and added HCPCS code

Effective DateOct 3, 2025

Next Review Date

Key ActionObtain prior authorization and submit medical records documenting diagnosis, EDSS, prescriber consultation, and prior treatment history when required.

SourceLink

POLICY UPDATE CHANGES

Site of Service Medical Necessity criteria clarified to apply to injection drugs and added site-of-service review for Ocrevus Zunovo (ocrelizumab-hyaluronidase-ocsq).

Clarified that Site of Service Medical Necessity criteria does not apply to Alaska fully insured members; infusion and injection drug medical necessity criteria apply instead.

Prescriber requirement and age requirement added for multiple listed drugs (Briumvi, Lemtrada, Ocrevus, Ocrevus Zunovo, Tyruko, Tysabri).

New HCPCS code J2351 was added for ocrelizumab with hyaluronidase (effective 04/01/25).

6MS drugs listed for site-of-service review

13+Minimum age for site-of-service review

12 mo

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Coverage and Medical Necessity Criteria

Tyruko (natalizumab-sztn) and Tysabri (natalizumab) — medical necessity

Covered when ALL of the following are met:

Tyruko/Tysabri initiation criteria: The individual is aged 18 years or older; must have an Expanded Disability Status Scale (EDSS) score less than 6; the medication is not used concurrently with other MS disease-modifying drugs; and the medication is prescribed by or in consultation with a neurologist or a physician who specializes in the treatment of multiple sclerosis.EDSS < 6

Due to safety concerns, enrollment in the TOUCH registry (for Tysabri) or the Tyruko REMS program is required; prescriber and EDSS requirements apply.

Briumvi (ublituximab-xiiy) — medical necessity

Covered when ALL of the following are met:

Briumvi initiation criteria: The individual is aged 18 years or older; must have an Expanded Disability Status Scale (EDSS) score less than 6; Briumvi is not used concurrently with other MS disease-modifying drugs; and the medication is prescribed by or in consultation with a neurologist or a physician who specializes in the treatment of multiple sclerosis.EDSS < 6

Prescriber and EDSS requirements specified.

Ocrevus (ocrelizumab) and Ocrevus Zunovo (ocrelizumab-hyaluronidase-ocsq) — medical necessity

Covered when ALL of the following are met (relapsing forms):

Ocrevus/Ocrevus Zunovo relapsing forms: For relapsing forms: the individual is aged 18 years or older; must have an Expanded Disability Status Scale (EDSS) score less than 6; the medication is not used concurrently with other MS disease-modifying drugs; and the medication is prescribed by or in consultation with a neurologist or a physician who specializes in the treatment of multiple sclerosis.EDSS < 6

Prescriber and concurrency restrictions apply.

Ocrevus/Ocrevus Zunovo primary progressive MS: For primary progressive MS (PPMS): the individual is aged 18 years or older; must have an Expanded Disability Status Scale (EDSS) score less than 7; the medication is not used concurrently with other MS disease-modifying drugs; and the medication is prescribed by or in consultation with a neurologist or a physician who specializes in the treatment of multiple sclerosis.EDSS < 7

Applies to Ocrevus and Ocrevus Zunovo for PPMS.

Lemtrada (alemtuzumab) — medical necessity

Covered when ALL of the following are met:

Lemtrada initiation criteria: The individual is aged 17 years or older; Lemtrada is not used concurrently with other MS disease-modifying drugs; the individual has had an inadequate response to two or more disease-modifying drugs indicated for multiple sclerosis (examples include beta-interferons, dimethyl fumarate, fingolimod, glatiramer, natalizumab, ocrelizumab, ofatumumab, ozanimod, ponesimod, siponimod, teriflunomide); and the medication is prescribed by or in consultation with a neurologist or a physician who specializes in the treatment of multiple sclerosis.

Prior inadequate response to two or more DMTs is required; no concurrent use with other DMTs.

Site of Service — hospital-based outpatient setting medical necessity

Hospital outpatient infusion is considered medically necessary when ANY of the following apply:

Hospital outpatient justified scenarios: Initial course of infusion or injection of a pharmacologic or biologic agent, or re-initiation of an agent after 6 months or longer following discontinuation of therapy; there is no outpatient infusion center within 50 miles of the individual's home and no contracted home infusion agency will travel to the home (or a hospital is the only place that offers infusions/injections of this drug); the individual has a clinical condition that increases the risk of infusion complications (including known cardiac condition such as symptomatic cardiac arrhythmia, significant respiratory disease or %FVC ≤ 40%, unstable renal function, difficult vascular access, or acute mental status changes); a known history of severe adverse drug reactions and/or anaphylaxis to prior treatment with a related or similar drug; or the individual has cytokine release syndrome (CRS) that is grade 3 or 4 (temperature ≥ 38 °C, hypotension requiring one or more vasopressors, and hypoxia requiring high-flow oxygen or positive pressure ventilation) and inpatient admission is planned.%FVC ≤ 40% for respiratory risk; CRS criteria require all listed findings

The hospital-based outpatient site is considered medically necessary for the first 90 days in specified situations; CRS criteria must be fully met and inpatient admission planned.

Investigational/Off-label uses

Investigational statement: The medications listed in this policy are subject to FDA dosing and administration; all other uses of the medications listed in this policy are considered investigational.

Length of approval (initial and reauthorization) may be up to 12 months when drug-specific coverage criteria are met and chart notes demonstrate continued positive clinical response.

Uses of the medications listed in this policy are subject to the product's FDA dosing and administration. All other uses of the listed medications — including doses, schedules, or routes of administration not consistent with FDA-approved labeling — are considered investigational.

Hospital-based outpatient infusion services are covered only when the policy's site-of-service medical necessity criteria are met. When those criteria are not met (for example, the infusion is not an initial course or re-initiation after ≥6 months, there is an outpatient infusion center or home infusion service available within 50 miles, and no clinical condition increases the risk of infusion complications), provision of hospital outpatient infusion services is not medically necessary.

Billing and Coding

HCPCS codesHCPCS

J0202	Injection, alemtuzumab (Lemtrada), 1 mg
J2323	Injection, natalizumab (Tysabri), 1 mg
J2329	Injection, ublituximab-xiiy (Briumvi), 1 mg
J2350	Injection, ocrelizumab (Ocrevus), 1 mg
J2351	Injection, ocrelizumab, 1 mg and hyaluronidase-ocsq (Ocrevus Zunovo) (new code effective 04/01/25)
Q5134	Injection, natalizumab-sztn (Tyruko), biosimilar (Tyruko), 1 mg

Expanded Disability Status Scale (EDSS) thresholds — drug distinctions

EDSS threshold for relapsing formsEDSS less than 6 is required for relapsing forms of MS (applies to Briumvi, Ocrevus relapsing indication, Tyruko/Tysabri).

EDSS threshold for primary progressive MS (Ocrevus / Ocrevus Zunovo)EDSS less than 7 is required for primary progressive MS when using Ocrevus or Ocrevus Zunovo.

Drug-specific distinctionOcrevus and Ocrevus Zunovo have a higher EDSS threshold (less than 7) for the primary progressive MS indication versus EDSS <6 for relapsing indications.

Provider Requirements and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization (medical necessity review) is required for the listed multiple sclerosis (MS) disease-modifying therapies and site-of-service requests. Typical initial and re-authorization approvals may be issued for up to 12 months when drug-specific coverage criteria are met.

Applies to: Briumvi, Ocrevus (IV), Ocrevus Zunovo (SC), Tyruko, Tysabri, Lemtrada and other MS drugs listed in this policy

Step Therapy

Step Therapy / Prior Treatment Requirements

Some drugs require documentation of prior treatment failure or inadequate response to other disease-modifying therapies before approval (step therapy). For example, Lemtrada requires inadequate response to two or more other MS DMTs and is not used concurrently with other MS DMTs.

Example prior treatment requirement: inadequate response to ≥2 DMTs (e.g., beta-interferons, dimethyl fumarate, fingolimod, glatiramer, natalizumab, ocrelizumab, ofatumumab, ozanimod, ponesimod, siponimod, teriflunomide).
Prescriptions must be by or in consultation with a neurologist or MS specialist when step therapy applies.

Background

Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the central nervous system resulting in variable neurologic symptoms and functional impairment. Disease courses include relapsing forms such as relapsing–remitting MS (RRMS), in which individuals experience discrete clinical attacks with periods of recovery, and progressive forms such as primary progressive MS (PPMS), characterized by steady neurologic decline without acute attacks and occurring in approximately 10% of people with MS. Disease-modifying therapies target immune pathways (for example, anti-CD20 B‑cell–directed agents) to reduce relapses and slow disability progression.

Key Definitions

Primary progressive multiple sclerosis (PPMS)

DefinitionPrimary progressive multiple sclerosis (PPMS) is a disease course with steady progression without acute attacks (progresses without relapses).

Prevalence noteApproximately 10% of individuals with multiple sclerosis have a primary progressive course.

Clinical contextProgressive-relapsing MS (related phenotype) is distinct and seen in about 5% of individuals; PPMS is addressed for treatment with Ocrevus/Ocrevus Zunovo when criteria are met.

Anti-CD20 therapies — definition and examples

DefinitionAnti-CD20 therapies are monoclonal antibodies that target CD20-positive B-lymphocytes and act as immunosuppressive disease-modifying treatments for MS.

Examples in this policyOcrevus (ocrelizumab) and Briumvi (ublituximab-xiiy) are anti-CD20 directed cytolytic antibodies referenced in the policy.

Policy Revision History

2025-10-03policy_effective_date_and_material_changeLatest

Site-of-service Medical Necessity criteria clarified to apply to injection drugs and site-of-service review was added for Ocrevus Zunovo; prescriber and age requirements were added for multiple listed drugs; site-of-service criteria exclusion for Alaska fully insured members noted — changes effective following 90-day provider notification.

2025-07-01interim_review

Interim review approved June 10, 2025, with changes to be effective October 3, 2025 following provider notification (clarifying SOS applies to injection drugs and adding Ocrevus Zunovo review).