ModifiedPremera BluecrossPolicy 5.01.28

Pharmacotherapy of Spinal Muscular Atrophy (SMA)

Policy governing medical and pharmacy benefit coverage and medical necessity criteria for Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec-xioi) for treatment of SMA; applies to Premera Bluecross members and their providers.

Policy Summary

PayerPremera Bluecross

PolicyPharmacotherapy of Spinal Muscular Atrophy (SMA)

Policy CodePolicy 5.01.28

Change TypeMaterial clinical updates and administrative clarifications

Effective Date

Next Review Date

Key ActionPrescriber must attest to providing clinical outcome information in the provider portal when requested for Zolgensma.

SourceLink

POLICY UPDATE CHANGES

Updated Zolgensma (onasemnogene abeparvovec-xioi) coverage criteria to require that the prescriber attest to providing clinical outcome information within the appropriate provider portal as requested by the Company plan.

Updated Zolgensma criteria to include coverage of individuals with 4 copies of the SMN2 gene.

Added safety information to Zolgensma regarding a black box warning for acute serious liver injury and acute liver failure.

Added criteria for Evrysdi (risdiplam) after FDA approval in August 2020 and later expanded approval to include infants under 2 months.

Clarified that non-formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months.

Clarified that medications listed in this policy are subject to the product's FDA dosage and administration prescribing information.

3FDA‑approved SMA treatments covered

≤1:50

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Coverage and Medical Necessity Criteria

inv-01: Evrysdi (risdiplam) — Initial therapy

Covered when ALL of the following are met

Evrysdi initial criteria: The individual has a diagnosis of SMA Type 1, 2, or 3 attributed to bi-allelic SMN1 mutations documented by genetic testing; the individual has not received onasemnogene abeparvovec (Zolgensma); medication is prescribed by a neurologist with expertise treating SMA; Evrysdi (risdiplam) will not be used in combination with Spinraza (nusinersen); dosing is limited as specified below.See dosing node

Dosing limits: 0.15 mg/kg/day for <2 months; 0.2 mg/kg/day for 2 months to <2 years; 0.25 mg/kg/day for ≥2 years and <20 kg; 5 mg/day for ≥2 years and ≥20 kg.

inv-02: Spinraza (nusinersen) — Initial therapy

Covered when ALL of the following are met

Spinraza initial criteria: The individual has a diagnosis of SMA Type 1, 2, or 3 attributed to bi-allelic SMN1 mutations documented by genetic testing; the individual has not received onasemnogene abeparvovec (Zolgensma); medication is prescribed by a neurologist with expertise treating SMA; Spinraza (nusinersen) will not be used in combination with Evrysdi (risdiplam); dosing follows the labeled loading and maintenance schedule.Recommended dosage: 12 mg per administration; loading: first 3 doses at 14-day intervals, 4th loading dose 30 days after 3rd; maintenance every 4 months.

Managed under the medical benefit; treatment may be continued long-term for Types 2 and 3.

inv-03: Zolgensma (onasemnogene abeparvovec-xioi) — Initial therapy

Covered when ALL of the following are met

Zolgensma initial criteria: The individual is aged less than 2 years at the time of infusion; has a diagnosis of SMA attributed to bi-allelic SMN1 mutations documented by genetic testing; documented SMN2 copy number of 4 or fewer; the individual does not have advanced SMA; baseline anti‑AAV9 antibody titer is ≤1:50; medication is prescribed by a neurologist with expertise treating SMA; Zolgensma (onasemnogene abeparvovec‑xioi) is administered as a one‑time intravenous infusion; the prescriber attests to providing clinical outcome information in the appropriate provider portal as requested by the Company plan.Dose = 1.1 x 10^14 vector genomes/kg IV over 60 minutes; one‑time administration.

Zolgensma is available only at certified treatment centers.

inv-04: Re-authorization for Evrysdi and Spinraza

Re-authorization may be approved when ALL of the following are met

Re-authorization criteria: Medical records demonstrate a positive clinical response to therapy as documented by improvement in functional measures appropriate to the individual's current abilities (e.g., ambulation, arm strength, or pulmonary function).Approvals generally up to 12 months.

Re-authorization applies to Evrysdi and Spinraraz; future re-authorization of Zolgensma beyond a one‑time infusion is considered investigational.

The policy specifies that use of Evrysdi (risdiplam) or Spinraza (nusinersen) after onasemnogene abeparvovec (Zolgensma) infusion is considered investigational. It also states that concurrent use of Evrysdi and Spinraza together is investigational. These investigational designations apply to uses not outlined in the policy and are listed explicitly among other investigational scenarios for Evrysdi and Spinraza.

Zolgensma is considered investigational when used in individuals with 5 or more copies of the SMN2 gene. The policy lists this SMN2 copy-number threshold as an explicit exclusion from coverage for Zolgensma under the investigational uses section.

The Zolgensma Phase I trial excluded subjects with baseline anti‑AAV9 antibody titers > 1:50; the policy references this trial exclusion as a basis for the antibody‑titer cutoff used in coverage considerations. The policy also notes that anti‑AAV9 antibody titer should be documented when seeking authorization for onasemnogene abeparvovec.

This medical policy does not apply to Medicare Advantage plans. Members and providers should consult the member benefit booklet or contact customer service to determine benefit limitations that may apply.

All other uses of Evrysdi, Spinraza, and Zolgensma that are not described in this policy are considered investigational. The policy gives examples including SMA not attributed to bi‑allelic SMN1 mutations and SMA Type 4 (adult‑onset), in addition to the listed investigational therapy combinations and post‑gene therapy uses.

Historically, the policy has consistently stated that uses outside the specified criteria are investigational; the original policy entry on 04/01/17 noted that Nusinersen (Spinraza) may be considered medically necessary when criteria are met and that all other uses were investigational. This historical position is retained in the policy history and investigational listings.

Coding and Identifiers

HCPCS codes referencedHCPCS

C9309	Injection, onasemnogene abeparvovec-brve, per treatment (new code effective 04/01/26)
J2326	Injection, nusinersen (Spinraza), 0.1 mg
J3399	Injection, onasemnogene abeparvovec-xioi, per treatment, up to 5x10^15 vector genomes (Zolgensma)

Policy-related HCPCS/Codes historyHCPCS

C9309	HCPCS code added effective April 1, 2026
J2326	HCPCS code previously added (effective 1/1/18)
C9489	HCPCS code added 7/1/17 (later terminated)
J3490	HCPCS code removed from policy
J3590	HCPCS code added previously (later removed)
J3399	HCPCS code added 02/01/21

Anti-AAV9 antibody titer

Maximum allowed baseline anti-AAV9 antibody titer≤ 1:50

Trial exclusion threshold (Phase I Zolgensma)Subjects with anti-AAV9 antibody titers >1:50 were excluded

Consequence for authorizationBaseline anti-AAV9 ≤1:50 required for Zolgensma initial coverage

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Benefit management and prior authorization

Prior Authorization Required: Prior authorization (PA) is required for Evrysdi, Spinraza, and Zolgensma. Benefit assignment: Evrysdi (risdiplam) is managed under the pharmacy benefit; Spinraza (nusinersen) and Zolgensma (onasemnogene abeparvovec-xioi) are managed under the medical benefit. Non-formulary exception review authorizations for drugs in this policy may be approved up to 12 months.

Evrysdi = Pharmacy benefit
Spinraza and Zolgensma = Medical benefit
PA required for all listed products

Prior Authorization

Prior authorization requirements for onasemnogene abeparvovec

Prior authorization for onasemnogene abeparvovec (Zolgensma) requires specific documentation prior to approval, including genetic testing confirming bi-allelic SMN1 mutations and documentation of 4 or fewer SMN2 copies, age less than 2 years at time of infusion, and that the individual does not have advanced SMA. Prescriber must be a neurologist with expertise treating SMA. Zolgensma is provided as a one-time infusion.

Agent-Specific Initial Therapy Evidence and Criteria

inv-39: Agent-specific initial therapy — initial authorization criteria per agent (aggregate)

Initial authorization criteria per agent

Evrysdi initial: See coverage criteria: genetically confirmed SMA (Types 1–3), no prior Zolgensma, neurologist prescriber, not combined with Spinraza, dosing limits by age/weight as specified.

Managed under pharmacy benefit.

Spinraza initial: See coverage criteria: genetically confirmed SMA (Types 1–3), no prior Zolgensma, neurologist prescriber, not combined with Evrysdi, dosing per label including 4 loading doses then maintenance every 4 months.

Managed under medical benefit.

Zolgensma initial: See coverage criteria: age <2 years at infusion, genetically confirmed SMA, SMN2 copy number ≤4, baseline anti‑AAV9 ≤1:50, not advanced SMA, administered as one‑time infusion at certified centers; prescriber attestation to provide outcome data.

Continuation and Reauthorization Criteria

inv-44: Evrysdi and Spinraza continuation — re-authorization requirements

Re-authorization may be approved when ALL of the following are met

Evrysdi and Spinraza continuation: For continuation (re‑authorization) of Evrysdi or Spinraza, medical records must document a positive clinical response to therapy demonstrated by improvement in functional measures appropriate to the individual's current abilities (e.g., ambulation, arm strength, pulmonary function).Approvals generally up to 12 months.

Reauthorization documentation should include chart notes of progress and functional measures.

inv-45: Reauthorization — reauthorization criteria and durations (historical additions noted)

Reauthorization criteria and duration have been added in prior revisions; specifics noted below

Reauthorization: Re‑authorization requires documentation of positive clinical response as described in policy documentation requirements; non‑formulary exception review and other approvals for Evrysdi and Spinraza may be granted for up to 12 months.

Step Therapy and Sequencing

Coverage rule	Notes / Rationale
Therapies must not be used in combination; prior receipt of Zolgensma (onasemnogene abeparvovec-xioi) excludes coverage of Evrysdi (risdiplam) or Spinraza (nusinersen).	Policy language lists Evrysdi and Spinraza not to be used together and specifies that individuals who have received Zolgensma are ineligible for Evrysdi or Spinraza; these uses are considered investigational.

Consideration	Evidence / Operational implication
Clinical trial sequencing and crossover considered in authorization decisions.	Reports and ongoing trials note that some trial participants subsequently received alternative SMA therapies (e.g., nusinersen after onasemnogene abeparvovec); comparative uncertainty and limited data on combination/sequencing should be considered when authorizing treatment.

Operational requirement	Applies to
Medication must be prescribed by a neurologist with expertise treating SMA.	Applies to Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec-xioi) as specified in policy coverage criteria and updates.

Step therapy summary	Operational note
No explicit step therapy steps defined in these policy sections.	Historical policy updates added agents and coding but did not establish a prescriptive step-by-step therapy sequence; treatment decisions guided by individual criteria and clinical evidence.

Administration Setting and Monitoring

Note

Site‑of‑care — certified treatment centers required

Zolgensma is available only at certified treatment centers and is administered as a one‑time intravenous infusion.

Arrange infusion at a certified treatment center.
Zolgensma is a single, one‑time IV infusion.

Note

Site‑of‑care — hospital outpatient / infusion center administration

Onasemnogene abeparvovec (Zolgensma) is administered as a single IV infusion in a hospital outpatient or infusion center setting with required pre‑ and post‑infusion monitoring and a documented corticosteroid plan.

Administer as single IV infusion over ~60 minutes with dosing per label (1.1 x 10^14 vg/kg).
Ensure pre‑infusion evaluation and post‑infusion monitoring, including liver labs and corticosteroid plan.

Note

Background and Definitions

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by bi‑allelic SMN1 mutations resulting in deficiency of SMN protein and progressive motor neuron loss. Disease severity correlates inversely with age of onset and is influenced by the number of SMN2 gene copies; clinical classification ranges from prenatal/Type 0 through adult‑onset Type 4, with earlier onset and fewer SMN2 copies generally associated with more severe disease.

SMA types — clinical classification

Type 0Prenatal/fetal onset; typical SMN2 copies = 1; highest achieved motor function = none

Type 1 (infantile)Onset <6 months; typical SMN2 copies = 2; severe disease; high early mortality

Type 2Onset 6–18 months; typical SMN2 copies = 3 or 4; sits independently

Type 3Onset >18 months; typical SMN2 copies = 3 or 4; walks independently

Type 4Adult onset (20s–30s); typical SMN2 copies = 4–8; milder course

Policy Summary

PayerPremera Bluecross

PolicyPharmacotherapy of Spinal Muscular Atrophy (SMA)

Policy CodePolicy 5.01.28

Change TypeMaterial clinical updates and administrative clarifications

Effective Date

Next Review Date

Key ActionPrescriber must attest to providing clinical outcome information in the provider portal when requested for Zolgensma.

SourceLink

On This Page

Documentation Required

Liver assessment and monitoring for onasemnogene abeparvovec

Liver assessment and monitoring are required for all individuals receiving Zolgensma due to risk of serious liver injury. Prior to infusion, assess liver function by clinical exam and laboratory testing (eg, AST, ALT, total bilirubin, prothrombin time). Corticosteroids should be administered before and after infusion, and liver function must be monitored for at least 3 months post-infusion.

Baseline LFTs: AST, ALT, total bilirubin, prothrombin time
Administer corticosteroids starting prior to infusion and continue post-infusion per prescribing information
Monitor liver function for ≥3 months after infusion
Individuals with pre-existing liver impairment may be at higher risk

Documentation Required

Pre-infusion and monitoring documentation for Zolgensma

Pre-infusion and monitoring documentation for Zolgensma must be provided with PA requests. Initial approval requires chart notes documenting diagnosis and genetic testing (bi-allelic SMN1 mutation and SMN2 copy number). Documentation must reflect plans for corticosteroid use and scheduled liver function monitoring.

Chart notes with diagnosis and genetic testing results (bi-allelic SMN1 and SMN2 copy number)
Plan for corticosteroid administration (dose/timing)
Schedule for pre- and post-infusion LFTs and clinical monitoring

Denial Risk

Adhere to FDA dosing and administration

Prescribers must follow the product's FDA dosing and administration instructions. Requests that do not adhere to FDA-recommended dosing/administration may be denied. For Zolgensma, the recommended dose is 1.1 x 10^14 vector genomes/kg IV over ~60 minutes; Spinraza and Evrysdi dosing must follow their respective FDA labels.

Zolgensma dosing: 1.1 x 10^14 vector genomes/kg IV infusion ~60 minutes
Spinraza and Evrysdi dosing per FDA prescribing information
Non-adherence to FDA dosing/administration may be grounds for denial

Note

Step therapy and sequencing (operational note)

No explicit step therapy requirements are specified in this policy for Evrysdi, Spinraza, or Zolgensma. Treatment sequencing considerations and prior therapy exclusions are addressed elsewhere (eg, prior Zolgensma excludes subsequent Evrysdi or Spinraza under investigational/unsupported uses).

No step-therapy mandates in policy text
Policy notes that Evrysdi and Spinraza use after Zolgensma is considered investigational/not supported
Therapy sequencing and combination use are uncertain and have limited evidence

inv-40: Risdiplam initial evidence — evidence summary for Evrysdi (trial outcomes and evidence highlights)

Risdiplam (Evrysdi) evidence summary

Efficacy signals: SUNFISH (Types 2/3): part two showed statistically significant improvements in MFM‑32 and Revised Upper Limb Module at 12 months versus placebo; part one reported a mean MFM‑32 increase and 58% with ≥3‑point change (N=43). FIREFISH (Type 1): part one showed median CHOP‑INTEND increases and high proportions achieving ≥4‑point increases; RAINBOWFISH (presymptomatic): interim data show presymptomatic infants with 2–3 SMN2 copies achieving motor milestones and survival without permanent ventilation at 12 months.

Some studies are open‑label or single‑arm; clinical significance varies by endpoint and MID data are limited.

inv-41: Nusinersen initial evidence — evidence summary for Spinraza

Nusinersen (Spinraza) evidence summary

Efficacy in infantile and later-onset SMA: Randomized and controlled trials (including ENDEAR) demonstrated reduced risk of death or permanent ventilation and improvements in motor milestones for infantile‑onset SMA; additional studies and pre‑symptomatic data show improved motor outcomes in later‑onset and presymptomatic populations.

Multiple trials exist with endpoints including survival, motor function, and milestone attainment.

inv-42: Onasemnogene abeparvovec initial evidence — evidence summary for Zolgensma

Onasemnogene abeparvovec (Zolgensma) evidence summary

Phase I and exploratory outcomes: Phase I single‑arm trial in infantile SMA (cohorts low and high dose) showed increases in CHOP‑INTEND scores and motor‑milestone attainment in the high‑dose cohort; none required permanent ventilation by reported follow‑up. Subjects with anti‑AAV9 titers >1:50 were excluded from trials.

Safety signals included serum aminotransferase elevations leading to corticosteroid use per protocol; exploratory milestones included sitting unassisted and other motor outcomes.