ModifiedPremera BluecrossPolicy N/A

Pharmacotherapy of Spinal Muscular Atrophy (SMA) — Evrysdi, Spinraza, Zolgensma coverage criteria

Defines medical necessity, benefit routing, dosing limits, documentation and re-authorization criteria for Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec-xioi) for treatment of SMA; applies to providers requesting coverage under Premera Blue Cross.

Policy Summary

PayerPremera Bluecross

PolicyPharmacotherapy of Spinal Muscular Atrophy (SMA) — coverage criteria for Evrysdi, Spinraza, Zolgensma

Policy CodePolicy N/A

Change TypeCriteria additions and clarifications (2019–2025)

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization with documented genetic confirmation of bi-allelic SMN1 mutations and required supporting chart documentation.

SourceLink

POLICY UPDATE CHANGES

Added criteria for Zolgensma (onasemnogene abeparvovec-xioi) when it was approved in 2019.

Added criteria for Evrysdi (risdiplam) following FDA approval in August 2020.

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

Updated Evrysdi coverage to include infants under 2 months of age based on RAINBOWFISH interim data.

Updated Spinraza criteria to require prescription by a neurologist with expertise treating SMA.

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

Non-formulary exception review authorizations for all drugs listed may be approved up to 12 months and medications are subject to FDA dosage and administering prescribing information.

3drugs addressed

<=2yage limit for Zolgensma

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

one-time infusion approvals

12mmax exception duration

black boxZolgensma liver warning

Coverage Criteria and Indications

Evrysdi (risdiplam) Initial Therapy

Covered when ALL of the following are met:

Evrysdi (risdiplam) initial criteria: 1) Diagnosis of SMA Type 1, 2, or 3 attributed to bi-allelic SMN1 mutations documented by genetic testing; 2) Individual has not received Zolgensma (onasemnogene abeparvovec-xioi); 3) Medication is prescribed by a neurologist with expertise treating SMA; 4) Evrysdi (risdiplam) will not be used in combination with Spinraza (nusinersen); 5) Dose is limited to FDA-specified weight/age-based dosing: 0.15 mg/kg/day for <2 months of age; 0.2 mg/kg/day for 2 months to <2 years of age; 0.25 mg/kg/day for >=2 years and <20 kg; 5 mg/day for >=2 years and >=20 kg.

From policy Evrysdi section (chunk 4).

Spinraza (nusinersen) Initial Therapy

Covered when ALL of the following are met:

Spinraza (nusinersen) initial criteria: 1) Diagnosis of SMA Type 1, 2, or 3 attributed to bi-allelic SMN1 mutations documented by genetic testing; 2) Individual has not received Zolgensma (onasemnogene abeparvovec-xioi); 3) Medication is prescribed by a neurologist with expertise treating SMA; 4) Spinraza (nusinersen) will not be used in combination with Evrysdi (risdiplam); 5) Recommended dosing: 12 mg per administration with 4 loading doses (first 3 at 14-day intervals; 4th loading dose 30 days after 3rd), then maintenance dose every 4 months thereafter.

From policy Spinraza section (chunks 4-5).

Zolgensma (onasemnogene abeparvovec-xioi) Initial Therapy

Covered when ALL of the following are met:

Zolgensma (onasemnogene abeparvovec-xioi) initial criteria: 1) Individual is aged less than 2 years at the time of infusion; 2) Diagnosis of SMA attributed to bi-allelic SMN1 mutations documented by genetic testing; 3) Documented genetic test confirms 4 or fewer copies of SMN2; 4) Individual does not have advanced SMA; 5) Baseline anti-AAV9 antibody level <= 1.50; 6) Medication is prescribed by a neurologist with expertise treating SMA; 7) Administered as a one-time intravenous infusion at 1.1 x 10^14 vector genomes/kg over 60 minutes; 8) Prescriber must attest to providing clinical outcome information within the appropriate provider portal as requested by the Company plan.

From policy Zolgensma section (chunk 5) and prescriber attestation requirement (chunk 12).

Continuation Therapy / Re-authorization

Covered when ALL of the following are met:

Re-authorization for Evrysdi and Spinraza: 1) Medical records demonstrate a positive clinical response to therapy; 2) Improvement documented using functional measures appropriate to the individual's current abilities (e.g., ambulation, arm strength, pulmonary function); 3) Requests for renewal may be approved for up to 12 months when criteria are met; 4) Chart notes documenting progress must be provided as part of re-authorization documentation.

From policy re-authorization language (chunks 6 and 7).

Covered therapies and high-level coverage statements

High-level coverage summary:

Covered therapies and high-level statements: Policy includes distinct coverage criteria for the three SMN-directed therapies: onasemnogene abeparvovec (Zolgensma), nusinersen (Spinraza), and risdiplam (Evrysdi); criteria were added/updated across 2019–2025 to reflect approvals, age/SMN2 copy eligibility, safety warnings (including Zolgensma liver risk), and administrative clarifications such as non-formulary exception durations up to 12 months.

Summary of policy updates and high-level coverage statements (chunks 36–39, 41).

All uses of Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec‑xioi) that are not specifically described in this policy are considered investigational. Examples include SMA that is not attributable to bi‑allelic SMN1 mutations, SMA Type 4 (adult onset), use of Evrysdi or Spinraza after a Zolgensma infusion, and concurrent use of Evrysdi and Spinraza.

The evidence base is judged insufficient to support use of onasemnogene abeparvovec‑xioi (Zolgensma) in SMA Type 0, later‑onset SMA (Types II and III), Type IV, and many presymptomatic populations due to limited or noncomparative data. Similarly, assessments have concluded that evidence is insufficient for nusinersen (Spinraza) in Type 0 and Type IV SMA.

Medications addressed in this policy must be prescribed and administered in accordance with the product's FDA dosage and administration prescribing information. Non‑formulary exception review authorizations for the drugs listed in this policy may be approved for up to 12 months where applicable, consistent with the administrative limits noted in the policy.

Historically, uses of nusinersen (Spinraza) and other SMA therapies outside the specified indications in earlier policy versions were designated investigational. The policy continues to treat requests for uses not enumerated in current criteria as investigational and requires documentation consistent with stated coverage criteria for reconsideration.

Requests to use Evrysdi (risdiplam) or Spinraza (nusinersen) in individuals who have previously received onasemnogene abeparvovec (Zolgensma) are considered investigational / not medically necessary under this policy and may be denied unless otherwise justified by new evidence consistent with the policy.

Overall, the reviewed evidence supports use of the three SMN‑directed therapies in selected populations (infantile‑onset and certain later‑onset groups), but evidence is insufficient for multiple off‑label or less‑studied populations and for many sequencing or combination scenarios. The policy therefore restricts coverage to the indications and conditions specified and treats other applications as investigational.

Initial Therapy — Evidence and Requirements

Initial therapy

Initial coverage when ALL top-level conditions for the selected drug are met:

Evrysdi (risdiplam): See Evrysdi initial criteria: genetic confirmation of bi-allelic SMN1 mutations; not previously treated with Zolgensma; prescriber is a neurologist with SMA expertise; not used with Spinraza; age/weight-based dosing limits per FDA label.

Refer to Evrysdi Initial Therapy (chunk 4).

Spinraza (nusinersen): See Spinraza initial criteria: genetic confirmation of bi-allelic SMN1 mutations; not previously treated with Zolgensma; prescriber is a neurologist with SMA expertise; not used with Evrysdi; loading and maintenance dosing schedule per policy.

Refer to Spinraza Initial Therapy (chunks 4–5).

Zolgensma (onasemnogene abeparvovec-xioi): See Zolgensma initial criteria: age <2 years at infusion, genetic confirmation of bi-allelic SMN1 mutations, <=4 SMN2 copies, baseline anti-AAV9 antibody <=1.50, prescriber attestation to reporting outcomes, and one-time IV infusion dosing per FDA label.

Continuation and Re-authorization Criteria

Re-authorization

Re-authorization covered when ALL of the following are met:

Re-authorization detailed criteria: 1) Chart notes document continued clinical benefit with measurable improvement or stabilization using functional measures appropriate to the individual's abilities (e.g., ambulation, arm strength, pulmonary function); 2) Documentation of ongoing care by a neurologist with expertise in SMA may be required; 3) Renewable approvals for Evrysdi and Spinraza may be granted for up to 12 months when criteria are satisfied; 4) Requests for therapy after Zolgensma (for Evrysdi or Spinraza) are considered investigational and are not approved under this re-authorization pathway.

From re-authorization and investigational-use language (chunks 6–7).

Continuation therapy evidence

Evidence notes relevant to continuation/long-term use:

Observed long-term outcomes: Longer-term follow-up and extension studies for Spinraza and Zolgensma show sustained motor gains and survival benefits in infantile-onset cohorts; extension data support continued benefit in appropriate patients.

Prior Authorization, Documentation, and Provider Requirements

Prior Authorization

Authorization Requirements and Benefit Routing

Prior authorization is required for Evrysdi (risdiplam), Spinraza (nusinersen), and Zolgensma (onasemnogene abeparvovec-xioi). Benefit routing: Evrysdi is managed under the pharmacy benefit; Spinraza and Zolgensma are managed under the medical benefit. All requests must follow the member's benefit limits — consult the benefit booklet or contract.

Evrysdi (risdiplam) – Pharmacy benefit
Spinraza (nusinersen) – Medical benefit
Zolgensma (onasemnogene abeparvovec-xioi) – Medical benefit

Prior Authorization

Prior Authorization Required for SMA Therapies

Prior authorization is required for all SMA disease‑modifying therapies in this policy. Requests must document genetic confirmation of SMA due to bi‑allelic SMN1 mutations and meet the specific age, copy number, and clinical criteria for each product.

Genetic testing documenting bi‑allelic SMN1 mutation required

Coding and Billing

HCPCS CodesHCPCS

J2326	Injection, nusinersen (Spinraza), 0.1 mg
J3399	Injection, onasemnogene abeparvovec-xioi, per treatment; up to 5x10^15 vector genomes (Zolgensma)

Historical HCPCS coding updatesHCPCS

C9489	HCPCS code (previously added then removed in policy history)
J2326	HCPCS code (added 1/1/18)
J3399	HCPCS code (added 02/01/21)
J3590	HCPCS code (added 07/01/19 then removed 02/01/21)
J3490	HCPCS code (removed 05/01/18)

inv-14: Baseline anti-AAV9 antibody — numeric threshold value for eligibility

Baseline anti-AAV9 (AAV9) antibody<= 1.50

Test requirement timingBaseline level required prior to onasemnogene abeparvovec infusion

Interpretation for eligibilityLevels at most 1.50 meet policy threshold for Zolgensma consideration

inv-15: Age for Zolgensma infusion — age limit value for infusion eligibility

Maximum age at infusion< 2 years (individual aged less than 2 years at time of infusion)

Benefit routing noteZolgensma managed under the medical benefit and administered as a one-time IV infusion

Administration Setting and Site-of-Care Requirements

Step Therapy

Zolgensma: one‑time IV infusion per FDA label

Zolgensma is administered as a single intravenous infusion per the FDA label; document the one‑time IV administration in the authorization and arrange appropriate infusion setting.

Policy specifies Zolgensma administered as a one‑time IV infusion (1.1 x 10^14 vg/kg over ~60 minutes).

Documentation Required

Document corticosteroid plan and monitoring for Zolgensma infusion

For onasemnogene abeparvovec administration, document the corticosteroid plan and monitoring: corticosteroids should be given before and after infusion and liver function monitored for at least 3 months; arrange infusion in hospital outpatient or infusion center per institutional practice.

Document pre‑ and post‑infusion corticosteroid administration and plans for liver monitoring for at least 3 months.
Site of care may be hospital outpatient or infusion center consistent with the product label and monitoring needs.

Sequencing, Step Therapy, and Comparative Trials

Coverage statement	Notes
Evrysdi (risdiplam) and Spinraza (nusinersen) must not be used concurrently.	Policy explicitly states Evrysdi will not be used in combination with Spinraza and Spinraza will not be used in combination with Evrysdi.
Evrysdi or Spinraza use after receipt of Zolgensma (onasemnogene abeparvovec-xioi) is not allowed.	Policy lists Evrysdi or Spinraza use after Zolgensma as investigational / not medically necessary.

Evidence topic	Policy note / trials referenced
Comparative evidence between Zolgensma and nusinersen (Spinraza)	Report concluded evidence was insufficient to compare onasemnogene abeparvovec-xioi versus nusinersen for infantile-onset SMA; some pivotal-trial patients later received nusinersen and combination/sequential effects are not well studied.
Ongoing trials examining sequencing and post-gene-therapy outcomes	RESPOND (NCT04488133), DEVOTE (NCT04089566), and ASCEND (NCT05067790) are listed as ongoing trials evaluating sequencing or treatment after prior therapies; completion dates vary (e.g., RESPOND Oct 2025, DEVOTE Jun 2024, ASCEND Jun 2027).

Prescriber requirement	Policy summary
Neurologist with expertise treating SMA	Policy requires that Evrysdi, Spinraza, and Zolgensma be prescribed by a neurologist with expertise treating SMA; this identical language was added/clarified in updates.
Documentation of prescriber's specialty/experience may be required	Policy notes that documenting the prescriber's specialty or experience treating SMA may be required for approval and was added to Spinraza and applied across therapies.

Policy history entry	What changed (step-therapy relevance)
04/01/17 – New policy	Initial policy established nusinersen (Spinraza) coverage criteria (Types 1–3) and investigational uses; no step-therapy rules present at inception.
07/01/19 – Annual Review	Added criteria for Zolgensma (onasemnogene abeparvovec-xioi); HCPCS coding updates noted. No explicit step-therapy sequencing rules added beyond therapy-specific criteria.
11/01/20 – Annual Review	Added criteria for Evrysdi (risdiplam) following FDA approval (2020); subsequent updates (2021 onward) clarified prescriber expertise and safety information but did not introduce formal step-therapy tiers in the excerpt.

Key Definitions and Genetic Terms

inv-36: Genetic diagnosis required — bi-allelic SMN1 mutation definition

DefinitionBi-allelic SMN1 mutation — genetic diagnosis showing two mutated or deleted copies of SMN1 documented by genetic testing

Required documentationGenetic testing report confirming homozygous disruption (two mutated/deleted copies) of SMN1 must be submitted for initial approval

Relevance to coverageBi-allelic SMN1 mutation is a core eligibility criterion for Evrysdi, Spinraza, and Zolgensma per policy

inv-37: SMN2 copy number — used to characterize disease severity and Zolgensma eligibility

SMN2 copy number roleNumber of SMN2 gene copies is used to characterize disease severity and guide therapy eligibility

Zolgensma-specific threshold

Background on Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by homozygous disruption of the SMN1 gene, leading to reduced survival motor neuron (SMN) protein, progressive loss of anterior horn motor neurons, and progressive muscle weakness and atrophy. SMA is classified clinically by age of onset and highest achieved motor milestone (Types 1–4), and SMN2 copy number is a genetic modifier used to predict disease severity and guide therapy decisions.

Policy Summary

PayerPremera Bluecross

PolicyPharmacotherapy of Spinal Muscular Atrophy (SMA) — coverage criteria for Evrysdi, Spinraza, Zolgensma

Policy CodePolicy N/A

Change TypeCriteria additions and clarifications (2019–2025)

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization with documented genetic confirmation of bi-allelic SMN1 mutations and required supporting chart documentation.

SourceLink

On This Page

Refer to Zolgensma Initial Therapy (chunk 5).

Initial therapy evidence

Evidence summaries supporting initial coverage decisions:

Zolgensma evidence: Phase I single-arm trials in infantile-onset SMA showed improved motor outcomes (CHOP INTEND increases, milestone attainment) and avoidance of permanent ventilation in treated cohorts; liver enzyme elevations occurred and were managed with corticosteroids.

See Zolgensma trial outcomes and safety (chunks 24–25).

Spinraza evidence: Randomized, sham-controlled trials (e.g., ENDEAR) demonstrated reduced risk of death or permanent ventilation and improved motor milestones in infantile-onset SMA; pre-symptomatic treatment exceeded expected outcomes.

See Spinraza efficacy evidence (chunk 21).

Evrysdi evidence: SUNFISH and FIREFISH trials and interim RAINBOWFISH safety data show efficacy and safety profiles consistent with other SMA therapies; no significant difference in SAE occurrence in SUNFISH between risdiplam and placebo.

See risdiplam efficacy and safety summaries (chunk 18).

Initial therapy criteria additions

Additions to initial therapy criteria at time of approval:

2019–2020 additions: Zolgensma criteria were added in 2019 upon FDA approval; Evrysdi criteria were added following FDA approval in August 2020. Spinraza prescribing information was reviewed with no change to core criteria at those times.

Policy history and initial additions (chunks 36–37).

See continuation evidence and exploratory outcomes (chunks 21, 25).

Continuation/exception duration

Administrative continuation and exception guidance:

Non-formulary exception duration: Non-formulary exception review authorizations for all drugs listed in this policy may be approved for up to 12 months.12 months

2025 clarification (chunk 41).

SMN2 copy number documentation as applicable (e.g., Zolgensma criteria)

Prior Authorization

Prior Authorization Requirements — Therapy Specific

Therapy‑specific prior authorization notes and limits: Evrysdi authorization must show the individual meets criteria for Type 1, 2, or 3 SMA and that Evrysdi will not be used in combination with Spinraza. Spinraza authorization must document loading/maintenance dosing plan and that it will not be used in combination with Evrysdi. Zolgensma authorization must document age <2 years at infusion (except where policy updates allow coverage with 4 SMN2 copies per policy revision), baseline AAV9 antibody titer ≤1.50, and that it will be administered as a one‑time infusion.

Evrysdi dosing per FDA labeling; contraindicated with concurrent Spinraza use
Spinraza: 4 loading doses (first 3 at 14‑day intervals, 4th at 30 days after 3rd), then maintenance every 4 months
Zolgensma: single IV infusion at 1.1 x 10^14 vg/kg; baseline AAV9 antibody ≤1.50

Denial Risk

Triggers for Potential Denial

Authorizations may be denied when required documentation is missing or exclusion criteria are met. Common denial triggers include absence of genetic testing confirming bi‑allelic SMN1 mutations, documentation of prior Zolgensma (when use after Zolgensma is excluded), requests for combination therapy (Evrysdi + Spinraza), or use outside FDA‑approved indications.

Missing genetic test confirming bi‑allelic SMN1 mutation
Request for Evrysdi after Zolgensma or Spinraza/Evrysdi combination use
Use for SMA types or situations considered investigational (e.g., non‑SMN1 causes, adult‑onset type 4)

Denial Risk

Liver Assessment and Monitoring for Zolgensma

Zolgensma has important liver safety considerations. Prior to infusion, assess liver function by clinical exam and laboratory testing (eg, AST, ALT, total bilirubin, prothrombin time). Individuals with preexisting liver impairment are at higher risk for acute serious liver injury or acute liver failure.

Baseline hepatic aminotransferases (AST, ALT), total bilirubin, and prothrombin time required prior to infusion
Consider clinical exam documenting baseline liver status

Documentation Required

Liver Testing and Steroid Plan for Onasemnogene Abeparvovec

A corticosteroid plan and liver monitoring schedule are required with onasemnogene abeparvovec (Zolgensma). Corticosteroids should be administered before and after infusion, and liver function must be monitored for at least 3 months post‑infusion. Document the corticosteroid regimen and monitoring plan in the medical record at time of authorization.

Documented corticosteroid plan (eg, prednisolone regimen) before and after infusion
Laboratory monitoring plan for at least 3 months post‑infusion (AST, ALT, total bilirubin, PT)

Documentation Required

Prescriber Attestation (Zolgensma)

Prescribers of Zolgensma must attest to providing clinical outcome information within the appropriate provider portal as requested by the Company plan. Failure to attest or provide requested outcome data may affect coverage.

Prescriber attestation to submit outcomes data in provider portal at requested cadence
Coverage may be contingent on submission of requested data

Note

Follow FDA Prescribing Information

All medications in this policy must be prescribed and administered in accordance with the FDA‑approved prescribing information (dosage and administration). Prior authorization requests should reference the planned dosing and administration consistent with product labeling.

Dosing and administration must follow current FDA labeling for Evrysdi, Spinraza, and Zolgensma
Deviations from labeled dosing should be justified in the documentation

Denial Risk

Combination Use Restrictions

Combination use restrictions: concurrent Evrysdi with Spinraza is prohibited. Evrysdi or Spinraza use after Zolgensma infusion is considered investigational and is excluded unless specifically allowed by updated policy language.

Evrysdi and Spinraza may not be used together
Evrysdi or Spinraza following Zolgensma is considered investigational per policy

Note

Therapy Sequencing Considerations

Therapy sequencing considerations: there is limited comparative data on sequencing or combining these therapies. Evidence on the optimal order of treatment is limited; decisions should be individualized and documented. Authorization reviewers will consider available trial data, FDA indications, and clinical rationale when evaluating sequencing requests.

Limited comparative data between Zolgensma and nusinersen; some patients in trials received sequential therapies with uncertain effects
Document clinical rationale when requesting therapy sequencing or a change in modality

Documentation Required

Prescriber Specialty Requirement

Prescriber specialty requirement: SMA disease‑modifying therapies must be prescribed by a neurologist with expertise in treating SMA. Documentation of prescriber specialty and experience should be included in the request.

Prescriber must be a neurologist with SMA expertise
Include evidence of prescriber expertise in the submission (eg, specialty, clinic affiliation)

Historical contextAge consideration added in original Zolgensma criteria (2019) and reiterated in policy updates

Billing Rule

Follow FDA dosing/administration when selecting site of care

Administer medications in the site of care consistent with the FDA dosing and administration; document site selection per the product label when submitting the authorization.

Policy reiterates that dosing/administration and site/setting decisions are guided by the FDA prescribing information.

Documentation Required

Document adherence to FDA dosing/administration

Ensure all requests and administration plans adhere to the product’s FDA dosing and administration prescribing information and document this in the authorization materials.

Policy states medications listed are subject to the product's FDA dosage and administration prescribing information.

Documented genetic test must confirm 4 or fewer copies of SMN2 for Zolgensma eligibility

Clinical correlationSMN2 copy number inversely correlates with SMA severity and is part of phenotype classification

inv-38: SMN-directed therapies — definition of therapy classes (nusinersen, risdiplam, onasemnogene abeparvovec)

SMN-directed therapy classesTherapies that increase SMN protein or replace SMN1 function: antisense oligonucleotide (nusinersen), oral SMN2 splicing modifier (risdiplam), and AAV9-mediated gene replacement (onasemnogene abeparvovec)

Mechanisms — nusinersenAntisense oligonucleotide that increases exon 7 inclusion in SMN2 mRNA to raise functional SMN protein (Spinraza)

Mechanisms — risdiplamOral SMN2 splicing modifier that increases production of full-length SMN protein (Evrysdi)

inv-39: SMN2 copy number (genetic modifier) — additional reference entries

SMN2 as genetic modifierSMN2 copy number is a genetic modifier used to predict SMA severity and guide therapy decisions

Typical copy rangesSMN2 copy number commonly differs across SMA types and is referenced in clinical classification tables

Policy usagePolicy explicitly uses SMN2 copy number (≤4) to determine Zolgensma eligibility

inv-40: SMA drug names — list of drug names referenced in policy

NusinersenSpinraza (nusinersen)

RisdiplamEvrysdi (risdiplam)

Onasemnogene abeparvovecZolgensma (onasemnogene abeparvovec-xioi)

Policy mentionsThese three therapies are the disease-modifying SMA treatments referenced throughout the policy