ModifiedPremera BluecrossPolicy N/A

Alpha-1 Proteinase Inhibitors

This policy governs medical benefit coverage and site-of-service review for FDA-approved intravenous alpha1-proteinase inhibitors (Aralast NP, Prolastin-C, Zemaira, Glassia) used to treat emphysema due to severe alpha1-antitrypsin deficiency in adults, and describes documentation, coding, and approval durations.

Policy Summary

PayerPremera Bluecross

PolicyAlpha-1 Proteinase Inhibitors

Policy CodePolicy N/A

Change TypeAuthorization length increasedsite-of-service review addedGlassia moved to non-preferred with step requirement

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization (up to 12 months) and document genetic testing, serum alpha1‑PI <11 μM, FEV1 30–65%, and prior trial/failure of first-line agents before requesting Glassia.

SourceLink

POLICY UPDATE CHANGES

Site of service review was added for Aralast NP, Glassia, Prolastin-C, and Zemaira and Glassia was changed to a non-preferred product with updated coverage criteria requiring inadequate response or intolerance to other listed products.

Clarified that the medications listed are subject to the product's FDA dosage and administration prescribing information and that non-formulary exception review authorizations may be approved up to 12 months; added site-of-service exceptions for CRS and Alaska HB 226 applicability.

Initial authorization length for Aralast NP, Prolastin-C, Zemaira, and Glassia was changed from 6 months to 12 months.

Added an exception to the site-of-service requirements for certain individuals receiving treatment for cytokine release syndrome (CRS).

Site of service review was added for Aralast NP, Glassia, Prolastin-C, and Zemaira.

Policy updated to indicate that Site of Service Medical Necessity criteria does not apply to Alaska fully-insured members pursuant to Alaska HB 226.

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Coverage Criteria for Alpha‑1 Proteinase Inhibitors

Initial Therapy — First-line products

Covered when ALL of the following are met

First-line product coverage criteria: The individual is aged 18 years or older AND genetic testing documents a mutation in the SERPINA1 gene AND serum alpha1-antitrypsin is less than 11 micromole/L (approximately 57 mg/dL by nephelometry) AND forced expiratory volume in one second (FEV1) is 30-65% of predicted AND is receiving treatment for emphysema with a long-acting inhaled bronchodilator and/or corticosteroid AND is a non-smoker or is enrolled in a smoking cessation programsee individual nodes

Applies to Aralast NP, Prolastin-C, Zemaira

Initial Therapy — Second-line product (Glassia)

Covered when ALL of the following are met

Second-line (Glassia) coverage criteria: The individual is aged 18 years or older AND genetic testing documents a mutation in the SERPINA1 gene AND serum alpha1-antitrypsin is less than 11 micromole/L (approximately 57 mg/dL by nephelometry) AND forced expiratory volume in one second (FEV1) is 30-65% of predicted AND is receiving treatment for emphysema with a long-acting inhaled bronchodilator and/or corticosteroid AND is a non-smoker or is enrolled in a smoking cessation program AND medication is prescribed by or in consultation with a pulmonologist or geneticist AND the individual has had an inadequate response or intolerance to Aralast NP, Prolastin-C, OR Zemairasee individual nodes

Glassia designated second-line; requires trial/failure/intolerance to first-line agents

Continuation Therapy / Re-authorization

Re-authorization covered when ALL of the following are met

Re-authorization criteria: Chart notes at the time of re-authorization show an increase from baseline of alpha1-antitrypsin levels AND slowing of decline in lung functiondocumented increase in alpha1-PI and slowing of lung function decline

All drugs listed in this policy may be approved for up to 12 months if these criteria are met

Coverage context and operational criteria

Clinical efficacy and product administration context informing coverage:

Product dosing and goals: Administer 60 mg/kg IV once weekly aiming to maintain trough serum alpha1‑PI ≥11 μM; infusion rates vary by product (Glassia infusion rate not to exceed 0.2 mL/kg/min; Prolastin-C and Zemaira infusion rates not to exceed 0.08 mL/kg/min).60 mg/kg weekly; trough ≥11 μM

Product-specific infusion rates and pharmacokinetic non-inferiority demonstrated in trials

Efficacy evidence limits: Randomized controlled trials demonstrate augmentation and maintenance of serum and epithelial lining fluid (ELF) alpha1‑PI levels but have not demonstrated modification of the clinical course of pulmonary emphysema or reduction in exacerbation frequency in adequately powered RCTs.

Clinical outcomes not proven in adequately powered randomized, controlled clinical trials

Authorization and site-of-service rules: Initial authorizations for listed products may be approved for up to 12 months; site-of-service review applies to Aralast NP, Glassia, Prolastin‑C, and Zemaira; Glassia requires inadequate response or intolerance to Aralast NP, Prolastin‑C, or Zemaira to be approved as a non-preferred agent.

Policy Updates and Administrative Coverage Criteria

Policy-level coverage and administrative criteria updates

Authorization duration: Initial authorization for Aralast NP, Prolastin-C, Zemaira, and Glassia is up to 12 months12 months

Revised from 6 months to 12 months

Site-of-service requirements: Site-of-service medical necessity review applies to the listed infusion products; exceptions include Alaska fully-insured members (per Alaska HB 226) and certain individuals receiving treatment for cytokine release syndrome (CRS).

Site-of-service review added Nov 1, 2024; Alaska and CRS exceptions noted in subsequent updates

Product preference: Glassia is designated non-preferred and requires an inadequate response or intolerance to Aralast NP, Prolastin-C, or Zemaira for coverage.

Change effective January 3, 2025

All uses of the medications listed in this policy that are not specifically described in the coverage criteria are considered investigational and are not covered under this policy.

The clinical trials for Zemaira and other alpha1‑proteinase inhibitor products demonstrate augmentation and maintenance of serum alpha1‑PI levels (with mean troughs maintained above 11 μM), but have not demonstrated an effect on the clinical course of pulmonary emphysema or on exacerbation frequency in adequately powered randomized, controlled trials.

Per statutory guidance, the policy’s site-of-service medical necessity criteria does not apply to Alaska fully‑insured members pursuant to Alaska HB 226. For those members, only the medical necessity criteria for the infusion drug itself apply.

When the site-of-service medical necessity criteria in this policy are not met, a hospital-based outpatient infusion site (including outpatient hospital IV infusion departments and hospital-based outpatient clinical levels of care) is considered not medically necessary for infusion or injectable therapy services covered by this policy, except where specific exceptions (e.g., cytokine release syndrome meeting criteria) apply.

Historical updates reflect additions and clarifications to coverage stance and operational requirements: site-of-service review for Aralast NP, Glassia, Prolastin‑C, and Zemaira was added (effective November 1, 2024), Glassia was designated non‑preferred and updated to require prior inadequate response or intolerance to first‑line products (effective January 3, 2025), and the policy was clarified to state that the listed medications are subject to the product’s FDA dosage and administration prescribing information. The policy also documents an exception to site‑of‑service requirements for certain individuals receiving treatment for cytokine release syndrome and a statutory exception for Alaska fully‑insured members.

Billing Codes, Clinical Thresholds, and Dosing

Covered HCPCS Codes (Aralast NP, Prolastin-C, Zemaira)HCPCSCovered

J0256

Injection, alpha 1-proteinase inhibitor, human, 10 mg, not otherwise specified (Aralast NP, Prolastin-C, Zemaira)

Covered HCPCS Codes (Glassia)HCPCSCovered

J0257

Injection, alpha 1 proteinase inhibitor (human), (Glassia), 10 mg

Named HCPCS CodesHCPCS

J0256	HCPCS code added for Aralast NP, Prolastin-C, Zemaira (historical)
J0257	HCPCS code added for Glassia (historical)

inv-14: Serum alpha1-antitrypsin level — clinical threshold

ThresholdSerum alpha1-antitrypsin < 11 micromole/L (approximately 57 mg/dL by nephelometry)

Diagnostic requirementGenetic testing documents mutation in the SERPINA1 gene

Clinical contextApplies to adults (aged 18 years or older) with clinically evident emphysema due to severe AAT deficiency

inv-15: FEV1 — pulmonary function requirement

Required rangeFEV1 30-65% of predicted

Associated criteriaIndividual must have clinically evident emphysema and be receiving appropriate maintenance inhaled therapy

Prior Authorization, Documentation, and Site‑of‑Service Requirements

Prior Authorization

Prior Authorization Required; Duration and Site‑of‑Service Review

Prior authorization is required for all listed alpha1-proteinase inhibitor products. Initial and renewal approvals may be granted for up to 12 months when drug-specific coverage criteria are met. Site-of-service medical necessity review applies for Aralast NP, Prolastin‑C, Zemaira, and Glassia for administration outside of Alaska fully-insured members (per policy exceptions). Site-of-service review may trigger denial or an alternate payment arrangement if the medical necessity site-of-service criteria are not met for members aged 13 and older.

Initial and re-authorization approvals: up to 12 months when criteria are met
Site-of-service review applies for ages 13+; failure to meet SOS criteria may result in denial or alternate payment
Site-of-service review added for Aralast NP, Prolastin‑C, Zemaira, and Glassia
Glassia is a non-preferred (second-line) product and requires inadequate response or intolerance to Aralast NP, Prolastin‑C, or Zemaira before coverage
Providers must follow the product's FDA dosage and administration prescribing information when documenting treatment
Required documentation: office visit notes with diagnosis, relevant history, physical evaluation, and medication history

Clinical Background on Alpha‑1 Antitrypsin Deficiency

Alpha1‑antitrypsin (AAT) deficiency is an inherited disorder caused by mutations in the SERPINA1 gene that produce low circulating AAT levels and increase the risk of early‑onset emphysema; smoking accelerates lung injury. Severe deficiency is typically defined by serum AAT levels below 11 micromole/L (approximately 57 mg/dL). Intravenous augmentation with alpha1‑proteinase inhibitor products aims to raise serum and epithelial lining fluid AAT concentrations (target trough ≥ 11 μM) and is dosed commonly at 60 mg/kg once weekly, but randomized trials have demonstrated biochemical augmentation rather than definitive modification of emphysema progression.

Key Definitions and Clinical Targets

inv-32: Severe alpha1-antitrypsin deficiency — SERPINA1 mutations and serum threshold

Genetic definitionSevere alpha1-antitrypsin deficiency is characterized by SERPINA1 mutations

Serum thresholdEndogenous serum AAT levels below 11 micromole/L (approximately 57 mg/dL) define increased emphysema risk

Common phenotypesPiZZ phenotype comprises ~95% of identified AAT deficient individuals and often has serum levels <35% of normal

inv-33: Target trough level — Trough serum alpha1‑PI level ≥11 μM

Target troughTrough serum alpha1‑PI level ≥11 μM (clinical trial target and augmentation goal)

Trial resultsTrials demonstrated trough levels rising above 11 μM by Week 2 with stability Weeks 7–12

Policy Summary

PayerPremera Bluecross

PolicyAlpha-1 Proteinase Inhibitors

Policy CodePolicy N/A

Change TypeAuthorization length increasedsite-of-service review addedGlassia moved to non-preferred with step requirement

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionObtain prior authorization (up to 12 months) and document genetic testing, serum alpha1‑PI <11 μM, FEV1 30–65%, and prior trial/failure of first-line agents before requesting Glassia.

SourceLink

On This Page

Documentation Required

Documentation and Dosing/Administration Requirements

Medical records submitted for review must document that medical necessity criteria are met and must follow the product-specific FDA dosing and administration prescribing information. Documentation should include office visit notes containing the diagnosis, relevant history, physical evaluation, medication history, and any information supporting site-of-service selection.

Document diagnosis, relevant history, physical evaluation, and medication history in office visit notes
Follow FDA dosage and administration prescribing information for the specific product when documenting dose, frequency, and route
Include documentation of inadequate response or intolerance to first-line products when requesting Glassia
Chart notes at re-authorization must demonstrate treatment response (e.g., increase from baseline of alpha1-antitrypsin levels and slowing of decline in lung function) where applicable