CurrentAetnaPolicy 0145

Alpha 1-Proteinase Inhibitors

This policy governs medical necessity, precertification, and coverage criteria for alpha 1‑proteinase inhibitor therapy (Aralast NP, Glassia, Prolastin‑C, Zemaira) for treatment of emphysema due to alpha1‑antitrypsin deficiency in Aetna commercial medical plans.

Policy Summary

PayerAetna

PolicyAlpha 1-Proteinase Inhibitors

Policy CodePolicy 0145

Change TypeNo material change

Effective DateJul 17, 1996

Next Review DateFeb 22, 2024

Key ActionObtain precertification/prior authorization for specified alpha1‑proteinase inhibitor HCPCS codes prior to infusion.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

<11 μMserum AAT threshold for coverage

FEV1 25–80%lung function range for initial approval

60 mg/kg/wkrecommended dose

J0256/J0257/S9346HCPCS codes referenced

04/25/2023last review date

Coverage Criteria

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Initial Therapy

Covered when ALL of the following are met:

Initial approval criteria: 1. Pretreatment serum AAT level < 11 micromol/L (80 mg/dL by radial immunodiffusion or 50 mg/dL by nephelometry); 2. Pretreatment post-bronchodilation FEV1 >= 25% and <= 80% of predicted; 3. Documented PiZZ, PiZ (null), or Pi (null, null) (homozygous) AAT deficiency or other phenotype/genotype associated with serum AAT < 11 micromol/L; 4. Member does not have PiMZ or PiMS AAT deficiency.see nodes

All four conditions required

Continuation Therapy

Covered when ALL of the following are met:

Continuation criteria: Member is experiencing beneficial clinical response from therapy (clinical benefit).clinical response

Ongoing benefit must be documented

Coverage stance — investigational and established therapies (descriptive)

Investigational and emerging therapies described (no explicit coverage criteria stated):

Gene therapy: AAV‑mediated AAT gene transfer (AAVrh.10hAAT) is under phase I/II investigation with dosing cohorts and routes (intrapleural and IV) aiming for sustained epithelial lining fluid (ELF) levels; safety and efficacy data are pending.

Inhaled AAT: Inhaled alpha-1 proteinase inhibitor formulations (including dry-powder and nebulized approaches) have been studied and can increase airway/sputum AAT, but long-term clinical effectiveness and outcomes remain unestablished; inhaled AAT is considered investigational.

PEGylated and recombinant AAT: PEGylated AAT and recombinant AAT‑Fc fusion constructs have demonstrated prolonged residence or superior protection in preclinical and early development studies compared to plasma‑derived AAT; further clinical development and evidence are required.

Established augmentation therapy:

Replacement therapy with alpha‑1 proteinase inhibitor is considered experimental and investigational when used in individuals who do not have clinical evidence of emphysema. The policy rationale notes that panacinar emphysema does not develop in some persons with alpha‑1 antitrypsin (AAT) deficiency, and in those without clinical emphysema replacement therapy has no proven value and is therefore not an established indication.

Inhaled formulations of alpha‑1 antitrypsin have demonstrated biochemical activity and short‑term safety in small studies, but their clinical effectiveness and impact on long‑term outcomes remain unproven. Short randomized phase IIa studies showed that inhaled alpha‑1 preparations can increase sputum AAT and are generally well tolerated, yet there is a lack of adequately powered phase II/III trials with clinical end points (lung function, imaging, exacerbations, health status, mortality) to establish long‑term benefit.

Aetna applies a brand‑preference rule for plasma‑derived augmentation products: Aralast NP, Glassia, and Zemaira are regarded as medically necessary only when the member has a documented contraindication, intolerance, or an ineffective trial of the lower‑cost alternative Prolastin‑C. The policy states there is insufficient evidence to show these branded products are superior to Prolastin‑C for augmentation/maintenance therapy.

Inhaled alpha‑1 antitrypsin preparations are designated investigational. While aerosol delivery can increase local airway AAT levels and short‑term studies report established safety and biochemical efficacy, the policy emphasizes that inhaled therapy’s effectiveness for chronic clinical outcomes has not been established and additional larger, longer randomized trials are required before inhaled formulations can be considered standard therapy.

Coding

Related CPT/Pathology CodesCPT

82103	Alpha-1-antitrypsin; total.
82104	Phenotype.

Covered HCPCS CodesHCPCSCovered

J0256	Injection, alpha 1 - proteinase inhibitor - (human), not otherwise specified, 10 mg.
J0257	Injection, alpha 1 proteinase inhibitor - (human), (glassia), 10 mg.
S9346	Home infusion therapy, alpha-1-proteinase inhibitor (e.g., Prolastin); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem.

CPT Codes Not Covered / Related (gene therapy)CPTNot Covered

38204

Management of recipient hematopoietic progenitor cell donor search and cell acquisition [ alpha-1 antitrypsin deficiency gene therapy].

Covered ICD-10 CodesICD-10Covered

E88.01	Alpha-1-antitrypsin deficiency [only covered when billed with panlobular emphysema].
J43.1	Panlobular emphysema [panacinar emphysema].

ICD-10 Codes Not Covered for Indications ListedICD-10Not Covered

D80.2	Selective deficiency of immunoglobulin A [IgA deficient with IgA antibodies].
E84.0-E84.9	Cystic fibrosis.
J80	Acute respiratory distress syndrome.
T86.90-T86.99	Complication of unspecified transplanted organ and tissue.

No billing or procedure codes in this excerptmixed

No codes listed

Serum AAT level threshold

Protective plasma AAT thresholdSerum AAT < 11 micromol/L

Equivalent by radial immunodiffusion80 mg/dL

Equivalent by nephelometry50 mg/dL

Pretreatment post‑bronchodilation FEV1

Allowed pretreatment FEV1 range>= 25% and <= 80% of predicted

Measurement conditionPost-bronchodilation forced expiratory volume in 1 second (FEV1)

Role in approvalRequired for initial approval of augmentation therapy when all other criteria met

Serum AAT entry criterion

Trial enrollment serum AAT criterionSerum AAT < 11 μM for inclusion in AAVrh.10hAAT trial

Target genotypes for trialIndividuals with ZZ or Z null genotype (serum AAT < 11 μM)

Dose cohorts referencedTwo dose cohorts described: 8×10^12 and 8×10^13 genome copies

ELF target concentration

ELF lung protective target>1.2 μM AAT in epithelial lining fluid (ELF)

Study aimSustained ELF concentration >1.2 μM was the goal of AAVrh.10hAAT trial

Relation to serum thresholdTrial enrolled subjects with serum AAT < 11 μM to attempt achieving ELF >1.2 μM

Ex-vivo assay 50% inhibition

Ex‑vivo assay 50% inhibition range2.5–5.0 mg/ml AAT achieved ~50% inhibition in PCR gene‑expression assays

Assay contextPCR analyses on expression of IKBKE, NOD1, TLR1, and TRAD genes in whole blood

Implication for dosingFindings suggested weekly doses >90 mg/kg may be necessary for optimal therapeutic effect in that study

Provider Actions & Requirements

Prior Authorization

Precertification / Prior Authorization Required

Precertification of alpha 1-proteinase inhibitors (Aralast NP, Glassia, Prolastin-C, and Zemaira) is required for all Aetna participating providers and members in applicable plan designs. Call (866) 752-7021 or fax (888) 267-3277 for precertification. Statement of Medical Necessity (SMN) precertification forms are available via Specialty Pharmacy Precertification. Site of Care Utilization Management Policy applies for infusions.

Affected products: Aralast NP, Glassia, Prolastin-C, Zemaira (HCPCS: J0256, J0257)
Precertification phone: (866) 752-7021; fax: (888) 267-3277
SMN forms: Specialty Pharmacy Precertification
Site-of-care policy: Utilization Management Policy on Site of Care for Specialty Drug Infusions

Note

Prior Authorization — None Specified (Informational)

No additional payer-specific prior authorization algorithms or step-therapy sequences beyond the precertification and brand-preference rule are specified in this excerpt. There are no explicit prior authorization conditions described other than the general precertification requirement.

No separate prior authorization forms or extra PA pathways specified in this excerpt
Informational: CPT/HCPCS/ICD-10 code lists provided but PA specifics not further detailed

Documentation Required

Administrative / Contact / Reference Information

This section contains administrative and reference information (policy history, review dates, and references/prescribing information). No explicit denial triggers are listed in this excerpt; however, lack of required precertification may result in claim delay or denial per plan rules.

Policy effective date: 07/17/1996; Last review: 04/25/2023; Next review: 02/22/2024
References and prescribing information cited (e.g., Aralast NP, Zemaira, Baxalta/CSL prescribing information)
Administrative note: Clinical Policy Bulletins are informational and subject to change

Step Therapy

Brand Selection / Step

Brand-preference rule: Prolastin-C is the lower-cost preferred product. Aralast NP, Glassia, and Zemaira are considered medically necessary only when the member has a contraindication, intolerance, or inadequate response to Prolastin-C.

Preferred agent: Prolastin-C (use required unless contraindicated/intolerant/ineffective)
Alternatives (allowed if Prolastin-C contraindicated/intolerant/ineffective): Aralast NP, Glassia, Zemaira

Documentation Required

Required Clinical Documentation

Required clinical documentation to support medical necessity includes pretreatment serum AAT level, pretreatment post-bronchodilation FEV1, and genotype/phenotype confirming severe deficiency. Continuation of therapy requires evidence of clinical benefit.

Pretreatment serum AAT level < 11 micromol/L (80 mg/dL by radial immunodiffusion or 50 mg/dL by nephelometry)
Pretreatment post-bronchodilation FEV1 between ≥25% and ≤80% predicted
Documented genotype/phenotype consistent with severe deficiency (e.g., PiZZ, PiZ null, homozygous null)
Exclusion: PiMZ or PiMS phenotypes not eligible
Continuation: documentation of beneficial clinical response

Note

No Step Therapy / References

No step therapy algorithms, required prior failures, or explicit denial triggers are described in this excerpt beyond the brand-preference requirement and the precertification requirement. References and prescribing information cited in the policy may be used to support clinical decision-making and documentation.

No formal step-therapy algorithm or mandatory trial lengths specified
References: policy reference list and manufacturer prescribing information (Aralast NP, Zemaira, Baxalta/CSL)
HCPCS codes: J0256, J0257; administrative code: S9346

Background

Alpha‑1 antitrypsin (AAT) is a circulating plasma antiprotease that inhibits neutrophil elastase. Congenital deficiency of AAT (AATD, due to SERPINA1 mutations) reduces protection against proteolytic lung injury and is associated with early‑onset panacinar emphysema. Replacement augmentation therapy with plasma‑derived alpha‑1 proteinase inhibitors is intended to restore protective levels of AAT in plasma and lung and is used for lifelong augmentation in adults with clinically evident emphysema due to severe AAT deficiency. The policy also notes important safety considerations, including contraindication in patients with IgA deficiency with anti‑IgA antibodies because of anaphylaxis risk, and defines the protective plasma threshold as AAT < 11 μM (equivalent values by common assays are cited elsewhere in the policy).

Definitions

AAT < 11 micromol/L — protective threshold plasma AAT level (equivalents by assay)

Protective plasma AAT thresholdAAT < 11 micromol/L

Radial immunodiffusion equivalent80 mg/dL

Nephelometry equivalent50 mg/dL

AATD — definition

DefinitionAlpha-1 antitrypsin deficiency (AATD) — genetic deficiency of the protease inhibitor AAT (SERPINA1 mutations)

Clinical associationsAssociated with AATD lung disease (emphysema) and AATD liver disease (mutant AAT aggregation)

Therapeutic implicationPlasma‑derived AAT augmentation can treat the pulmonary manifestations; liver disease currently treated by transplantation

ELF protective level — epithelial lining fluid AAT concentration

ELF protective concentration>1.2 μM AAT in epithelial lining fluid (ELF)

ContextTarget lung 'protective level' specified as the goal of the AAVrh.10hAAT phase I/II trial

Relation to therapyELF >1.2 μM aimed to indicate persistent therapeutic alveolar AAT levels after gene transfer

Initial Therapy Criteria

Initial Therapy

Initial therapy — clinical entry criteria (detailed):

Serum AAT threshold: Pretreatment serum AAT level less than 11 micromol/L (80 mg/dL by radial immunodiffusion or 50 mg/dL by nephelometry).

Lung function: Pretreatment post‑bronchodilation FEV1 greater than or equal to 25% and less than or equal to 80% of predicted.

Genotype/phenotype: Documented severe AAT deficiency such as PiZZ, PiZ (null), or Pi (null, null) (homozygous) or other genotype/phenotype associated with serum AAT < 11 micromol/L.

Exclusion by genotype: Member does not have PiMZ or PiMS AAT deficiency (these phenotypes are excluded from augmentation eligibility).

Initial therapy — investigational formulations

Investigational formulations and delivery strategies (descriptive):

PEGylated AAT: Mono‑PEGylated AAT formulations preserved inhibitory activity in vitro and may prolong half‑life, potentially decreasing infusion frequency; evidence to date is preclinical/early development.

Recombinant dry‑powder inhalation: Recombinant AAT formulated as a respirable dry powder has been developed and shown acceptable in‑vitro aerodynamic performance and stability in early studies, but clinical effectiveness is unestablished.

AAT‑Fc fusion proteins: Recombinant AAT‑IgG1 Fc‑fusion proteins demonstrated greater protection than plasma AAT in animal models and immunomodulatory effects ex‑vivo; further clinical development is needed.

Continuation of Therapy Criteria

Continuation of Therapy

Continuation of therapy — coverage requirements:

Ongoing benefit: Member demonstrates a continued beneficial clinical response to alpha 1‑proteinase inhibitor therapy (documented clinical benefit).

Ongoing benefit must be documented in the medical record

Safety/monitoring: No contraindication to continued therapy (e.g., known IgA deficiency with anti‑IgA antibodies); monitor for adverse events per product labeling.

Continuation therapy — safety observations and long‑term repeat dosing notes

Continuation therapy — safety observations and long‑term dosing notes:

Pediatric T1D safety observations: Repeated AAT infusions (up to 36 doses) in AAT‑sufficient pediatric type 1 diabetes patients were reported to be safe and well tolerated with long‑term follow‑up up to 5 years and no serious adverse events observed in the cited extension study.

Long‑term data and monitoring: Long‑term safety and repeat dosing data are limited outside of specific study populations; continue monitoring and document absence of serious adverse events during ongoing therapy.

Step Therapy

Step	Preferred agent	Non-preferred agents	Requirement / Failure criteria
1	Prolastin-C	Aralast NP; Glassia; Zemaira	Aralast NP, Glassia, and Zemaira are considered medically necessary only if the member has a contraindication, intolerance, or ineffective trial to lower‑cost Prolastin‑C.

Step	Description	Notes / References	Requirement / Failure criteria
[{"text":"1","status":""},{"text":"No formal step therapy algorithm specified in these sections; content provides background and citations regarding investigational and established therapies (gene therapy, inhaled AAT, PEGylated/recombinant constructs).","status":""},{"text":"Policy references and background citations (selected): Abboud et al.; Chiuchiolo & Crystal; CSL Behring Zemaira PI; Franciosi et al.; Gaggar et al.","status":""},{"text":"No step therapy requirements are stated in the cited background/references.
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Site of Care

Billing Rule

Follow Aetna Site of Care policy for infusions

Site of Care Utilization Management Policy applies to specialty drug infusions; follow Aetna's site‑of‑service policy for alpha1‑proteinase inhibitor infusions whether provided in an infusion center or at home.

Adhere to Utilization Management Policy on Site of Care for Specialty Drug Infusions

Note

Site of care and routes: IV established; others investigational

Routes under study include intravenous, intrapleural, intramuscular gene transfer, and inhalation; established augmentation therapy is administered by weekly intravenous infusion in infusion center, home, or hospital outpatient settings.

Established augmentation: weekly IV infusion
Investigational/under study: intrapleural, intramuscular gene transfer, inhalation (clinic/home)

OpenPayer

Alpha 1-Proteinase Inhibitors

Coverage Criteria

Coding

Provider Actions & Requirements

Background

Definitions

Initial Therapy Criteria

Continuation of Therapy Criteria

Step Therapy

Site of Care

Revision History & Administrative