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Alpha-1 Antitrypsin Therapy (e.g., Prolastin-C®, Aralast NP®, Glassia®, Zemaira®)
08.00.91f

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

EMPHYSEMA WITH ALPHA-1 ANTITRYPSIN DEFICIENCY
Alpha-1 antitrypsin (AAT) therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) is considered medically necessary and, therefore, covered for individuals 18 years of age and older who have AAT deficiency and clinical evidence of chronic emphysema without evidence of AAT-associated liver disease, when all of the following criteria are met:
  • The individual has a low serum concentration of alpha 1-antitrypsin (AAT) less than 80 mg/dL (radial immunodiffusion) or 50 mg/dL (nephelometry) or less than 11 μmol/L (nephelometry) or less than 0.8 g/L (35% of normal), which is considered the threshold thought to protect against emphysema.
  • The individual has a documented diagnosis of congenital AAT deficiency confirmed by one of the following:
    • Pi*ZZ, Pi*Z(null) or Pi(null)(null) protein phenotypes (homozygous)
    • Other rare AAT disease-causing alleles associated with serum AAT level <11 μmol/L
  • The individual has progressive emphysema with a documented rate of decline in forced expiratory volume in 1 second (FEV1).
  • The individual is a nonsmoker.
ACUTE GRAFT VERSUS HOST DISEASE (GVHD) AFTER HEMATOPOIETIC CELL TRANSPLANTATION
AAT therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) administered intravenously is considered medically necessary and, therefore, covered for individuals 18 years of age and older who have acute GVHD following hematopoietic cell transplantation in conjunction with systemic corticosteroids following no response (steroid-refractory disease) to first-line therapy options.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of AAT therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, alpha-1 antitrypsin (AAT) therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy is met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Alpha-1 proteinase inhibitor/Alpha-1 antitrypsin therapy (Prolastin-C) was approved by the FDA on October 16, 2009, for the treatment of individuals with AAT deficiency and evidence of emphysema.

Alpha-1 proteinase inhibitor/Alpha-1 antitrypsin therapy (Aralast NP) was approved by the FDA on May 4, 2007, for chronic augmentation therapy in patients having AAT deficiency with clinically evident emphysema.

Alpha-1 proteinase inhibitor/Alpha-1 antitrypsin therapy (Glassia) was approved by the FDA on July 1, 2010, and is indicated for chronic augmentation and maintenance therapy in adults with emphysema.

Alpha-1 proteinase inhibitor/Alpha-1 antitrypsin therapy (Zemaira) was approved by the FDA on July 8, 2003, for treatment of individuals with deficiency and evidence of emphysema.

PEDIATRIC USE 
AAT therapy is not indicated for use in pediatric individuals less than 18 years of age.

Description

Alpha-1 antitrypsin (AAT; also known as congenital alpha-1 proteinase inhibitor) deficiency is an autosomal, codominant genetic disorder, differentiated by deficient serum and lung concentrations of AAT. The most common form of AAT deficiency is associated with allele Z, or homozygous Pi*Z (ZZ). A deficiency in AAT leaves the neutrophil elastase uninhibited. Uncontrolled neutrophil elastase leads to progressive destruction of the pulmonary connective tissue and loss of the alveoli.

Some individuals with certain phenotypic variants have an increased risk of developing progressive emphysema. Individuals with the Pi*ZZ variant typically have a serum AAT levels less than 35% of the average normal. Ninety-five percent of clinically symptomatic AAT-deficient individuals are Pi*ZZ phenotype. Individuals with Pi(null)(null) are associated with undetectable serum AAT levels or levels less than 1% of the normal amount. Individuals with these low serum AAT levels have a markedly increased risk of developing emphysema over their lifetime. In addition, individuals with the Pi*SZ phenotype, whose serum AAT levels range from approximately 9 to 23 μM, are considered to have moderately increased risk of developing emphysema.

AAT (alpha proteinase inhibitor) is used as a replacement therapy for individuals with severe AAT deficiency and clinical evidence of emphysema. Several biological drugs have been approved by the US Food and Drug Administration (FDA) for AAT therapy, with orphan drug status. Prolastin, Aralast NP, Glassia, and Zemaira were approved by the FDA for the treatment of individuals with AAT deficiency and evidence of emphysema. Prolastin was replaced by Prolastin-C in spring 2010.

AAT therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) uses highly purified human AAT derived from human plasma. Studies comparing AAT preparations involved a limited number of participants with AAT deficiency and emphysema. All preparations produced similar increases in the serum AAT concentration and antigenic AAT activity in lung epithelial lining fluid. Data from cohort studies, although limited, indicate that such replacement therapy is associated with a lower rate of decline of forced expiratory volume, thus protecting the lung tissue from further destruction. Safety and effectiveness have not been established in pediatric individuals.

American Thoracic Society guidelines recommend using AAT therapy for individuals with moderate airflow obstruction with a forced expiratory volume in 1 second (FEV1) that is 30% to 65% predicted. The guidelines also recommend continuing optimal management of stable individuals with AAT deficiency, which should include many of the interventions recommended for AAT-replete individuals with emphysema.  ​

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Alpha1-proteinase inhibitor (Human). Drug Information 2022. [Lexicomp Web site]. 03/28/2022. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed April 18, 2025.

American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900.

Aralast® NP (alpha-proteinase inhibitor [human]) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals, Inc. 12/22/2022. Available at:  https://www.shirecontent.com/PI/PDFs/ARALASTNP_USA_ENG.pdf. Accessed April 18, 2025.

Elsevier's Clinical Pharmacology Compendium. Alpha-1-proteinase inhibitor. [Clinical Key Web site]. 04/15/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed April 18, 2025.

Glassia® (alpha-proteinase inhibitor [human]) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals, Inc. 09/27/2022. Available at: https://www.glassialiquid.com/. Accessed April 18, 2025.

IBM Micromedex® DRUGDEX® (electronic version). Alpha-1 proteinase inhibitor human. [Micromedex® Web site]. IBM Watson Health, Greenwood Village, Colorado, USA. 08/14/2024. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed April 18, 2025.

Lexi-Drugs Compendium. Alpha1-proteinase inhibitor. [Lexicomp Web site]. 02/11/2025. Available at: https://online.lexi.com/lso/action/home [via subscription only]. Accessed April 18, 2025.

Magenau JM, Goldstein SC, Peltier D, et al. α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018;131(12):1372-1379.

Marciniuk, DD, Hernandez P, Balter M, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012;19(2):109-116. 

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology – Hematopoietic Cell Transplantation (HCT). V1.2025. [NCCN Web site]. 02/28/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf. Accessed April 04, 2025.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. [NCCN Web site].  Alpha1-proteinase inhibitor (Human). Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed April 04, 2025.

Prolastin®-C (alpha-proteinase inhibitor [human]) [prescribing information]. Los Angeles, CA: Grifols USA, LLC. 09/21/2017. Available at:  https://www.prolastin.com/en/hcp. Accessed April 18, 2025.

Stockley, RA. Alpha1-antitrypsin review. Clin Chest Med. 2014;35(1):39-50.

Stoller JK. Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency. [UpToDate Web site]. 09/13/2022. Available at: https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-natural-history-of-alpha-1-antitrypsin-deficiency?search=alpha 1 antitrypsin deficiency&source=search_result&selectedTitle=1~99&usage_type=default&display_rank=1 [via subscription only]. Accessed April 18, 2025.

Stoller JK. Treatment of alpha-1 antitrypsin deficiency. [UpToDate Web site]. 11/04/2021. Available at: https://www.uptodate.com/contents/treatment-of-alpha-1-antitrypsin-deficiency?search=Treatment of alpha-1 antitrypsin deficiency&source=search_result&selectedTitle=1~99&usage_type=default&display_rank=1 [via subscription only]. Accessed April 18, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Alpha1-Proteinase Inhibitor (Human) (Aralast® NP). Product Information. [FDA web site]. 10/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/aralast-np. Accessed April 04, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Alpha1-Proteinase Inhibitor (Human) (Glassia®). Prescribing Information. [FDA Web site]. 01/2025. Available at: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/glassia. Accessed April 04, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Alpha1-Proteinase Inhibitor (Human) (Human) (Prolastin®-C). Prescribing Information. [FDA web site]. 09/21/2020. Available at: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/prolastin-c. Accessed April 04, 2025.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Alpha1-Proteinase Inhibitor (Human) (Zemaira®). Prescribing Information. [FDA Web site]. 01/2024. Available at: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/zemaira. Accessed April 04, 2025.

Zemaira® (alpha proteinase [human]) [prescribing information]. Kankakee, IL: CSL Behring, LLC. 01/2024. Available at: https://www.zemaira.com/prescribing-information. Accessed April 04, 2025.

Coding

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.​​

HCPCS Level II Code Number(s)

J0256 Injection, alpha 1 proteinase inhibitor (human), not otherwise specified, 10 mg

J0257 Injection, alpha 1 proteinase inhibitor (human), (GLASSIA), 10 mg

Revenue Code Number(s)
N/A



Coding and Billing Requirements

Policy History

Revisions From 08.00.91f:

7/01/2025
This version of the policy will become effective 07/01/2025.

This policy has been updated to communicate the coverage criteria, in alignment with the US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN).


The coverage criteria for the following indications were revised ​to include clinically evident emphysema as per FDA labeling.  

All of the ICD-10 CM codes have been removed from this policy, since they are informational. Report the most appropriate diagnosis code in su pport of medically necessary criteria as listed in the policy.​​


Revisions From 08.00.91e:​

05/01/2024
​The policy has been reviewed and reissued to communicate the Company’s continuing position on alpha 1-antitrypsin therapy (e.g., Prolastin-C®, Aralast NP®, Glassia®, Zemaira®​)​.​
04/05/2023
​The policy has been reviewed and reissued to communicate the Company’s continuing position on alpha 1-antitrypsin therapy (e.g., Prolastin-C®, Aralast NP®, Glassia®, Zemaira®​)​.
06/01/2022
​The policy has been reviewed and reissued to communicate the Company’s continuing position on alpha 1-antitrypsin therapy (e.g., Prolastin-C®, Aralast NP®, Glassia®, Zemaira®​)​.​
​11/17/2021
​The policy has been reviewed and reissued to communicate the Company’s continuing position on alpha 1-antitrypsin therapy (e.g., Prolastin-C®, Aralast NP®, Glassia®, Zemaira®​)​.
01/04/2021
This version of the policy will become effective 01/04/2021. The following criteria has been added to this policy in accordance with the National Comprehensive Cancer Network 03/23/2020: criteria for acute steroid-resistant graft versus host disease in individuals who have undergone a hematopoietic cell transplantation.​

Revisions from 08.00.91d:
03/02/2020This version of the policy will become effective 03/02/2020.
The following criteria have been added to this policy:
  • The individual has a documented diagnosis of congenital alpha1-antitrypsin deficiency confirmed by one of the following:
    • PiZZ, PiZ(null) or Pi(null)(null) protein phenotypes (homozygous)
    • Other rare AAT disease-causing alleles associated with serum alpha1-antitrypsin (AAT) level <11µmol/L
  • The Individual must be 18 years or older for Alpha 1-antitrypsin therapy
The following ICD-10 CM code has been deleted from this policy:
J43.8 Other emphysema

The following HCPCS code has been deleted from this policy:
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

The following ICD-10 CM code has been added to this policy:
J43.9 Emphysema, unspecified
________________________________

Note: on 01/14/2020 the following revisions were made to this policy in Notification:

ICD-10 code will NOT be added to this policy: J43.9 Emphysema, unspecified. This unspecified code will not be added and the more specific ICD-10 codes per policy criteria remain.

A billing requirement statement has been added to clarify, that for alpha 1-antitrypsin therapy (e.g., Prolastin-C®, Aralast NP™, Glassia™, Zemaira™), both of the following diagnoses are required:

E88.01 Alpha-1-antitrypsin deficiency AND J43.1 panlobular emphysema


Revisions From 08.00.91c:
09/26/2018This policy has been reissued in accordance with the Company's annual review process.

Effective 10/05/2017 this policy has been updated to the new policy template format.
7/1/2025
7/1/2025
08.00.91
Medical Policy Bulletin
Commercial
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Independence Blue Cross is a subsidiary of Independence Health Group, Inc. — independent licensees of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.