CurrentUnitedHealthcarePolicy 2024D0067I

Alpha1-Proteinase Inhibitors

Defines UnitedHealthcare medical benefit drug policy coverage criteria for alpha1-proteinase inhibitors (Aralast NP, Glassia, Prolastin-C, Zemaira) for treatment of emphysema due to congenital alpha1-antitrypsin (AAT) deficiency, including initial and continuation authorization requirements, applicable codes, background, and limitations/unproven indications.

Policy Summary

PayerUnitedHealthcare

PolicyAlpha1-Proteinase Inhibitors

Policy CodePolicy 2024D0067I

Change TypeSupporting information; Template update

Effective DateNov 1, 2024

Next Review Date

Key ActionObtain prior authorization and ensure documentation of genotype or disease-causing allele and serum AAT level < 11 µmol/L, confirmation of emphysema by pulmonary function testing, nonsmoker status, evidence of optimal conventional therapy, and dosing per FDA labeling.

POLICY UPDATE CHANGES

11/01/2024: Updated References section and archived previous policy version 2023D0067H.

07/01/2025: Template Update and updated Benefit Considerations.

1Primary covered indication (emphysema due to congenital AAT deficiency)

2Drug HCPCS codes listed

1ICD-10 diagnosis code listed

<11 µmol/LAAT serum threshold

Coverage Summary

Defines UnitedHealthcare medical benefit drug policy coverage criteria for alpha1-proteinase inhibitors (Aralast NP, Glassia, Prolastin-C, Zemaira) for treatment of emphysema due to congenital alpha1-antitrypsin (AAT) deficiency. Initial authorization requires confirmed congenital AAT deficiency by genotype or disease-causing allele, circulating serum AAT level <11 µmol/L (with method-specific equivalents noted), confirmation of emphysema by pulmonary function testing, evidence of continued optimal conventional therapy, nonsmoker status, dosing per FDA labeling, and is authorized for up to 12 months. Continuation (re-authorization) requires that the patient is currently receiving therapy, remains a nonsmoker, demonstrates a positive clinical response (for example, decreased exacerbation frequency, improved symptoms, or slowed FEV1 decline), dosing per FDA labeling, and reauthorization is for up to 12 months. The policy also lists applicable codes and documents limitations: use for conditions other than emphysema related to congenital AAT deficiency is considered unproven or not medically necessary and use in patients without established congenital deficiency is not indicated per FDA statements.

Key thresholds & dates

Serum AAT threshold< 11 µmol/L (corresponds to < 80 mg/dL radial immunodiffusion; < 57 mg/dL nephelometry)

Effective dateNovember 1, 2024

Last reviewJuly 1, 2025

Policy stanceCovered with criteria (augmentation therapy for emphysema due to congenital AAT deficiency)

Initial Therapy — Medical Necessity Criteria

Medically necessary — Initial therapy

Covered when ALL of the following are met:

ALL of the following

ALL of the following
- ONE of
  - Pi*ZZ, Pi*Z(null) or Pi*(null)(null) protein phenotypes (homozygous)
  - Other rare AAT disease-causing alleles associated with serum alpha1-antitrypsin (AAT) level < 11 µmol/L (e.g., Pi (Malton, Malton))
Circulating serum concentration of alpha1-antitrypsin (AAT) level < 11 µmol/L
Corresponds to < 80 mg/dl if measured by radial immunodiffusion or < 57 mg/dl if measured by nephelometry
Continued optimal conventional treatment for emphysema (e.g., bronchodilators, supplemental oxygen if necessary)
Current nonsmoker
Diagnosis of emphysema confirmed with pulmonary function testing
Dosing is in accordance with the United States Food and Drug Administration approved labeling
Initial authorization will be for no more than 12 months

Continuation / Reauthorization Criteria

Medically necessary — Continuation (re-authorization) therapy

Covered when ALL of the following are met:

ALL of the following

Patient is currently receiving therapy for emphysema due to congenital alpha1-antitrypsin (AAT) deficiency
Documentation of a positive clinical response (e.g., decreased frequency of exacerbations, improvement in symptom burden, slowed rate of FEV1)
Patient remains a nonsmoker
Dosing is in accordance with the United States Food and Drug Administration approved labeling
Reauthorization will be for no more than 12 months

Unproven / Not Medically Necessary

Not medically necessary / Unproven

Not covered / unproven when ANY of the following apply:

ANY of the following

Conditions other than emphysema associated with alpha1-antitrypsin deficiency (alpha1-proteinase inhibitor is unproven)
Treatment of lung disease in patients without established congenital A1-PI deficiency (per FDA statements)
Use for cystic fibrosis: clinical endpoints not established; considered unproven pending larger studies
Use for other conditions (refractory bronchial asthma, fibromyalgia, panniculitis, vasculitis) — evidence limited to case reports and considered investigational/unproven

Provider Actions

Prior Authorization

Initial prior authorization requirements

Obtain prior authorization for initial augmentation therapy. Requirements include documented congenital AAT deficiency genotype or disease-causing allele, circulating serum AAT level below the policy threshold, confirmation of emphysema by pulmonary function testing, evidence of continued optimal conventional therapy for emphysema, current nonsmoker status, and dosing per FDA-approved labeling. Initial authorization is limited to no more than 12 months.

Genotype or disease-causing allele (e.g., Pi*ZZ, Pi*Z(null), Pi*(null)(null), or other rare alleles associated with AAT < 11 µmol/L)
Circulating serum AAT level < 11 µmol/L (note equivalence: < 80 mg/dl radial immunodiffusion; < 57 mg/dl nephelometry) with assay method documented
Diagnosis of emphysema confirmed with pulmonary function testing
Documentation of continued optimal conventional treatment for emphysema (e.g., bronchodilators, supplemental oxygen if necessary)
Current nonsmoker status
Dosing in accordance with FDA-approved labeling
Initial authorization ≤ 12 months

Prior Authorization

Reauthorization requirements

For continuation (reauthorization), provide documentation that the patient is currently receiving augmentation therapy for emphysema due to congenital AAT deficiency, remains a nonsmoker, demonstrates a positive clinical response (for example decreased exacerbation frequency, improved symptoms, or slowed FEV1 decline), and is receiving dosing per FDA labeling. Reauthorization is limited to no more than 12 months.

Current receipt of augmentation therapy for emphysema due to congenital AAT deficiency
Documentation of positive clinical response (e.g., fewer exacerbations, symptomatic improvement, slowed rate of FEV1 decline)
Patient remains a nonsmoker
Dosing in accordance with FDA-approved labeling
Reauthorization ≤ 12 months

Documentation Required

Genotype and lab documentation

Document the patient's genotype (for example Pi*ZZ) or specified disease-causing allele and provide a measured serum AAT level. Note the laboratory assay method used (radial immunodiffusion or nephelometry) so the policy threshold can be applied.

Example genotype: Pi*ZZ
Serum AAT level with assay method noted (radial immunodiffusion or nephelometry)
Threshold: AAT < 11 µmol/L (corresponds to < 80 mg/dl radial immunodiffusion; < 57 mg/dl nephelometry)

Denial Risk

Denial risk for non-indicated uses

Claims for uses other than treatment of emphysema with confirmed congenital A1-PI (AAT) deficiency are considered unproven or not indicated and are at risk for denial.

Cystic fibrosis (CF)
Other non-emphysema conditions (e.g., refractory bronchial asthma, fibromyalgia, panniculitis, vasculitis)

Clinical Evidence

Clinical evidence includes observational and cohort studies suggesting benefit but limited randomized long-term data on exacerbations and disease progression. Tonelli et al. (PI ZZ cohort) reported an adjusted mean difference in FEV1 change favoring augmentation therapy of 47.6 mL/year (p = 0.05). An NHLBI registry observational study found augmentation therapy was associated with decreased mortality (risk ratio 0.64; 95% CI 0.43–0.94), with particularly lower mortality in the subgroup with initial FEV1 35–49% predicted. Nonrandomized cohort studies (Wencker and Seersholm) reported reduced annual FEV1 decline in treated groups versus untreated, with treatment-associated slower loss of lung function in multiple analyses. Overall, randomized controlled long-term data demonstrating effects on exacerbations and emphysema progression are limited.

Evidence highlights (compact)

FEV1 benefit (Tonelli)Adjusted mean change favoring augmentation: +47.6 mL/year (p=0.05)

Registry mortalityObserved lower mortality with augmentation: RR=0.64 (95% CI 0.43–0.94)

LimitationsLong-term randomized RCT data on effects for exacerbations and emphysema progression are limited or not demonstrated

Background

Alpha1-proteinase inhibitors (Aralast NP, Glassia, Prolastin-C, Zemaira) are plasma-derived human A1-PI products that are FDA-labeled for chronic augmentation therapy in patients with congenital AAT deficiency and clinically evident emphysema. Augmentation therapy refers to chronic intravenous infusion of plasma-derived alpha1-proteinase inhibitor to raise serum and lung AAT levels. The products carry limitations noted by the FDA, including that effects on pulmonary exacerbations and progression of emphysema have not been demonstrated in randomized controlled trials, long-term clinical data are limited, they are not indicated for lung disease without established congenital AAT deficiency, and they are derived from pooled human plasma with associated theoretical infectious risks.

Definitions

AATAlpha1-antitrypsin (alpha1-proteinase inhibitor)

Augmentation therapyChronic intravenous infusion of plasma-derived alpha1-proteinase inhibitor to raise serum and lung AAT levels