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Alpha 1-Antitrypsin Inhibitor Therapy

Number: 0145



Policy

Aetna considers alpha 1-antitrypsin (AAT) inhibitor therapy (e.g., Aralast NP, Glassia, Prolastin-C, and Zemaira) medically necessary for selected adult members with emphysema due to AAT deficiency when all of the following criteria are met:

  1. Member has a low serum concentration of AAT less than 80 mg per deciliter (mg/dL) (0.8 g/L) by radial immundiffusion (or less than 50 mg/dL (0.5 g/L) if measured by nephelometry) or less than 11 uM/L (35 % of normal), which is considered the threshold thought to protect against emphysema; and
  2. Member has PiZZ, PiZ(null) or Pi(null, null) phenotype (homozygous) AAT deficiency or other phenotypes associated with serum AAT concentrations of less than 80 mg/dL. (AAT inhibitor therapy is considered not medically necessary for use in individuals with the PiMZ or PiMS phenotypes of AAT deficiency because these individuals appear to be at small risk of developing panacinar emphysema); and
  3. Member has progressive panacinar emphysema with a documented rate of decline in forced expiratory volume in 1 second (FEV1); and
  4. Member is a non-smoker; and
  5. Member is not IgA antibody deficient with antibodies to IgA.

Because panacinar emphysema does not develop in some individuals who have AAT deficiency, replacement therapy with AAT inhibitor is of no proven value in affected individuals without clinical evidence of emphysema and is therefore considered experimental and investigational for these individuals.

Aetna considers AAT inhibitor experimental and investigational for treatment of cystic fibrosis. Aetna considers AAT inhibitor therapy experimental and investigational when criteria are not met.

Aetna considers repeat doses of AAT inhibitor therapy medically necessary for members who met the requirements for AAT inhibitor at therapy initiation and who demonstrate a substantial reduction in rate of deterioration of lung function.

Aetna considers alpha-1 antitrypsin deficiency gene therapy experimental and investigational because its effectiveness has not been established.

Aetna considers inhaled alpha-1 antitrypsin therapyexperimental and investigational because its effectiveness has not been established.

Background

Alpha 1-antitrypsin is an antiprotease found in human plasma that inhibits the neutrophil elastase enzyme from degrading elastin tissues in the lung.  Alpha-1-antitrypsin (AAT) deficiency is a hereditary disorder associated with the early onset of severe pulmonary emphysema in adults.  Although alpha 1-antitrypsin inhibitor therapy (Prolastin, Aralast) has not been shown to prevent or reverse emphysema in these patients affected by AAT deficiency, there is reason to believe that maintenance of antitrypsin serum levels may be compatible with retardation of the progression of emphysema.

Once initiated, therapy will usually be continued for the remainder of the patient's life.  Recipients of alpha 1-antitrypsin inhibitor therapy should be immunized against hepatitis B.  It is also recommended that this medication not be used in patients with immunoglobulin antibody IgA deficiency that is known to have antibodies against IgA (anti-IgA antibody).  These patients may experience severe reactions, including anaphylaxis to IgA, which may be present in human alpha 1-antitrypsin inhibitor.

According to American Thoracic Society (2003) guidelines, a “protective” threshold plasma AAT level of 11 mol/L corresponds to 80 mg/dl if measured by radial immunodiffusion and to 50 mg/dl if measured by nephelometry. This protective threshold has evolved from the observation that patients with heterozygote phenotypes whose levels of AAT exceed this level are usually free from emphysema. 

Alpha‐1 Proteinase inhibitors are contraindicated in IgA deficient patients with antibodies against IgA, since these products may contain trace amounts of IgA and cause an increased risk for severe hypersensitivity.

Abboud and colleagues (2005) stated that AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients.  There was a suggestion of a slower progression of emphysema by computed tomography scan in a small randomized trial.  Two non-randomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV1 before and after replacement therapy, suggested a possible benefit for selected patients.  Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, these investigators recommended reserving AAT replacement therapy for deficient patients with impaired FEV1 (35 to 65 % of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1 after a period of observation of at least 18 months.

An assessment by the Canadian Agency for Drugs and Technologies in Health (Chen et al, 2007) concluded that evidence showing health improvement from alpha-1 antitrypsin inhibitor therapy is inconclusive.  The assessment found that, in controlled trials, augmentation therapy has not shown reduced lung function impairment in patients with AAT deficiency and chronic obstructive pulmonary disease (COPD), compared with normal care.  Conversely, the assessment reported that in observational studies, alpha-1 antitrypsin inhibitor therapy is associated with outcomes suggestive of therapeutic benefit in patients with severe AAT deficiency and moderate airflow obstruction.  The assessment found that severe adverse events from treatment have been reported in approximately 1 % of study populations.

The assessment concluded that use of alpha-1 antitrypsin inhibitor therapy in patients without COPD is experimental (Chen et al, 2007).  The assessment found no evidence evaluating the use of alpha-1 antitrypsin inhibitor therapy in patients with AAT deficiency and no lung function impairment.

On July 1, 2010, Kamada, Ltd., (Beit Kama, Israel) received approval from the Food and Drug Administration for manufacturing Glassia (alpha-1-proteinase inhibitor [human]), which is an intravenously administered biologic product indicated for chronic augmentation and maintenance therapy in individuals with emphysema due to congenital deficiency of alpha-1-proteinase inhibitor, also known as AAT deficiency.

Inhaled Human Alpha-1 Antitrypsin Therapy

Franciosi et al (2015) stated that alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition characterized by low circulating levels of AAT.  Significant work has been performed in the development of AAT augmentation therapy for AATD.  While the majority of this activity has focused on intravenous (i.v.) augmentation, evidence of a significant clinical benefit is still debated and i.v. therapy is expensive, onerous and time consuming.  Inhalation therapy offers the opportunity for easier and more efficient delivery of AAT directly to the lungs with some evidence of a reduction in local inflammatory and proteolytic activity, potentially offering an alternative therapeutic option to the i.v. route.  There are, however, theoretical obstacles to the potential effectiveness of aerosol-delivered AAT and although there have been a number of short-term studies examining inhaled AAT and its effect on lung inflammation, there has only been 1 long-term study to date in AATD looking at clinical outcomes, which is as yet unpublished.

Gaggar et al (2015) noted that inhaled alpha-1 proteinase inhibitor (PI) is known to reduce neutrophil elastase burden in some patients with cystic fibrosis (CF).  In a phase IIa, randomized, double-blind, placebo-controlled study, these researchers tested inhaled Aapha-1 HC, a new aerosolized alpha1-PI formulation, in CF patients.  These investigators evaluated the safety of 100 or 200 mg of inhaled Alpha-1 HC once-daily for 3 weeks in subjects with CF.  A total of 30 adult subjects were randomized in a 2:1 ratio to receive alpha-1 HC or placebo.  Drug delivery was confirmed by a dose-dependent increase in the sputum alpha1-PI; 7 (20.0 %) of the 35 adverse events in the 100-mg dose group, 3 (13.0 %) of 23 in the 200-mg dose group, and 4 (14.3 %) of 28 in the placebo group were drug-related in these subjects.  One serious adverse event occurred in 1 subject within each group.  The authors concluded that alpha-1 HC inhalation was safe and well-tolerated.  However, the effectiveness of inhaled alpha-1 antitrypsin therapy has yet to be established.

Alpha-1 Antitrypsin Deficiency Gene Therapy

Guo et al (2014) noted that AAT is a serum protease inhibitor that belongs to the serpin superfamily.  Mutations in AAT are associated with AATD, a rare genetic disease with 2 distinct manifestations: AATD lung disease and AATD liver disease.  The former is caused by loss-of-function of AAT and can be treated with plasma-derived AAT; the latter is due to the aggregation and retention of mutant AAT protein in the liver.  The only treatment available for AATD liver disease is liver transplantation.  These researchers demonstrated that anti-sense oligonucleotides (ASOs) targeting human AAT efficiently reduced levels of both short and long human AAT transcript in-vitro and in transgenic mice, providing a novel therapy for AATD liver disease.  In addition, ASO-mediated depletion of mouse AAT may offer a useful animal model for the investigation of AATD lung disease.

Wozniak et al (2015) stated that a number of identified mutations in the SERPINA1 gene encoding this protein result in AATD.  A decrease in AAT serum concentration or reduced biological activity causes considerable risk of chronic respiratory and liver disorders.  As a monogenic disease, AATD appears to be an attractive target for gene therapy, particularly for patients with pulmonary dysfunction, where augmentation of functional AAT levels in plasma might slow down respiratory disease development.  The short AAT coding sequence and its activity in the extracellular matrix would enable an increase in systemic serum AAT production by cellular secretion.  In-vitro and in-vivo experimental AAT gene transfer with gamma-retroviral, lentiviral, adenoviral, and adeno-associated viral (AAV) vectors has resulted in enhanced AAT serum levels and a promising safety profile.  Human clinical trials using intramuscular viral transfer with AAV1 and AAV2 vectors of the AAT gene demonstrated its safety, but did not achieve a protective level of AAT greater than 11 μM in serum.  These researchers provided an in-depth critical analysis of current progress in AATD gene therapy based on viral gene transfer.  The factors affecting transgene expression levels, such as site of administration, dose and type of vector, and activity of the immune system, were discussed further as crucial variables for optimizing the clinical effectiveness of gene therapy in AATD subjects.

Appendix

Note: Prolastin-C is a more purified and concentrated form of alpha1-antitrypsin (AAT) that may be infused over a shorter period of time than Prolastin (15 minutes on average).

Aralast NP is a similar product to Aralast (now off the market), containing the same active components of plasma alpha1 –proteinase inhibitor with identical formulations. However, Aralast NP should be stored at room temperature, not to exceed 25°C (77°F). Refrigeration is not needed.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes not covered for indications listed in the CPB:
38204 Management of recipient hematopoietic progenitor cell donor search and cell acquisition [ alpha-1 antitrypsin deficiency gene therapy]
Other CPT codes related to the CPB:
82103 Alpha-1-antitrypsin; total
82104      phenotype
HCPCS codes covered if selection criteria are met:
J0256 Injection, alpha 1 - proteinase inhibitor - (human), not otherwise specified, 10 mg[Aralast NP Prolastin-C]
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
ICD-10 codes covered if selection criteria are met:
J43.1 Panlobular emphysema [panacinar emphysema]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D80.2 Selective deficiency of immunoglobulin A [IgA deficient with IgA antibodies]
E84.0 - E84.9 Cystic fibrosis
F17.200 - F17.299 Nicotine dependence [member must be nonsmoker]


The above policy is based on the following references:
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    3. MacDonald JL, Johnson CE. Pathophysiology and treatment of alpha 1-antitrypsin deficiency. Am J Health Syst Pharm. 1995;52(5):481-489.
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    5. Canadian Thoracic Society. Current status of alpha-1-antitrypsin replacement therapy: Recommendation for the management of patients with severe hereditary deficiency. Ad Hoc Committee on alpha-1-antitrypsin replacement therapy of the Standards Committee, Canadian Thoracic Society. CMAJ. 1992;146(6):841-844.
    6. Stoller JK. Augmentation therapy for severe alpha 1-antitrypsin deficiency: Is the jury still out on a trial? Thorax. 1998;53(12):1007-1009.
    7. Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. Am J Respir Crit Care Med. 1998;158(1):49-59.
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    22. No authors listed. What is the pathophysiology, epidemiology and treatment of alpha-1 antitrypsin deficiency? What tests are required to make the diagnosis? ATTRACT Database. Gwent, Wales, UK: National Health Service; December 18, 2002. Available at:http://www.attract.wales.nhs.uk/question_answers.cfm?question_id=1066. Accessed February 15, 2006.
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