Medical Policy



Subject: Alpha-1 Proteinase Inhibitor Therapy
Document #: DRUG.00072 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses indications for the use of alpha-1 proteinase inhibitors as therapy for individuals with a deficiency of alpha-1 antitrypsin (AAT). Alpha-1 proteinase inhibitors approved by the U.S. Food & Drug Administration (FDA) include: Aralast NP (Baxter Healthcare, Westlake Village, CA), Glassia® (Baxter Healthcare, Westlake Village, CA), Prolastin-C® (Talecris Biotherapeutics, Inc., Research Triangle Park, NC) and Zemaira® (CSL Behring, LLC, Kankakee, IL).

Position Statement

Medically Necessary:

Augmentation therapy with intravenous alpha-1 proteinase inhibitors is considered medically necessary for adults with congenital alpha-1 antitrypsin deficiency when all of the following criteria are met:

  1. Documented alpha-1 antitrypsin level is less than or equal to 11 µmol/L*; and
  2. Individual is currently a non-smoker; and
  3. Individual has clinically evident emphysema; and
  4. One of the following:
    1. Moderate airflow obstruction is evidenced by forced expiratory volume (FEV1 ) of 30-65% of predicted value, prior to initiation of therapy; or
    2. Individual has a rapid decline in lung function as measured by a change in FEV1 greater than 120 ml/year.

*Note: Serum levels of alpha-1 antitrypsin can be assessed by immunodiffusion, immune turbidimetry, rocket immunoelectrophoresis, or nephelometry. Given the variations in testing modalities, it is essential to know the range of normal values for the test used in a given individual. For example, 11 µmol/L is approximately equivalent to a commercial standard level of 80 mg/dL by immunodiffusion or 57 mg/dL by nephelometry.

Not Medically Necessary:

Use of alpha-1 proteinase inhibitors is considered not medically necessary for individuals with IgA antibodies.

Investigational and Not Medically Necessary:

Use of alpha-1 proteinase inhibitors is considered investigational and not medically necessary when the criteria above are not met and for all other indications including, but not limited to:

  1. Bronchopulmonary dysplasia
  2. Cystic fibrosis
  3. Diabetes mellitus
  4. Graft versus host disease (GVHD)
  5. Post-lung transplantation for acute rejection or infection episodes.
Rationale

Augmentation therapy with alpha-1 proteinase inhibitors is used to treat individuals with congenital AAT deficiency and clinically evident emphysema to slow the progression of the disease. The goal of therapy is to correct the imbalance of neutrophil elastase (NE) by increasing the functional NE proteinase inhibitors to protect the lower respiratory tract. NE is an enzyme which degrades proteins from damaged or aging cells and is normally found in blood serum and the lower respiratory tract. Without sufficient AAT, an excessive level of NE results in progressive degradation of healthy lung tissue, and ultimately emphysema. NE levels increase in the lungs in response to irritants such as infection, and cigarette smoke. A significant risk factor impacting the decline in FEV1 is current smoking. Therefore, use of augmentation therapy is recommended only for individuals who are former or non-smokers. Panacinar (that is, panlobular; involving all lung fields) emphysema is a major cause of disability and mortality for individuals with severe alpha-1 antitrypsin deficiency (AATD) (American Thoracic Society/ European Respiratory Society [ATS/ERS], 2003; Wewers, 2013).

Alpha-1 proteinase inhibitors are derived from pooled human plasma and may contain trace amounts of IgA. Therefore, individuals with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Alpha-1 proteinase inhibitors are contraindicated in individuals with antibodies against IgA due to the risk of severe hypersensitivity (Product Information [PI] Labels 2009, 2010, 2013, 2014).

In a 2003 statement by the ATS/ERS, standards for diagnosis and management of individuals with AATD include:

AAT genotypes that confer an increased risk for developing pulmonary emphysema are those in which deficiency or null alleles are combined in homozygous or heterozygous states, which encode AAT plasma levels below a protective threshold, that is, 11 µmol/L. On the basis of plasma levels and function of AAT, variants are categorized into the following:

Normal: Common M types, accounting for 95% of those found in Caucasian individuals, and characterized by normal plasma levels (more than 20 µmol/L).

Deficiency: Characterized by plasma levels less than 20 µmol/L. Z variant AAT is the commonest deficient variant, with plasma levels among homozygotes of about 5–6 µmol/L, whereas the S variant is more frequent in the Mediterranean area and is associated in homozygotes with plasma levels about 60% of normal. Other, rare, deficient variants are grouped within the terms "M-like" or "S-like" types.

Null: Rare variants associated with no detectable circulating AAT in the plasma.

Dysfunctional: For example, the AAT Pittsburgh converted from an elastase inhibitor to a thrombin inhibitor, or the PI*F variant where the association with elastase is markedly reduced.

The PI*ZZ protein phenotype indicates individuals with a genotype of two deficient alleles and is associated with significantly reduced AAT and an increased risk for panlobular emphysema. According to the Canadian Thoracic Society clinical practice guideline (Marciniuk, 2012), the definition of AATD included the individuals with AAT levels below 11µmol/L and any of the following phenotypes: "Pi*ZZ, Pi*Z (null) and Pi* (null) (null) and other rare phenotypes."

Low levels of AAT alone do not cause emphysema. The ATS/ERS (2003) standards note "Fewer than 60% of individuals with severe AAT deficiency develop significant airflow limitations." In addition, the ATS/ERS (2003) standards did not recommend alpha-1 proteinase inhibitor augmentation therapy for individuals without emphysema, and because the benefits were not clear, did not recommend augmentation therapy for individuals with mild or severe airway obstruction (FEV1 ≥ 50-60% predicted; ≤ 35% predicted, respectively). The authors summarized the available nonrandomized data and noted that, for individuals with moderate obstruction of airflow (for example, FEV1 of 30-65% of the predicted values) and individuals with a rapid decline of lung function (as measured by a change in FEV1 > 120 ml/year) augmentation therapy appeared to improve overall mortality and slowed the progressively declining rate of FEV1 .

For individuals with advanced liver disease and AATD, the ATS/ERS standards (2003) did not recommend use of intravenous augmentation therapy with alpha-1 antiproteinase inhibitors as these agents do not confer any benefit for liver disease. Due to a lack of evidence to support the benefit of augmentation therapy, the ATS/ERS did not make a "firm recommendation" to treat acute episodes of rejection or infection for individuals who had a prior lung transplant.

In a systematic review by Chen and colleagues (2007), the authors concluded that the benefits from augmentation therapy including "…slower progression of lung function impairment, reduced rates of upper respiratory tract infections and prolonged survival…" were derived from nonrandomized and observational studies. The effectiveness of augmentation therapy for individuals with AATD and no impairment of lung function were not reviewed due to a lack of evidence.

Available data for alpha-1 proteinase inhibitor therapy are primarily derived from nonrandomized observational studies, case series and pharmacokinetic studies (Gøtzsche, 2010; PI Labels 2009, 2010, 2013, 2014). Large, randomized controlled trials and efficacy data are lacking. Criteria for augmentation with alpha-1 proteinase inhibitor therapy are based on FDA labeled indications, contraindications, available published data and specialty guideline recommendations.

At this time, there is no cure for AATD. There is an ongoing need for large prospective, randomized controlled trials to clarify the long-term efficacy of augmentation therapy and to better identify the most suitable candidates to benefit from this therapy. Factors that make the study design challenging include, but are not limited to the following: age, smoking status, frequency of augmentation therapy, FEV1 prior to initiating therapy, and accurate phenotyping.

Although recombinant and novel formulations of AAT have orphan designation for treatment of bronchopulmonary dysplasia and cystic fibrosis, the FDA has not conferred marketing approval for the orphan designations. Alpha-1 proteinase inhibitor is currently being studied in an inhaled formulation but has not yet received FDA approval. Additional indications for alpha-1 proteinase inhibitor therapy being investigated include treatment of diabetes mellitus and GVHD. However, the safety and efficacy outcomes from these trials have not been published.

Background/Overview

AATD is a condition that is inherited in an autosomal codominant pattern (that is, two different versions of expressed gene which impact the genetic trait). AAT is produced primarily in the liver and is the major antiprotease that inhibits neutrophil elastase, an enzyme which degrades proteins from damaged or aging cells and bacteria to promote healing of the alveolar walls. Individuals are commonly predisposed to COPD of AAT (ATS/ERS, 2003; Marciniuk, 2012). AATD can also affect the liver cells and cause liver injury and in some cases, liver failure. Individuals are often times not diagnosed with AATD but are commonly diagnosed with asthma, bronchitis, smoking induced emphysema, etc.

Usually, a diagnosis of AAT deficiency relies on laboratory assessment of the individual's serum. Serum levels of AAT can be assessed by immunodiffusion, immune turbidimetry, rocket immunoelectrophoresis, or nephelometry. The different tests have slightly different normal ranges and as a result, the optimal cut-off point for detecting AAT deficiency varies by test (ATS/ERS, 2003).

According to the National Institutes of Health (2013), AATD occurs worldwide with varying prevalence based on population. Approximately 1 in 1500 to 3500 individuals with European ancestry are affected. Severity of AATD is dependent on levels of AAT and the individual's genotype (Stoller, 2014). Many individuals with chronic obstructive pulmonary disease (COPD) may have undiagnosed AATD and may have other diagnoses such as asthma, dyspnea, or increased cough with sputum production (ATS/ERS, 2003; NIH, 2013; Stoller, 2014).

Warnings and Precautions
Warnings, precautions and recommendations from the PI labels (2009, 2010, 2013, 2014) include the following:

Definitions

Augmentation: Addition to improve or complete.

Chronic bronchitis: A condition of constant irritation and inflammation of the linings in the lung that results in thickened lining and thick mucus in the airways that impedes breathing.

Chronic obstructive pulmonary disease (COPD): A progressive lung disease that makes it difficult to breathe. Conditions included in this broad term are emphysema and chronic bronchitis.

Emphysema: A condition where the walls of the air sacs in the lungs are damaged resulting in fewer and larger air sacs instead of many tiny ones which are optimal for efficient air exchange.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met:

HCPCS    
J0256 Injection, alpha 1-proteinase inhibitor (human), not otherwise specified, 10 mg [Aralast NP, Prolastin-C, Zemaira]  
J0257 Injection, alpha 1 proteinase inhibitor (human), (Glassia), 10 mg  
   
ICD-10 Diagnosis  
E88.01 Alpha-1-antitrypsin deficiency
J43.0-J43.9 Emphysema

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed for those situations described in the Position Statement as not medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

 Peer Reviewed Publications:

  1. Campos MA, Kueppers F, Stocks JM, et al. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK). COPD. 2013; 10(6):687-695.
  2. Chapman KR, Stockley RA, Dawkins C, et al. Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD. 2009; 6(3):177-184.
  3. de Serres FJ, Blanco I, Fernández-Bustillo E. Estimating the risk for alpha-1 antitrypsin deficiency among COPD patients: evidence supporting targeted screening. COPD. 2006; 3(3):133-139.
  4. Gaggar A, Chen J, Chmiel JF, et al. Inhaled alpha1-proteinase inhibitor therapy in patients with cystic fibrosis. J Cyst Fibros. 2016; 15(2):227-233.
  5. Hersh CP, Dahl M, Ly NP, et al. Chronic obstructive pulmonary disease in alpha 1-antitrypsin PI MZ heterozygotes: a meta-analysis. N Engl J Med. 2004; 59(10):843-849.
  6. Parr DG, Dirksen A, Piitulainen E, et al. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency. Respir Res. 2009; 10:75.
  7. Parr DG, Guest PG, Reynolds JH, et al. Prevalence and impact of bronchiectasis in α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2007; 176(12):1215-1221.
  8. Sandhaus RA, Stocks J, Rouhani FN, et al. Biochemical efficacy and safety of a new, ready-to-use, liquid alpha-1-proteinase inhibitor, GLASSIA (alpha1-proteinase inhibitor (human), intravenous). COPD. 2014; 11(1):17-25.
  9. Stockley RA, Parr DG, Piitulainen E, et al. Therapeutic efficacy of α-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res. 2010; 11:136.
  10. Stocks JM, Brantly ML, Wang-Smith L, et al. Pharmacokinetic comparability of Prolastin-C to Prolastin in alpha 1-antitrypsin deficiency: a randomized study. BMC Clin Pharmacol. 2010; 10:13.
  11. The Alpha-1 Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of α1-antitrypsin. Am J Respir Crit Care Med. 1998; 158(1):49-59.
  12. Wewers MD, Crystal RG. Alpha-1 antitrypsin augmentation therapy. COPD. 2013; 10 Suppl 1:64-67.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. 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.
  2. Aralast NP (Baxter Healthcare Corp., Westlake Village, CA) Updated September 2016. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a9a5b46e-04da-41bd-bb5f-c4936b664fef . . Accessed on April 04, 2017.
  3. Chen S, Farahati F, Marciniuk D, et al. Human α1-proteinase inhibitor for patients with α1-antitrypsin deficiency [Technology report no 74]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007.
  4. Glassia (Kamada Ltd., Israel; Baxter Healthcare Corp., Westlake Village, CA). Updated June 2016. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83473cbb-48e4-42a2-81b6-4c851423da7b . . Accessed on April 04, 2017.
  5. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2010;(7):CD007851.
  6. Marciniuk DD, Hernandez P, Balter M, et al.; Canadian Thoracic Society COPD Clinical Assembly Alpha-1 Antitrypsin Deficiency Expert Working Group. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012; 19(2):109-116.
  7. Prolastin C [Product Information]. (Talecris Biotherapeutics, Inc., Research Triangle Park, NC) August 2016. Available at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91edab72-c889-470e-8315-1798b5548dca .  Accessed on April 04, 2017.
  8. Russi EW, Karrer W, Brutsche M, et al.; Swiss Respiratory Society. Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society. Respiration. 2013; 85(2):160-174.
  9. Stoller JK, Lacbawan FL, Aboussouan. Alpha-1 antitrypsin deficiency. GeneReviews (online). University of Washington, Seattle. Updated January 19, 2017. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1519/?report=classic. Accessed on April 04, 2017.
  10. Zemaira [Product Information]. (CSL Behring LLC, Kankakee, IL). Updated September 2015. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c3354b5-a1d8-4f98-ad55-2eafe4265c4e .  Accessed on April 04, 2017.
Websites for Additional Information
  1. American Thoracic Society. What Is Alpha-1 Antitrypsin Deficiency? 2014. Available at: https://www.thoracic.org/patients/patient-resources/resources/alpha-1-antitrypsin.pdf . Accessed on April 4, 2017.
  2. National Institutes of Health. What Is Alpha-1 Antitrypsin Deficiency? Reviewed October 11, 2011. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/aat. Accessed on April 04, 2017.
  3. U.S. National Library of Medicine. Genetics Home Reference. Alpha-1 antitrypsin deficiency. Reviewed January 2013. Available at: http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency.  Accessed on April 04, 2017.
Index

Aralast NP
Glassia
Prolastin-C
Zemaira

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated References and Websites sections.
Revised 05/05/2016 MPTAC review. Added a Note to clarify alpha-1 antitrypsin threshold in MN criteria. Updated Background/Overview, References and Websites sections.
Reviewed 02/04/2016 MPTAC review. Updated Description/Scope, Rationale, Background/Overview, Definitions, References and Websites sections. Removed ICD-9 codes from Coding section.
New 02/05/2015 MPTAC review. Initial document development.