Alpha 1-antitrypsin (also known as congenital alpha 1-proteinase inhibitor) deficiency is an autosomal, codominant genetic disorder, differentiated by a deficient serum and lung concentrations of alpha 1-antitrypsin. The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous Pi*Z (ZZ). A deficiency in alpha 1-antitrypsin 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 alpha 1-antitrypsin levels less than 35 percent of the average normal. Ninety-five percent of clinically symptomatic alpha 1-antitrypsin deficient individuals are Pi*ZZ phenotype. Individuals with Pi(null)(null) are associated with undetectable serum alpha 1-antitrypsin levels or levels less than one percent of the normal amount. Individuals with these low serum alpha 1-antitrypsin levels have a markedly increased risk of developing emphysema over their lifetime. In addition, Pi*SZ individuals, whose serum alpha 1-antitrypsin levels range from approximately 9 to 23 uM, are considered to have moderately increased risk of developing emphysema.
Alpha-1 Antitrypsin (alpha proteinase inhibitor) is used as a replacement therapy for individuals with severe alpha 1-antitrypsin deficiency and clinical evidence of emphysema. Several biological drugs have been approved by the US Food and Drug Administration (FDA) for alpha 1-antitrypsin therapy, with orphan drug status. Prolastin, Aralast NP, Glassia, and Zemaira were approved by the FDA for the treatment of individuals with alpha 1-antitrypsin deficiency and evidence of emphysema. Prolastin® was replaced by Prolastin-C in spring 2010.
Alpha 1-antitrypsin therapy (e.g., Prolastin-C, Aralast NP, Glassia, Zemaira) uses highly purified human alpha 1-antitrypsin derived from human plasma. Studies comparing alpha 1-antitrypsin preparations involved a limited number of participants with alpha 1-antitrypsin deficiency and emphysema. All preparations produced similar increases in the serum alpha 1-antitrypsin concentration and antigenic alpha 1-antitrypsin 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 Alpha 1-antitrypsin
therapy for individuals with moderate airflow obstruction with a Forced
Expiratory Volume in 1 second (FEV1) that is 30-65 percent 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.