Despite Challenges, New Treatments Abound for AAT Deficiency

With two new treatments available, earlier diagnosis of alpha1-antitrypsin deficiency won’t leave patients breathless for too long.

With two new treatments available, earlier diagnosis of alpha1-antitrypsin deficiency won’t leave patients breathless for too long.

Alpha1-antitrypsin (AAT) deficiency, a rare genetic disorder characterized by reduced serum levels of the enzyme AAT, causes a variety of conditions within humans including emphysema, COPD, bronchiectasis, chronic bronchitis, cirrhosis, neonatal hepatitis and jaundice, and rarely, necrotizing panniculitis.

Although the condition was first described in the 1960s by Swedish investigators, a treatment was not commercially available until 1988, when the FDA approved Prolastin, an AAT enzyme marketed by Bayer Healthcare.

Nearly 15 years after Bayer’s release of Prolastin, two other manufacturers developed processes that eventually led to the FDA approval of Aralast, manufactured by Baxter, in mid-2003 and Zemaira, manufactured by Aventis, in late 2003.

Developing AAT is a challenge

While other recombinant proteins have been created and marketed (think Kogenate, Humira, Amevive, Raptiva, Enbrel, Remicade, and others), no such manufacturing process has been developed for alpha1-antitrypsin. This protein is a challenge to create in a laboratory, as it is a 394-length, single-chain polypeptide amino acid with three carbohydrate side chains. To put this into perspective, this is about 8 times the length of insulin.

Since AAT is a human plasma-derived protein, extensive attention has been paid to mitigate against inadvertent viral or prion transmission from donor to recipient. Ensuring safety starts with rigorous screening of plasma donors and extensive screening for known pathogens. In fact, once a plasma donation is received, it is stored until the next plasma donation from the same donor is screened, thus helping to avoid the passage of a pathogen from a donor during a presymptomatic period. In addition, a complex series of steps is carried out under FDA oversight to remove or destroy viruses. Beyond that, several steps in the cleansing process are aimed at destroying or removing prions, i.e., transmissible spongiform encephalopathies such as mad cow disease.

Barely meeting existing demand

The new sources of AAT are heralded as a great advancement for AAT patients (the manufacturers report that fewer than 3,000 Americans are actually receiving treatment). Thus there appears to be a great deal of underdiagnosing and undertreatment in the U.S., with only 1 in 30 people with AAT deficiency actually being diagnosed. Even so, the AAT produced by Bayer was barely meeting the existing demand.

Under normal conditions, neutrophil elastase, a protease that works as a secondary defense mechanism, destroys invading proteins, thus helping to protect the lungs and other organs against infections and inflammation. Produced daily by the liver and found in the blood, AAT is the most abundant protease inhibitor found in the body.

In addition, AAT is an acute-phase reactant protein. Interleukin-6 causes induction of synthesis of AAT leading to a higher AAT serum concentration during infections, burns, inflammatory disorders, and some malignancies. But, being a protease, an enzyme that destroys proteins, neutrophil elastase can also damage healthy lung tissue proteins if left unchecked. AAT keeps the fine balance between having too much and just enough neutrophil elastase. Any tip one way or another results in the varied problems associated with the deficiency of functional AAT.

Left unchecked, neutrophil elastase destroys elastin, a protein that maintains the elasticity of the lungs, causing enlargement of the airways and alveoli with or without fibrosis. These are the hallmark signs of emphysema.

The AAT allele is a dominant allele, meaning only a single normal version of the gene is needed to prevent disease. Therefore, a person suffering from the disease must have inherited two abnormal alleles at the AAT locus. It is thought that nearly 100,000 people in the United States are genetically endowed with a pair of abnormal genes that cause the abnormal production or deficiency of alpha1-antitrypsin. There are several types of abnormal expressions of the gene.

DNA mutations within the gene or within the DNA that gives orders to the ATT gene can result in decreased gene expression, decreased RNA translation or decreased messenger RNA intracellular processing and result in little or no release of the enzyme.

An underdiagnosed condition

Because the symptoms mimic other diseases, most people with AAT deficiency are not aware of it. Some people with a relatively small deficiency have no clinical manifestations. The most predominant manifestation is chronic obstructive lung disease (COPD), often accompanied by panacinar emphysema. This type of COPD can occur in nonsmokers and often appears in a person’s third and fourth decade of life. The risk of developing COPD is enhanced by smoking and typically develops decades earlier than in AAT-deficient patients who are nonsmokers. It is thought that smoking causes increased numbers of inflammatory cells in the lungs, thus increasing neutrophil elastase. Another is that products of cigarette smoke may actually oxidize AAT directly, decreasing the level of AAT in those with already low levels of the enzyme further.

Testing people with suspected AAT deficiency requires a simple finger-stick test, similar to the heel stick testing of newborns. If the AAT concentration is low, typically less than 10-15 percent of normal, further testing is done to determine the exact phenotype of the individual. More than 75 different variants of the gene have been described. The abnormal genes are most common in Caucasians of northern European decent. The frequency varies from 1 in 2,000 people to 1 in 7,000 in various studies, similar to the prevalence of cystic fibrosis. Phenotyping is especially important for those people planning to have children and for family members of people suffering from AAT deficiency, to detect the silent carrier state.

Managed care’s role

AAT augmentation in those with proven AAT deficiency is administered by IV infusion once weekly and has been shown to produce a significant reduction in five-year mortality. In those patients with initial FEV1 values between 35 and 49 percent of predicted, AAT augmentation also slowed the lung function deterioration. This protein is of no use in COPD patients without AAT deficiency.

As far as managed care is concerned, expect to see more emphasis placed upon earlier diagnosis of AAT deficiency. Also, since the supply, even with the two new entrants, will be limited, prices are unlikely to decrease in the long term. But more Americans will be able to benefit from the increased availability.

And hopefully, Tomorrow’s Medicine will bring news of production of a recombinant product or gene therapy to improve the lives of those people suffering from this devastating genetic disorder.

Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 19 years of managed care experience at the payer or health plan level.

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