The efficacy and safety of inhaled human α-1 antitrypsin in people with α-1 antitrypsin deficiency-related emphysema

Abstract

α-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition characterized by low circulating levels of α-1 antitrypsin (AAT), a serine protease inhibitor. Significant work has been carried out in the development of AAT augmentation therapy for AATD. While the majority of this activity has focused on intravenous (iv.) augmentation, evidence of a significant clinical benefit is still debated and iv. 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 iv. route. There are, however, theoretical obstacles to the potential efficacy 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inflammation, there has only been one long-term study to date in AATD looking at clinical outcomes, which is as yet unpublished.

Keywords:

• aerosolized
• α-1 antitrypsin
• augmentation
• emphysema
• inhaled

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The use of intravenous alpha-1 antitrypsin (AAT) augmentation is expensive and costly and significant clinical effectiveness is still debated.

• Aerosolized AAT can elevate AAT levels in the alveolar compartment of the lung to above normal levels and restore the anti-neutrophil elastase capacity.

• There is evidence in both animals and humans that aerosolized AAT can augment the anti-protease defenses in the interstitium of the lung albeit to a limited degree.

• Aerosolized plasma-purified AAT appears to be well tolerated and safe in patients over the short term.

• The delivery of AAT to the alveolar compartment via nebulization is possible even in individuals with compromised lung function.

• It is still unclear what doses of AAT need to be delivered to the lung compartments to prevent progression of emphysema. It should be noted that this is also a problem with iv. AAT augmentation therapy, although in the case of iv. therapy there is an epidemiological-based rationale for the iv. doses chosen.

• The potential of aerosolized AAT lies in its cost–effectiveness and in its ease of delivery. The future is unclear, however, as to date no randomized controlled trial has shown a significant effect of aerosolized AAT upon clinical variables such as forced expiratory volume in 1 s, exacerbation rates or computed tomography lung densitometry in alpha-1 antitrypsin deficiency.