Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency

ABSTRACT

Introduction: Alpha-1 antitrypsin deficiency (AATD) is most often associated with chronic lung disease, early onset emphysema, and liver disease. The standard of care in lung disease due to AATD is alpha-1 antitrypsin augmentation but there are several new and emerging treatment options under investigation for both lung and liver manifestations.

Areas covered: We review therapeutic approaches to lung and liver disease in alpha-1 antitrypsin deficiency (AATD) and the agents in clinical development according to their mode of action. The focus is on products in clinical trials, but data from pre-clinical studies are described where relevant, particularly where progression to trials appears likely.

Expert opinion: Clinical trials directed at lung and liver disease separately are now taking place. Multimodality treatment may be the future, but this could be limited by treatment costs. The next 5–10 years may reveal new guidance on when to use therapeutics for slowing disease progression with personalized treatment regimes coming to the forefront.

KEYWORDS:

• Alpha-1 antitrypsin deficiency
• chronic obstructive pulmonary disease
• emphysema
• cirrhosis
• clinical trials

Article Highlights

• The main pathogenic mechanisms for therapeutic targeting in AATD are protease imbalance in the lung and polymer burden in the liver

• Intravenous AAT augmentation therapy is a viable option to reduce emphysema progression, but there remain uncertainties over optimal patient and dose selection

• Other approaches to address protease imbalance which are in clinical trials include oral neutrophil elastase inhibitors and nebulized hyaluronan

• Approaches to liver disease in clinical trials include siRNA to reduce transcription of mutant protein, and hence polymer formation, as well as carbamazepine to enhance degradation of mutant protein by autophagy

• Specific molecular approaches targeting polymerization of mutant protein are attractive because of potential to treat lung and liver simultaneously but remain at an early stage of development

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Declaration of interest

A Turner has received funding (current or last 3 years) from ATS Foundation, Alpha 1 Foundation, AstraZeneca, Chiesi, CSL Behring and NIHR. Grifols Biotherapeutics and has received personal fees and/or support to attend conferences from Boehringer Ingelheim, CSL Behring, Chiesi, AstraZeneca, Glaxo Smith Kline, Vertex, and pH pharma. The authors have no other 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.