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

Abstract

IntroductionAlpha-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 coveredWe 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 is described where relevant, particularly where progression to trials appears likely. Expert opinionClinical 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.

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: Initial report of EARCO

“…Whether this leads to different management to nonde cient Bx patients requires much more individual characterisation including bacterial colonisation, airways neutrophilia (and serine proteinase activity), as well as exacerbation history. Whereas this is important in all patients with exacerbations the presence of AATD will likely have an increased in ammatory load ( 12) amenable (at least in part) to AAT augmentation intravenously (13), by the inhaled route (20) or with more recent oral antiproteinase strategies in development (21).…”

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO

“…Whether this leads to different management to non-deficient Bx patients requires much more individual characterisation including bacterial colonisation, airways neutrophilia (and serine proteinase activity), as well as exacerbation history. Whereas this is important in all patients with exacerbations the presence of AATD will likely have an increased inflammatory load [ 12 ] amenable (at least in part) to AAT augmentation intravenously [ 13 ], by the inhaled route [ 20 ] or with more recent oral antiproteinase strategies in development [ 21 ].…”

<p>Obstacles to Early Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency: Current Perspectives</p>

“…Indeed many studies of alternative strategies are under way, which have been reviewed elsewhere. 66 Many of the trials of alternative lung directed therapies are recruiting patients in earlier stages of disease than augmentation is typically used; specific subgroup analyses by disease stage may be of interest in order to determine which treatments should/could be used at each stage. Table 4 summarizes currently recruiting studies and the severity stages applicable.…”

“…Whilst these new treatments have been reviewed extensively, 66 it is worth considering them briefly here for their potential in early disease. A synthetic recombinant AAT (rAAT) fused with another molecule to reduce any immune reactions with non-human proteins is being investigated in a dose-escalating Phase I trial; this would have similar limitations to augmentation in that it requires intravenous infusions, which might not be popular with relatively asymptomatic patients, although the frequency is likely to be less, which may be helpful.…”