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Page 6 of 12 Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18

Assessment of the clinical efficacy of AAT augmentation therapy is complicated by different study designs
and standard outcome measurements. The longstanding debate concerning the clinical impact of AAT
augmentation therapy was more recently addressed by the European Respiratory Society. A comprehensive
meta-analysis was undertaken and concluded a clinical benefit in reducing emphysema progression assessed
by computed tomographic densitometry and the slowing of lung function decline , although a longer
[50]
study of augmented and non-augmented patients showed no apparent benefit of augmentation as
determined by the decline in FEV . Nevertheless, although the benefit of augmentation on the loss of lung
[51]
1
tissue is now accepted, the progression continues even with this therapy, albeit at a slower rate, suggesting
that other factors are at play .
[52]
Modified AAT forms are also being explored for possible improved stability and better cost-effectiveness.
INBRX-101 (also known as rhAAT-Fc) is a modified AAT that is more resistant to oxidative inactivation .
[53]
Intraperitoneal administration of INBRX-101 in mice was more protective than using pooled plasma AAT
in emphysema induced by elastases (pancreatic porcine elastase and neutrophil elastase) or cigarette
smoke . Recently, the phase 1 trial of intravenous INBRX-101 every three weeks showed that it restored
[54]
functional AAT levels in the plasma of AATD patients, comparable to those of healthy individuals
(40.4 μM), which was sustained over the course of the study period . However, the full results or any
[55]
potential biochemical efficacy have yet to be released . INBRX-101 may be more sustainable than
[55]
traditional AAT augmentation therapy and possibly have a greater effect than conventional plasma-purified
AAT in abrogating disease progression.

ALTERNATIVE STRATEGIES FOR AATD INFUSION
Increase Alpha-1 antitrypsin secretion
Alpha-1 antitrypsin folding drug
In Z AATD, the reduced circulating levels of AAT are not due to a lack of production of AAT, but rather a
result of intracellular Z AAT aggregation impeding secretion into the circulation. Based on this concept,
[56]
drugs such as ZF874 and VX864 were developed to help rescue the misfolding of the Z AAT, thereby
[57]
potentially preventing aggregation and increasing the release of monomeric AAT into the bloodstream and,
thus, partially restoring inhibitory capacity. Phase 2 trials for both drugs have recently been completed.
Results for both drugs are currently undocumented, although details relating to side effects have been
released. It was announced that high-dose treatment of VX864 in patients with Z AATD over 28 days
lowered plasma Z AAT polymers by approximately 90% and the level of functional plasma AAT was
increased. However, the magnitude of this increase was deemed insufficient to protect the lung
[57]
adequately . A 48-week trial is currently underway to assess the long-term effects of VX864 in AATD
patients.

Inhaled therapy
Delivering AAT directly to the airways might have a greater impact on airway inflammation than giving it
intravenously, thereby focussing the distribution in the lung. The direct effect (if any) on emphysema
remains unknown. A randomised controlled trial that assessed the effects of aerosolised AAT over 50 weeks
in AATD patients with severe emphysema did not reduce the time to exacerbation (the primary outcome)
compared to the placebo cohort , although post hoc analysis suggested a benefit on FEV . While inhalation
[58]
1
studies have shown that AAT levels rise in lavage fluid [59,60] , the levels are unlikely to reach the alveolar
region where emphysema occurs and subsequently penetrate through epithelial tight junctions into the
interstitium.