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Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18 Page 7 of 12

Another strategy to control excessive proteinase activity would be to give SLPI, a proteinase inhibitor
[20]
already enriched in airway secretions produced locally by bronchoepithelial cells . SLPI also inactivates
[61]
neutrophil elastase via direct 1:1 inhibition and can additionally inhibit elastin-bound neutrophil elastase
which is AAT-resistant [21,62] . SLPI levels in sputum or epithelial lining fluids are, however, influenced by
local neutrophil elastase falling during inflammation [61,63] . This is also a feature of AATD as significantly
lower levels of SLPI are present in the sputum of such individuals, likely a result of the increased local serine
proteinase activity and hence forming a potentiating inflammatory proteinase-rich loop.
[36]

SLPI has been given by inhalation for other conditions with excessive airway neutrophilic inflammation
(such as in cystic fibrosis) showing an antiproteinase effect , but again in AATD where proteinase burden
[64]
is high, a high concentration of SLPI will also have to reach the distal airways and penetrate into the
[22]
interstitium. Furthermore, SLPI has no inhibitory activity on Proteinase 3 and Proteinase 3 also degrades
SLPI , suggesting that SLPI may be less appropriate, especially as Proteinase 3 potentially has a major or
[65]
even greater impact on driving disease progression than neutrophil elastase.

Neutrophil elastase inhibitors
Reagents (especially oral ones) capable of direct inhibition of neutrophil elastase would be a strong potential
strategy based on the current understanding of elastase being a key direct mediator of emphysema and
disease progression in AATD. Neutrophil elastase also orchestrates a series of proinflammatory responses,
including cleavage activation of metalloproteinases , inducing the release of danger signals , and
[67]
[66]
[69]
stimulating aberrant growth factor release as well as impairing lung host defence mechanisms . Thus, in
[68]
addition to directly suppressing elastolysis, inhibiting neutrophil elastase could also prevent amplification of
the inflammatory response and improve host defences.
[70]
AZD9668 is described as a potent selective inhibitor of neutrophil elastase . Though the exact mechanism
of action is currently unpublished, in vitro studies of AZD9668 successfully reduced plasma neutrophil
elastase activity following whole blood stimulation by inhibiting both membrane-bound and liberated
neutrophil elastase . The disease-modifying potential of AZD9668 was validated in rodent models as oral
[70]
[70]
administration of the drug attenuated systemic inflammation and neutrophil elastase-induced injury .
Furthermore, it was recently announced that oral administration of AZD9668 (Alvelestat or MPH966)
successfully suppressed plasma evidence of neutrophil elastase activity in a phase 2 study in patients with Z
AATD, demonstrating a progressive decline in the systemic fibrinogen biomarker of neutrophil elastase
[71]
activity (AaVal360) in the high-dose treatment arm . However, any effect on clinical outcomes has yet to
be reported.

Modulation of neutrophils
Neutrophil chemotaxis
AAT-deficient neutrophils appeared to be inherently primed. When compared to healthy neutrophils, more
AAT-deficient neutrophils spontaneously adhered to the endothelium and displayed enhanced
[72]
chemotactic response toward the chemoattractants LTB4 and CXCL8 which are abundant in the AATD
lung . The high chemoattractant burden, increasing neutrophil influx to the lung, and the resultant tissue
[43]
damage suggest that modulating neutrophil migration to attenuate neutrophil-driven inflammatory effects
could be advantageous. In the inflamed lung milieu, where a multiplicity of chemoattractants are present,
chemokine receptor blockade offers an alternative approach to modulating elastase-mediated tissue damage.

CXCR2 is a membrane chemokine receptor expressed on neutrophils involved in regulating neutrophil
chemotaxis. Preclinical studies investigating CXCR2 antagonism successfully prevented CXCL8-mediated
chemotaxis . The effect of CXCR2 blockade was also shown in a phase 2 trial with 615 COPD patients
[73]