TREATMENT
Evidence for AATD treatment
Key clinical trials have demonstrated a disease-modifying effect of therapy in AATD-related
pulmonary emphysema
Joanna Chorostowska-
Wynimko MD PhD
Pawel Kuca MD PhD
National Institute of
Tuberculosis and Lung
Diseases, Warsaw, Poland
Alpha 1 Antitrypsin (AAT) plays a key role in
maintaining the protease–anti-protease
balance in vivo. As a central component of the
anti-elastase defence, it protects the connective
tissue of the lungs from the uncontrolled,
destructive effects of proteolytic enzymes produced
mainly by neutrophils. 1 A low level of AAT in the
circulation reflected in the respiratory system leads
to a gradual and irreversible reduction of lung
elasticity. Due to excessive activity of neutrophil
elastase, elastin, the main component of elastic
fibres in the lower respiratory tract, as well as other
components of the extracellular matrix, are degraded.
This process is exacerbated in the presence of
any inhaled noxious gases or particles, but
particularly tobacco smoke. It contains a variety
of irritants that cause the influx of activated
neutrophils and macrophages to the lungs.
Also smoking exacerbates oxidative stress in
the respiratory system that further inactivates
circulating AAT. Therefore, an additional burden of
exposure to irritants proves particularly devastating
to the respiratory system in AAT-deficient subjects
with low serum levels of mutated AAT protein
(below 11mM) characterised by abnormally
low (PiZZ) or no (Pi(null,null)) anti-proteolytic
activity. Consequently, the most common clinical
manifestations of severe AATD are emphysema,
particularly of early onset (before age of 45),
symptomatic chronic obstructive pulmonary disease,
bronchial asthma with incompletely reversible
obstruction and bronchiectasis. 2
Evidence for treatment efficacy
Attempts to introduce specific treatment for patients
with emphysema due to severe AATD were made
as far back as the 1980s. It was demonstrated
BOX 1
EXACTLE study and integrated analysis of EXACTLE
and Danish–Dutch studies
EXACTLE study
• CT lung densitometry demonstrated a trend towards slower emphysema
progression (p=0.068) and fewer severe exacerbations (p=0.013).
• Reduction in lung density decline by 38% was observed in treated patients
versus placebo.
Integrated analysis
• The integrated analysis of EXACTLE and Danish–Dutch trials revealed
a significant effect of treatment on the yearly reduction of lung density assessed
by CT densitometry in AATD-related emphysema (p=0.006).
• Reduction in the lung tissue loss compared with the placebo arm was 36%.
16 | 2019 | hospitalpharmacyeurope.com
that weekly intravenous infusions of AAT protein
purified from healthy donors’ blood was a viable
method to supplement this protein level and activity
not only in peripheral blood but also in epithelial
lining fluid. 3,4
The US AATD registry provided first observational
retrospective data from a large cohort of 1129
patients including treated and untreated with AAT
therapy. The analysis demonstrated significantly
lower relative risk of death in treated subjects
(RR=0.64, p=0.02) and slower rate of lung function
loss represented by forced expiratory volume in
1 second (FEV1) in a subgroup with baseline FEV1
of 31–49% predicted. 5 Analogous conclusions came
from the analysis of the smaller European cohort
(n=195). 6 Yet, subsequent studies (Danish–Dutch 7 and
EXACTLE 8 ) failed to demonstrate clinical efficacy
of AAT substitution versus placebo in patients
with AATD-related emphysema. It was a general
consensus that both were underpowered with 56
and 77 AATD patients, respectively, and not lengthy
enough for the classic randomised, double-arm,
placebo-controlled design. Also, the need for more
sensitive endpoints became very clear as FEV1
proved not optimal to follow slow-progressing
changes in emphysematous lungs. Instead, lung
density quantified using computer tomography (CT)
imaging was proposed as a candidate biomarker as it
is 2.5-fold more sensitive in monitoring progression
of emphysema. Also, both trials reported a clear,
favourable trend on lung density loss in treated
AATD subjects. 9
The RAPID clinical trial included 180 patients
with severe AATD and emphysema with FEV1
between 35% and 70% of predicted treated for two
years with weekly infusions of AAT (60mg/kg) or
placebo. 10 It was followed by a two-year open label
RAPID extension study (RAPID-OLE), with one
arm treated with the standard dose (60mg/kg) of
AAT. 11 The RAPID trial demonstrated a significant
difference in the annual rate of decline in lung
density (0.74g/l; p=0.033) between treated and
placebo arms, which corresponded to a reduction of
34% in the annual rate of lung density decline. The
RAPID-OLE study showed the maintained efficacy
of treatment extrapolated to improved survival,
with an estimated gain of 5.6 life years. It also
demonstrated that switching patients from placebo
to treatment resulted in a reduction in the decline in
lung density (36%). Yet, the loss of normal lung tissue
while on placebo was not regained upon initiation
of treatment. As in previous trials, no significant
effect was seen on other outcome measures, such
as lung function and quality of life. The RAPID and
RAPID-OLE trials demonstrated, for the very first