HPE Alpha 1 Antitrypsin Deficiency - Page 16

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