Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency

Abstract

Alpha-1 antitrypsin deficiency (AATD) is associated with premature onset of emphysema resulting from low serum A 1 -PI levels. The only available pharmacological treatment affecting the underlying cause of AATD is A 1 -PI therapy. AATD-related emphysema is considered a good model to study disease-modifying effects of treatment as the causative process has been identified. Disease modification is a sustained improvement in disease state following therapeutic intervention that persists when therapy is discontinued. Appropriate trial design and the use of valid study endpoints are key to illustrating disease modification, particularly in clinical trials of rare diseases where it can be difficult to recruit sufficient numbers of patients. Delayed-start trials are advantageous ethically as all patients ultimately receive active treatment and imaging techniques have proven promising as valid study endpoints. Specifically, computed tomography (CT) measured lung density has been used to monitor emphysema and is considered a more sensitive outcome than pulmonary function tests to monitor disease progression. This review will discuss the importance of clinical endpoints and trial design to determine disease modification and will review the evidence for disease modification in AATD-related emphysema. Until recently, clinical studies have not shown a significant effect of A 1 -PI therapy, possibly due to insufficient numbers of patients, short duration of clinical trials and lack of appropriate trial design. A recently completed randomised trial and open-label extension study followed a larger study population for a longer duration and incorporated a delayed-start design. The results demonstrated clinical efficacy of A 1 -PI therapy and indicate that treatment is disease-modifying.

Advances in managing COPD related to α1‐antitrypsin deficiency: An under‐recognized genetic disorder

“…Most patients continued into the 2‐year RAPID open‐label extension trial, in which all patients were treated with active therapy; thus, the patients formed two groups: early‐start (4 years of active treatment) and delayed‐start (2 years of placebo followed by 2 years of active treatment). In both RAPID trials, the loss of lung parenchyma was statistically significantly slowed by approximately 34% in individuals treated with AAT, as ascertained by CT‐measured lung density at total lung capacity . The RAPID trials support the efficacy of augmentation therapy in slowing disease progression during 4 years of treatment and, as lost lung density during placebo treatment never recovered following augmentation therapy in the delayed‐start group, the trials highlight the importance of early initiation of augmentation therapy (Figure ).…”

Does urinary peptide content differ between COPD patients with and without inherited alpha1-antitrypsin deficiency?

“…To remove higher molecular mass proteins, such as albumin and immunoglobulin G, each sample was ultrafiltered using a Centrisart ultracentrifugation filter device (20 kDa cutoff Vivaspin; Sartorius, Goettingen, Germany) at 3,000× g until 1.1 mL of filtrate was obtained. To remove urea, electrolytes and salts and to enrich polypeptides, the filtrate was then applied to a PD-10 desalting column (GE Healthcare BioSciences AB, Uppsala, Sweden) equilibrated with 0.01% NH 4 OH in high-performance liquid chromatography grade water (Roth, Bavaria, Germany). Finally, the samples were lyophilized and stored at 4°C.…”

“…3 A fraction of patients with COPD has inherited PiZZ (Glu342Lys) alpha-1 antitrypsin deficiency (A1ATD), a major genetic determinant influencing the development of early-onset COPD with emphysema, especially in cigarette smokers. 4 The identification of biomarkers that can distinguish between A1ATD-PiZZ and non-A1ATD-PiMM COPD phenotypes could improve our understanding of the disease-driving mechanisms.…”

Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence

“…[45] The program consisted of the 2-year, randomized, double-blind, placebo-controlled study (RAPID-RCT) followed by the 2-year open-label extension study (RAPID-OLE). The primary endpoint was annual rate of decrease in lung density as assessed by adjusted PD15.…”