Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Abstract

Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

Keywords: alpha1 antitrypsin deficiency; augmentation therapy; rare diseases; replacement therapy.

Figure 1

Diagram indicating alpha1 antitrypsin in plasma from normal individuals diffusing across the alveolar capillary endothelial barrier into the interstitium. AAT, Alpha1 antitrypsin; ELF, epithelial lining fluid. The sizes of the vascular, interstitial, and alveolar compartments are not to scale, for educational purposes.

Figure 2

Initial study evaluating the biochemical efficacy of AAT augmentation therapy. Reproduced with permission from Reference [6]. (A) The response of serum al-antitrypsin levels to the infusion of 4.0 g of AAT. (B) Serum neutrophil elastase inhibitory activity following weekly intravenous infusions of 4.0 g of AAT. (C) Lower respiratory tract al-antitrypsin levels during intravenous replacement therapy with 4.0 g of AAT. (D) Lower respiratory tract neutrophil elastase inhibitory activity following weekly intravenous infusions of 4.0 g of AAT.

Figure 3

Purified A1AT reduces SERPINA1 expression in a dose-dependent manner in primary human hepatocytes. Exogenously added purified AAT reduced SERPINA1 expression in primary human hepatocytes isolated from both proficient and deficient liver tissue. The reduction was more prominent following Oncostatin M (OSM 10 ng/mL) stimulation, known to increase expression of SERPINA1. *, P < 0.05; **, P < 0.001; ***, P < 0.001; ****, P < 0.0001). © 2017 Karadagi, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Obtained from Reference [44].

Figure 4

Temporal distribution of the years of approval of augmentative AAT treatments in the USA (upper) and Europe and European countries, with their own presentation (lower). In red: year of initial official approval. In blue: year when company changed. LFB, Laboratoire français du fractionnement et des biotechnologies.

Figure 5

List of studies evaluating biochemical efficacy by type of preparation.

Figure 6

Total number of pulmonary exacerbations per month in the 19 patients in Ireland receiving AAT augmentation therapy for AAT deficiency–associated emphysema during the year before the study (black line) and during the withdrawal period (red line), as reported in the original article. Reproduced with permission from Reference [54]. On the right, we have added (dashed line) two possible hypothetical changes that the curve could have had if the patients had been followed longer, with two possibilities: curve A, with a persistent increase of exacerbations risk, and curve B, with a transient increase in the exacerbation risk. COPD, chronic obstructive pulmonary disease.