Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Kenneth R Chapman, Joanna Chorostowska-Wynimko, A Rembert Koczulla, Ilaria Ferrarotti, Noel G McElvaney, Kenneth R Chapman, Joanna Chorostowska-Wynimko, A Rembert Koczulla, Ilaria Ferrarotti, Noel G McElvaney

Abstract

Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

Keywords: alpha 1 antitrypsin deficiency; computed tomography; efficacy; emphysema.

Conflict of interest statement

Disclosure Professor McElvaney reports grants and personal fees from CSL Behring, grants, personal fees and non-financial support from Grifols, outside the submitted work. Professor Chapman reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants from Baxter, grants and personal fees from CSL Behring, grants and personal fees from Grifols, grants from GlaxoSmithKline, grants and personal fees from Sanofi, grants and personal fees from Genentech, grants and personal fees from Kamada, grants from Amgen, grants and personal fees from Roche, grants and personal fees from Novartis, personal fees from Merck and personal fees from CIHR-GSK Research Chair in Respiratory Health Care Delivery, UHN, during the conduct of the study. Professor Koczulla reports personal fees from CSL Behring, outside the submitted work. Dr Ferrarotti reports personal fees from CSL Behring, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study design of the RAPID-RCT and RAPID-OLE trials employing lung density measures by CT scans at 0, 3, 12, 21, 24, 36 and 48 months. Abbreviations: AAT, alpha 1 antitrypsin; CT, computed tomography; IV, intravenous; OLE, open-label extension; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial.
Figure 2
Figure 2
Annualized rate of decline in physiologically adjusted P15 lung density (g/L) at TLC over 48 months. Notes: Slopes estimated based on data acquired from Early-Start (N=75) and Delayed-Start (N=64) subjects who had completed both RAPID-RCT and RAPID-OLE trials. Reproduced from The Lancet Respiratory Medicine, Vol 5. McElvaney NG, et al. Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE), pp. 51–60. Copyright (2017), with permission from Elsevier. Abbreviations: AAT, alpha 1 antitrypsin; adjusted P15, lung volume-adjusted 15th percentile of the lung density; OLE, open-label extension; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial; TLC, total lung capacity.
Figure 3
Figure 3
Change in clinical outcome measures after administration of a disease-modifying therapy. Notes: Reproduced with permission from Taylor & Francis. The Version of Scholarly Record of this Article is published in COPD: Journal of Chronic Obstructive Pulmonary Disease (2016), available online at: http://www.tandfonline.com/10.1080/15412555.2016.1178224. This article was distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives license. Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency, COPD: Journal of Chronic Obstructive Pulmonary Disease, Chorostowska-Wynimko J, Vol 13, pp. 807–815, published online: 12 May 2016, http://www.tandfonline.com reprinted by permission of the publisher.
Figure 4
Figure 4
Extrapolation of the effect of AAT replacement therapy on the predicted time to reach terminal respiratory function in RAPID-RCT. Notes: Reproduced from The Lancet Respiratory Medicine, Vol 5. McElvaney NG, et al. Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE), pp. 51–60. Copyright (2017), with permission from Elsevier. Abbreviations: AAT, alpha 1 antitrypsin; RAPID, Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency; RCT, randomized controlled trial.
Figure 5
Figure 5
ACSM exercise recommendations for pulmonary rehabilitation. Abbreviation: ACSM, American College of Sports Medicine.

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