Exploring the Landscape of Clinical Research in AATD: A Cross-Sectional Review of Registered Studies in ClinicalTrials.gov, Clinicaltrialsregister.eu, and WHO ICTRP

Background: Since the approval of human alpha-1 proteinase inhibitor in 1987 for treating alpha-1 antitrypsin deficiency (AATD)-related emphysema, no new targeted therapies have been authorized for this condition. Notably, effective treatments addressing the extrapulmonary manifestations of AATD remain lacking. This review provides a comprehensive overview of the current landscape and progress in clinical development for AATD therapies. Methods: A comprehensive search of all registered trials was performed on 26 March 2025 across the web-based databases of ClinicalTrials.gov, Clinical Trials Register Europe, and the World Health Organization International Clinical Trials Registry Platform. Results: A total of 147 studies were identified. Of these, 112 (76.2%) were interventional studies and 35 (23.8%) were observational studies. The planned enrollment in the interventional studies was with a mean of 69.5 participants. The pharmaceutical industry (57%) was the main source of financial support for these studies. The most prominent study locations were North America (51.7%) and Europe (42.9%), followed by Australia and Oceania (16.3%). Clinical research on AATD treatments includes human and recombinant protein therapies delivered intravenously, inhalatively or subcutaneously, as well as gene- and RNA-based therapies. Additional approaches, such as folding correctors and neutrophil elastase inhibitors, are under investigation. Currently, RNA interference therapeutics and inhaled AAT proteins are the most advanced, with Phase 3 trials ongoing. Conclusion: The development of novel therapies holds promise to broaden treatment options for AATD patients, targeting both pulmonary and extrapulmonary manifestations. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany