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 median actual enrollment in interventional studies was 33 participants, compared with a median planned enrollment of 55 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 Oceania (16.3%). Clinical research on AATD treatments includes human and recombinant protein therapies delivered intravenously, by inhalation or subcutaneously, as well as gene- and RNA-based therapies. Additional approaches, such as AAT protein folding correctors and neutrophil elastase inhibitors, are under investigation. Currently, RNA interference therapeutics are the most advanced therapeutic approach, with Phase 3 clinical trials ongoing. Conclusion The development of novel therapies holds promise to broaden treatment options for patients with AATD, targeting both pulmonary and extrapulmonary manifestations. Clinical trial number Not applicable