Advances in Orphan Drug Development for Alpha-1 Antitrypsin Deficiency: an update from the FDA and EMA

Background: Research into safe and effective treatments for alpha-1 antitrypsin deficiency (AATD) has been ongoing for more than four decades. There is still a high medical need for better treatment options: Safe, effective, and convenient therapies that target both the lungs and other AATD organ manifestations are eagerly awaited by patients. The purpose of this study is to provide a quantitative clinical-regulatory insight into the current status of the Food and Drug Administration (FDA) and European Medicines Agency (EMA) orphan drug approvals and designations for compounds intended to treat AATD. Methods: A search of the FDA and EMA orphan drug databases was conducted on 20 January 2025. Results: In 1987, the FDA approved the first human alpha1-proteinase inhibitor, representing the only approved active substance (5%) out of 20 with orphan drug designation in the FDA for the treatment of AATD. Conversely, the EMA has granted orphan drug designation to nine active substances, though none of these have yet been approved. However, there are several new active substances that have been granted orphan drug designation: oral neutrophil elastase inhibitor (FDA 2021, EMA 2025), IgG4 Fc-bound recombinant human AAT (FDA 2022), HSV vector therapy (FDA 2023) and A1AT modulator/protein folding stabilizer (FDA 2023, EMA 2024). Furthermore, the development of RNA interference therapeutics has progressed in the United States and Europe. Conclusion: The development of new therapies may offer expanded treatment options for patients with AATD in the future. In addition to pulmonary manifestations, extrapulmonary manifestations could also be treated in the future. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany