The outcome of more than 3 decades of orphan drug development in alpha-1-antitypsin deficiency – a cross sectional analysis of the FDA Orphan Drug Product designation database

Abstract Introduction Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD.Methods: Cross-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database: 16 July 2021. STROBE criteria were respected.Results Primary: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994.Secondary: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy.Conclusion: Drug development activities in the field were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need is to fill the gap of missing agents for therapy of extrapulmonary manifestations of AATD. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may, encompass a more holistic therapeutic approach.