Advances in orphan drug development for alpha-1 antitrypsin deficiency: a 2025 update from the FDA and EMA

Abstract

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.

Objectives:

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.

Design:

A cross-sectional approach was applied, involving a one-time comprehensive search of relevant databases.

Methods:

The primary endpoint of this study was to determine the number and nature of FDA and EMA-approved orphan drugs. The secondary endpoint was the registration of compounds with orphan drug designation status. All database searches were performed since the inception of the FDA database in 1983 and the EMA database in 2000, as well as for all compounds listed in the FDA and EMA drug label databases up to 20 January 2025. The search terms ‘antitrypsin’ and ‘proteinase’ were used.

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 stabiliser (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.

Plain language summary

New progress in developing medicines for Alpha-1 Antitrypsin Deficiency: an update from the FDA and EMA

The development of medicines to treat Alpha-1 Antitrypsin Deficiency (AATD) has been going on for over 40 years. So far, the only type of medicine approved by both the FDA and EMA for AATD are human alpha-1-proteinase inhibitors. There are five of these approved medicines listed by the FDA, and they differ in how they are made and what they contain. Only the first one was approved through the special orphan drug process. In Europe, two of these medicines are approved. One is called Respreeza, which is listed by the EMA, and the other is Prolastin, which has been approved in Germany since the 1980s by the Paul Ehrlich Institute. This is because the EMA was created only in 1995. These medicines aim to slow down lung damage caused by emphysema. Right now, there is no approved treatment for other symptoms of AATD outside the lungs. Recently, some new types of medicines have received orphan drug status, and some of them have shown good results in early clinical trials (phase I and II). There has also been progress in developing RNA interference treatments. If these new treatments continue to do well in testing, there might be a chance in the future to use a combination of these medicines for better treatment of AATD.

Introduction

Alpha-1-antitrypsin deficiency (AATD, OMIM #613490) is a rare autosomal-codominant disorder caused by mutations in the SERPINA-1 gene. ¹ It is associated with early-onset emphysema, particularly in smokers, and liver disease. ¹ The most common clinically relevant mutation (Pi*Z) is caused by a single nucleotide polymorphism of one base (Glu342Lys), ² which occurs in 1 out of 25 people of European descent (1 in 2000 people of European descent are homozygous). ¹ There are more than 7600 known mutations in the SERPINA-1 gene worldwide. ³

AAT is mainly formed in the endoplasmic reticulum of the liver and is secreted into the bloodstream. ¹ In the case of the Z mutation, a misfolded glycoprotein is formed, which remains predominantly in the hepatocytes and forms intracellular polymers. These polymers can lead to liver disease through proteotoxic stress. ⁴ A cross-sectional biopsy study showed clinically significant liver fibrosis in 35% of adults with PI ZZ AAT deficiency. ¹

The most significant physiological effect of AAT is the inactivation of proteolytic enzymes within the lung tissue, particularly neutrophil elastase. ⁵ In the context of AATD, neutrophil elastase has the capacity to cleave elastin, an essential supporting structure of the airways and lung parenchyma. This can result in obstructive lung disease with early-onset pulmonary emphysema. ⁴ In addition to its important role as an antiprotease, AAT exerts an immunomodulatory effect. ¹ Furthermore, in addition to other lung diseases such as bronchiectasis and asthma, other comorbidities such as neutrophilic panniculitis and ANCA-positive vasculitis have also been described with an increased prevalence in AATD. ¹

In 1987, the U.S. Food and Drug Administration (FDA) approved a human alpha-1-proteinase-inhibitor (A1-PI), which had been designated in 1984. ⁶ To date, this is the only compound approved worldwide for the treatment of AATD, although companies have been researching different therapeutic approaches for more than 40 years. An overview of orphan drugs for the treatment of AATD has already been described. ⁷ However, a number of new classes of drugs and advances in gene therapy have been made in recent years, so an update of orphan drugs is needed. In addition to a chronological update, the geographical scope will be expanded to include Europe to provide an overview of which new, promising compounds may be approved in the near future.

Methods

This is a cross-sectional observational study. The design, conduct, analysis, and reporting met the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria. ⁸ The methodological approach was similar to the preliminary work by Trudzinski et al in 2022. ⁷ However, their search was limited to results from the FDA database. In the present study, both the FDA and EMA databases were examined with regard to active substances in clinical development for the treatment of AATD. All database searches were performed since the inception of the FDA database in 1983 and the EMA database in 2000 for orphan drug designations, as well as for all compounds listed in the FDA and EMA drug label databases up to 20 January 2025.

Endpoints

The aim of this analysis was to determine the number and nature of FDA and EMA-approved orphan drugs. The secondary endpoint was the registration of compounds with orphan drug designation status.

Data sources

To search for orphan drug designations and approvals, the FDA database (https://www.accessdata.fda.gov/scripts/opdlisting/oopd/) and the EMA database for orphan drug designations (https://ec.europa.eu/health/documents/community-register/html/reg_od_act.htm?sort=a) were accessed on 20 January 2025. As part of the search in the FDA database, the search terms ‘antitrypsin’ and ‘proteinase’ were used in the ‘Orphan Designation’ field. The search resulted in 18 and 2 hits respectively, all of which addressed the AATD. A search in the Community Register of Orphan Medicinal Products of the EMA using the terms ‘antitrypsin’ and ‘proteinase’ resulted in 11 (9 hits for treatment of AATD, 2 hits related to other indications) and 4 hits (2 hits for treatment of AATD, 2 hits related to other indications) respectively. Among the 11 hits for AATD treatment, 9 were different, and 2 appeared twice.

The results were then downloaded in Excel format. The following available variables were included in the search for results: generic name of compound, year of orphan drug designation, orphan designation (intended treatment indication), orphan designation status (designated, withdrawn, or approved), name and country of sponsor company.

Furthermore, an investigation was undertaken to ascertain whether alternative pharmaceutical agents are approved for the treatment of AATD that are not included in the orphan drug databases. Therefore, a search was performed in the FDA Drug Label Database (https://nctr-crs.fda.gov/fdalabel/ui/search) and the EMA Drug Label Database (https://www.ema.europa.eu/en/medicines). To conduct a search within the FDA drug label database, the search terms ‘antitrypsin’ and ‘proteinase’ were input into the ‘Labelling Section(s)’ within the ‘Indications and Usage’ section. Upon entering the search term ‘antitrypsin,’ 4 results were returned, while ‘proteinase’ yielded a total of 5 results. All of the retrieved results were relevant to the treatment of AATD. Of this total of 9 hits, 5 were different hits and 4 were doubles.

A comparable methodology was employed with the aforementioned terms via a search of the EMA drug label database. The search (without button include documents) for ‘antitrypsin’ yielded 18 results (14 hits treatment of AATD including 12 hits in the orphan drug category, 4 hits related to other indications or were reports), while the search for ‘proteinase’ yielded 22 results (7 hits treatment of AATD including 3 hits in the orphan drug category, 15 hits related to other indications or were reports).

Definitions

The compounds were divided into important functional groups based on their biochemical properties, molecular mechanisms of action or therapeutic approaches. ⁹ These groups include: protein therapy, enzyme, anti-inflammatory substances, mucolytics, small molecules, gene therapy and cell therapy.

Descriptive analysis

The available data underwent a descriptive statistical analysis. Analysed variables were generic name, classification, year of orphan drug designation, orphan designation (i.e. intended therapeutic indication), orphan designation status (designated, withdrawn, approved), FDA or EMA orphan approval status, approved label indication, year of marketing approval, year of exclusivity end date, sponsor company and country.

Results

Primary endpoint: Orphan drug approvals by the FDA and EMA

The FDA designated a human alpha-1 protease inhibitor in 1984 and approved it in 1987 with market exclusivity until 1994. The EMA has not yet approved an orphan drug for AATD.

Currently, there are five approved human alpha-1-proteinase inhibitors listed in the FDA drug label database. These differ in terms of their galenics and composition, see Table 1. Of these, three were approved subsequent to the expiration of the market exclusivity of the first approved alpha-1 proteinase inhibitor. One marketing authorisation for a human alpha-1 protease inhibitor (Respreeza) was identified in the EMA drug label database. With the same composition and manufacturing method, Respreeza (in the EU) and Zemaira (in the USA) show no differences.

Table 1.

List of approved human alpha-1-proteinase inhibitors with details of galenics, composition, manufacturing process and functional properties. ¹⁰ .

Trade name	Product type	Route of administration	Galenics	Active ingredient/active moiety	Inactive ingredients	Manufacturing process for virus log reduction	Specific activity in mg functional alpha1-PI per mg of total protein
Glassia	plasma-derivate	i.v.	Solution	A1-PI (human) (1000 mg in 50 mL)	0.02 M Sodium Phosphate 0.7% Sodium Chloride water for injection	• modified version of the cold ethanol fractionation process • Nanofiltration • S/D treatment	⩾0.7 mg
Aralast NP*	plasma-derivate	i.v.	Lyophilised powder	A1-PI (human) (16mg in 1mL)	⩽5 mg/ml albumin 112 µg/ml polyethylene glycol 50 µg/ml polysorbate 80 1.0 µg/ml tri (n-butyl) phosphate 230 mEq/L sodium 3 ppm zinc	• Cold ethanol fractionation • Solvent detergent treatment • 15 N nanofiltration	⩾0.55 mg
Zemaira/ Respreeza	plasma-derivate	i.v.	Lyophilised powder	A1-PI (human) (1000 mg in 20 mL, 4000 mg in 76 mL and 5000 mg in 95 mL)	73–89 mM sodium 30–39 mM chloride 15–20 mM phosphate 121–168 mM mannitol hydrochloric acid and/or sodium hydroxide may have been added to adjust pH	• Cold ethanol fractionation • Heat treatment • Nanofiltration	⩾0.7 mg
Prolastin-C	plasma-derivate	i.v.	Lyophilised powder	A1-PI (human) (1000 mg in 20 mL)	100–210 mM sodium 60–180 mM chloride 13–25 mM sodium phosphate	• Cold Ethanol Fractionation • PEG Precipitation • Depth Filtration • Solvent/Detergent Treatment • 15 nm Virus Removal Nanofiltration	⩾0.7 mg
Prolastic-C Liquid	plasma-derivate	i.v.	Solution	A1-PI (human) (1000 mg in 20 mL)	2.76 mg/ml sodium phosphate 22.27 mg/ml L-alanine and water	• Cold Ethanol Fractionation • PEG Precipitation • Depth Filtration • Solvent/Detergent Treatment • 15 nm Virus Removal Nanofiltration	⩾0.7 mg

^*ARALAST NP contains approximately 2% Alpha1-PI with truncated C-terminal lysine (removal of Lys394), whereas ARALAST contains approximately 67% Alpha1-PI with the C-terminal lysine truncation.

Secondary endpoint: Orphan drug designations by the FDA and EMA

From 1984 to 20 January 2025, the FDA granted orphan drug designation to 20 active substances, five of which were withdrawn over time. Subsequent to the establishment of the European orphan drug regulation in 2000 to 20 January 2025, the EMA granted orphan drug designation to 9 active substances, none of which were withdrawn, see Figures 1 and 2 and Tables 2 and 3.

Figure 1.

Type of compound intended to treat alpha-1 antitrypsin deficiency by year of FDA orphan drug designation (circles) and registration of non-orphan compounds in the FDA drug label database (squares).

Green: approved compound. Black: designated compound. Red: withdrawn compound. Black arrow: Time until approval. Green dashed arrow: duration of market exclusivity. Grey box: time without orphan drug regulation.

Figure 2.

Type of compound intended to treat alpha-1 antitrypsin deficiency by year of EMA orphan drug designation (circles), registration of non-orphan compounds in the EMA drug label database (squares) and paediatric investigation plan (triangle).

Green: approved compound. Black: designated compound. Red: withdrawn compound. Grey box: time without orphan drug regulation.

Table 2.

FDA drug designations for compounds intended to treat alpha-1-antitypsin deficiency in reverse chronological order, sorted by year of drug designation.

Source	Generic name of compound	Classification	Year of FDA drug designation	Designation	Designation status	Sponsor company	Country of sponsor company
1	Oxoindoline carboxamide compound	Alpha-1-antiproteinase modulators, Protein folding stabiliser (small molecule drug)	2023	Treatment of alpha-1 antitrypsin deficiency	Designated	BioMarin Pharmaceutical Inc.	United States
1	A replication-defective, non-integrating herpes simplex virus type 1-based vector engineered to express full-length, functional human alpha-1 antitrypsin	Gene therapy (vector therapy)	2023	Treatment of Alpha-1 antitrypsin deficiency	Designated	Krystal Biotech, Inc.	United States
1	IgG4 Fc-linked recombinant human AAT	Protein therapy (recombinant)	2022	Treatment of Congenital Alpha-1 Antitrypsin Deficiency	Designated	Sanofi AATD Inc.	United States
1	Alvelestat	Orally bioavailable, affinity and selective inhibitor of neutrophil elastase	2021	Treatment of Alpha-1 Antitrypsin Deficiency	Designated	Mereo Biopharma 4 Limited	United Kingdom
1	CHO cell line produced human alpha-1 antitrypsin (CHO-AAT) protein	Protein therapy (recombinant)	2020	Treatment of alpha-1 antitrypsin deficiency	Designated	Caravella Biopharma SA	Switzerland
1	A synthetic double-stranded RNA oligonucleotide conjugated to N-acetyl-D-galactosamine aminosugar residues	Gene therapy (RNA interference)	2020	Treatment of alpha-1 antitrypsin deficiency	Designated	Dicerna Pharmaceuticals, Inc	United States
1	Recombinant human alpha-1 antitrypsin from Oryza sativa	Protein therapy (recombinant)	2020	Treatment of alpha-1 antitrypsin deficiency	Designated	Wuhan Healthgen Biotechnology Corporation	China
1	Double-stranded oligomer ADS-001 RNA interference-based liver-targeted therapeutic	Gene therapy (RNA interference)	2018	Treatment of alpha-1 antitrypsin deficiency	Designated	Arrowhead Research Corporation (Takeda Development Centre Americas, Inc)	United States
1	Three-dimensional bioprinted therapeutic liver tissue	Cell therapy (liver tissue)	2017	Treatment of alpha-1 antitrypsin deficiency	Designated/withdrawn	Organovo Inc	United States
1	Hyaluronic acid	mucolytic	2017	Treatment of emphysema due to alpha1-antitrypsin deficiency	Designated	Gerard M. Turino, MD	United States
1	Double-stranded oligomer AD00370 RNA interference-based liver-targeted therapeutic	Gene therapy (RNA interference)	2015	Treatment of Alpha-1 Antitrypsin deficiency	Designated/withdrawn	Arrowhead Research Corporation	United States
2	Alpha-1-proteinase Inhibitor (human) (Glassia)	Protein therapy (human)	2010	Treatment of Alpha-1 antitrypsin deficiency	Initial U.S. Approval: 2010	Takeda Pharmaceuticals, Inc.	United States
1	Alpha-1-proteinase inhibitor (human)	Protein therapy (human)	2010	Treatment of emphysema secondary to congenital alpha1-antitrypsin deficiency	Designated	Grifols Therapeutics, Inc.	United States
1	Alpha-1-proteinase Inhibitor (human)	Protein therapy (human)	2004	Inhalation therapy for the treatment of congenital deficiency of alpha1-proteinase inhibitor	Designated	Kamada Ltd	Israel
1	Recombinant adeno-associated virus alpha 1-antitrypsin vector	Gene therapy (vector therapy)	2003	Treatment of alpha-1-antitrypsin deficiency	Designated	University of Massachusetts Medical School	United States
2	Alpha-1-proteinase inhibitor (human) (Zemaira)	Protein therapy (human)	2003	Treatment of alpha-1 antitrypsin deficiency	Initial U.S. Approval: 2003	CSL Behring LLC	United States
1	Hyaluronic acid	mucolytic	2002	Treatment of emphysema in patients due to alpha-1 antitrypsin deficiency	Designated	CoTherix	United States
2	Alpha -Proteinase Inhibitor (human) (Aralast)	Protein therapy (human)	2002	Treatment of alpha-1 antitrypsin deficiency	Initial U.S. Approval: 2002	Takeda Pharmaceuticals, Inc.	United States
1	Alpha1-proteinase inhibitor (human)	Protein therapy (human)	1999	For slowing the progression of emphysema in alpha1-antitrypsin-deficient patients	Designated/withdrawn	CSL Behring L.L.C	United States
1	Transgenic human alpha-1 antitrypsin	Protein therapy (recombinant)	1999	Treatment of emphysema secondary to alpha-1 antitrypsin deficiency	Designated	PPL Therapeutics (Scotland) Limited	United Kingdom
1	Recombinant secretory leucocyte protease inhibitor	Protein therapy (recombinant)	1991	Treatment of congenital alpha-1 antitrypsin deficiency	Designated/withdrawn	Amgen Inc	United States
2	Alpha-1-proteinase inhibitor (human) (Prolastin-C)	Protein therapy (human)	1987	Treatment of alpha-1 antitrypsin deficiency	Initial U.S. Approval: 1987	Grifols Therapeutics LLC	United States
2	Alpha-1-proteinase inhibitor (human) (Prolastin-C Liquid)	Protein therapy (human)	1987	Treatment of alpha-1 antitrypsin deficiency	Initial U.S. Approval: 1987	Grifols Therapeutics LLC	United States
1	Alpha-1-antitrypsin (recombinant DNA Origin)	Protein therapy (recombinant)	1984	As supplementation therapy for alpha-1-antitrypsin deficiency in the ZZ phenotype population	Designated/withdrawn	Chiron Corporation	United States
1	Alpha1-proteinase inhibitor (human)a	Protein therapy (human)	1984	For replacement therapy in the alpha-1-proteinase inhibitor congenital deficiency state	Designated/approved	Bayer Corporation	United States

Source 1: FDA orphan drug database, source 2: FDA drug label database.

The present table lists all orphan drugs since the inception of the FDA database in 1983, as well as all compounds in the FDA drug label database up to January 20, 2025, that have been in clinical development for the treatment of AATD.

Table 3.

EMA drug designations for compounds intended to treat alpha-1-antitypsin deficiency in reverse chronological order, sorted by year of drug designation.

Source	Generic name of compound	Classification	Year of EMA drug designation	Designation	Designation status	Sponsor company	Country of sponsor company
3	Alvelestat	Oral neutrophil elastase inhibitor	2025	Treatment of congenital alpha-1 antitrypsin deficiency	Designated	Mereo Biopharma Ireland Limited	Ireland
3	N-[(1R)-1-[(S)-(2-Chloro-3-fluorophenyl)hydroxymethyl]butyl]-7-fluoro-2,3-dihydro-2-oxo-1H-indole-4-carboxamide	A1AT modulators, Protein folding stabilisers	2024	Treatment of congenital alpha-1 antitrypsin deficiency	Designated	BioMarin International Limited	Ireland
4	Alpha-1-proteinase inhibitor (human)	Protein therapy (PIP)	2021	Treatment of emphysema secondary to alpha-1-proteinase inhibitor deficiency	W: decision granting a waiver in all age groups for all conditions or indications	Baxalta Innovations GmbH (owned by Takeda)	Austria
4	Alpha-1-proteinase inhibitor (human)	Protein therapy (PIP)	2021	Treatment of emphysema secondary to congenital deficiency of alpha-1 antitrypsin	W: decision granting a waiver in all age groups for all conditions or indications	Kamada Ireland Limited	Ireland
3	Synthetic double-stranded siRNA oligonucleotide directed against SERPINA1 mRNA and containing four modified nucleosides, which form a ligand cluster of four N-acetylgalactosamine residues	Gene therapy (RNA interference)	2019	Treatment of alpha-1 antitrypsin deficiency (liver)	Designated	Dicerna Ireland Limited	Ireland
3	N-acetylgalactosamine-conjugated synthetic double-stranded oligomer specific to serpin family A member 1 gene	Gene therapy (RNA interference)	2018	Treatment of congenital alpha-1 antitrypsin deficiency (liver)	Designated	Takeda Pharma A/S	Denmark
4	Alpha-1-proteinase inhibitor (human) (Infinia)	Protein therapy (human)	2017	Treatment of Alpha-1 Antitrypsin deficiency	Withdrawn	Kamada BioPharma Limited	Israel
4	Synthetic double-stranded oligomer specific to the SERPINA1 gene and containing a cholesterol-conjugated, acyclic nucleobase analogue	Gene therapy (RNA interference)	2016	Treatment of congenital alpha-1 antitrypsin deficiency (liver)	Withdrawn	Pharma Gateway AB	Sweden
4	Alpha-1-proteinase inhibitor (human) (Respreeza)	Protein therapy (human)	2015	Treatment of alpha-1 antitrypsin deficiency	Authorised This medicine is authorised for use in the European Union	CSL Behring GmbH	Germany
4	Alpha1 proteinase inhibitor	Protein therapy (PIP)	2013	Inhalation therapy for the treatment of congenital deficiency of alpha-1-proteinase inhibitor	decision granting a waiver in all age groups for all conditions or indications	Triskel EU Services Ltd	United Kingdom
3	Cyclo[L-alanyl-L-seryl-L-isoleucyl-L-prolyl-L-prolyl-L-glutaminyl-L-lysyl-L-tyrosyl-D-prolyl-L-prolyl-(2S)-2-aminodecanoyl-L-alpha-glutamyl-L-threonyl] acetate salt	Protein therapy (recombinant)	2013	Inhalation therapy for the treatment of congenital alpha-1 antitrypsin deficiency	Designated	Santhera Pharmaceuticals GmbH	Germany
4	Alpha-1 proteinase inhibitor	Protein therapy (PIP)	2012	Treatment of chronic obstructive pulmonary disease due to alpha-1-antitrypsin deficiency Treatment of liver disease due to alpha-1-antitrypsin deficiency	W: decision granting a waiver in all age groups for all conditions or indications	CSL Behring GmbH	Germany
3	Alpha1-Proteinase Inhibitor (human)	Protein therapy (human)	2008	Inhalation therapy for the treatment of congenital alpha-1 antitrypsin deficiency	Designated	Grifols Deutschland GmbH	Germany
3	Recombinant adeno-associated viral vector containing human alpha-1 antitrypsin gene	Gene therapy (vector therapy)	2007	Treatment of congenital alpha-1 antitrypsin deficiency	Designated	Propharma Group The Netherlands B.V.	Netherlands
4	Alpha-1 proteinase inhibitor (human)	Protein therapy (human)	2006	Treatment of emphysema secondary to congenital alpha-1 antitrypsin deficiency	Withdrawn	Octapharma (IP) Limited	United Kingdom
3	Alpha-1-Proteinase Inhibitor (human)	Protein therapy (human)	2004	Inhalation therapy for the treatment of congenital deficiency of alpha1-proteinase inhibitor	Designated	Kamada Ireland Limited	Ireland
4	Recombinant human alpha-1 antitrypsin	Protein therapy (recombinant)	2002	Treatment of emphysema secondary to congenital alpha-1-antitrypsin deficiency	Withdrawn	Fulcrum Pharma (Europe) Ltd	United Kingdom
4	Recombinant human alpha-1 antitrypsin	Protein therapy (recombinant)	05/2001	Treatment of emphysema secondary to congenital alpha-1 antitrypsin deficiency	Withdrawn	Talecris Biotherapeutics GmbH	Germany
3	Alpha-1-Proteinase Inhibitor (human) (respiratory use)	Protein therapy (human)	07/2001	Inhalation therapy for the treatment of emphysema secondary to congenital alpha-1-antitrypsin deficiency	Designated	CSL Behring GmbH	Germany

Source 3: EMA orphan drug database, source 4: EMA drug label database.

The present table lists all orphan drugs since the inception of the EMA database in 2000, as well as all compounds in the EMA drug label database up to 20 January 2025, that have been in clinical development for the treatment of AATD.

The FDA Drug Label Database did not list any other active substances in addition to the five authorised substances mentioned above. A review of the EMA drug label database identified six active substances that did not have orphan drug status. Five of these were withdrawn during the development process and one was approved, as mentioned above. The chemical structures of the listed active substances can be found in Supplemental Tables 1 and 2.

Figure 3 shows the different therapeutic approaches of orphan drugs for the treatment of AAT. Protein therapies have been derived from a variety of sources, including human recombinant DNA, transgenic cells, Oryza sativa (rice), CHO cell lines or recombinant human fusion proteins. Another protein therapy is the recombinant secretory leucocyte protease inhibitor, whose orphan drug status was withdrawn in 1991. The EMA drug label database lists 4 human alpha-1 protease inhibitors that have orphan drug status in all age groups, particularly children. Gene therapies with orphan designation include vector therapies (adeno-associated, HSV-associated) and RNA interference therapies. The latter are intended for the treatment of hepatopathies associated with AATDs. One RNA interference therapy without orphan drug status was withdrawn during the project. The designation of a cell therapy for liver tissue was also withdrawn. Another drug that was granted orphan drug status in 2002 and 2017 is hyaluronic acid. In recent years, the FDA has granted orphan drug designation to a number of new active ingredients, including the oral neutrophil elastase inhibitor Alvelestat (2021), an IgG4 Fc- linked recombinant human AAT (2022), HSV vector therapy (2023) and A1AT modulators/protein folding stabilisers (2023). The latter received orphan drug designation from the EMA in 2024, and Alvelestat also received orphan drug designation from the EMA in 2025. The active ingredients listed by the FDA were provided by a total of 20 different sponsors, including large pharmaceutical companies and smaller biotechnology companies, as well as one medical university and one physician. The sponsors were distributed as follows: 15 in the United States, two in the United Kingdom and one each in Switzerland, China and Israel. At the EMA, 16 different sponsors were identified, ranging from larger pharmaceutical companies to specialised biotechnology companies. The distribution of sponsors across different countries shows that four were located in Ireland, four in Germany, three in the United Kingdom and one each in Austria, Denmark, Israel, Sweden and the Netherlands.

Figure 3.

Illustration of the different therapeutic approaches for the treatment of AATD. The left-hand side shows the protein therapies, oral neutrophil elastase inhibitor and mucolytics with the different routes of administration. (a) oral. (b) inhalation. (c) intravenous. On the right-hand side, the therapeutic approaches of vector therapy (green), RNA interference therapeutics (red) and protein folding stabilisers (yellow) are shown at the cellular level.

Discussion

The aim of this study was to provide an overview of orphan drug designations for AATD. Trudzinski et al. provided an overview of FDA orphan drug designations up to 16 July 2021. ⁷ Over the past few years, there have been several new active substances that have been granted orphan drug designation, so it was time for an update. The current study provides an update of approved and potential future compounds for the treatment of AATD until 20 January 2025. This is in a broader context, as the current analysis included the EMA orphan drug databases in addition to the FDA databases.

Primary endpoint: Orphan drug approvals by the FDA and EMA

The FDA has thus far approved one active substance (5%) out of 20 with orphan drug designation for the treatment of AATD, while the EMA has granted orphan drug designation to 9 active substances, none of which have yet been approved.

Currently, there are five approved human alpha-1-proteinase inhibitors listed in the FDA drug label database, which differ in terms of their galenics and composition. The human alpha-1 proteinase inhibitors Respreeza and Prolastin are authorised in Europe. Respreeza is listed in the EMA Drug Label Database, whereas Prolastin is listed by the German Paul Ehrlich Institute. This is due to the fact that the EMA was only founded in 1995, and Prolastin had already been authorised in the 1980s.

The Orphan Drug Act, enacted in 1983, aimed to promote the clinical development of drugs for rare diseases (prevalence less than 200,000 US citizens), for which there was limited economic incentive due to the small number of patients. ¹¹ The legislation provided manufacturers with incentives, including 7 years of market exclusivity, which prevents the approval of competing drugs for the same orphan indication during this period, tax reductions, and access to federal grants.^11,12 In comparison with the general approval process, orphan drug compounds are required to meet the same regulatory standards, yet smaller patient numbers are accepted. ¹³ Furthermore, orphan drug compounds have the option of an accelerated approval process. ¹⁴

In general, the likelihood of a drug being approved is higher for orphan drugs than for those intended for more common diseases. The success rate for clinical development of drugs for rare diseases from phase I to approval is 17%, according to a 2021 report. In comparison, the success rate for therapies for high-prevalence chronic diseases is 5.9%. ¹⁵

Weekly intravenous substitution therapy with plasma-purified human AAT, at a dosage of 60 mg/kg body weight, is the only approved disease-specific treatment for patients with AATD.^6,16 It is indicated for patients with an AAT serum level below 11 μmol/L (or <0.57 g/L) and evidence of progressive pulmonary emphysema. ¹⁶ According to the product information for Prolastin and Respreeza, FEV₁ is no longer considered a decisive criterion. However, expert statements recommend substitution therapy in patients with an FEV₁ between 30% and 65% of the predicted value, or in those with an FEV₁ above 65% who show an annual decline of more than 50 ml. ¹⁷ A plethora of randomised controlled trials and registry studies have demonstrated the efficacy of AAT therapy in decelerating the progression of AATD-related emphysema and enhancing survival prospects.^18–21 There are currently no specific therapies available for the treatment of extrapulmonary manifestations of AATD, and the effect of substitution therapy on these manifestations remains uncertain.

A notable limitation of this therapy is its dependence on large volumes of plasma collected from healthy donors. Current estimations indicate that approximately 900 plasma donations are required to administer the substitution therapy to one AATD patient over the course of a year. ²² In addition, despite the manufacturing process to reduce the viral load, the risk of infection cannot be completely ruled out. Moreover, due to the short half-life (3–5 days), ¹ weekly infusions are necessary, which could have a negative impact on quality of life and therapeutic adherence. Patients who are able to self-administer AAT therapy can do so, which can lead to an improvement in their quality of life. ²³ This option is not suitable for everyone (for a variety of possible reasons, such as fear of venipuncture, coordination problems, poor veins, limited ability to work sterilely) and is not desired by everyone. In addition, replacement therapy is associated with significant costs, reaching up to $200,000 per patient per year in the US in 2020. ²⁴ It is estimated that the purchase price could be reduced by around 40% by using recombinant plant-derived alpha-1 antitrypsin (AAT) instead of human plasma-derived AAT. ²⁴ In summary, developing alternative therapies and new therapeutic approaches is important for enabling specific treatments for extrapulmonary manifestations, improving patients’ quality of life and reducing therapeutic costs.

However, the development of new therapies for AATD faces several challenges. The low prevalence of severe AATD, in conjunction with the requirement for ongoing clinical trials to enrol patients with specific genotypes – for example, Pi*ZZ in the Redwood Study, NCT05677971 – results in considerable difficulty in the recruitment of suitable study participants. In addition, the heterogeneity of clinical manifestations among patients with the same genotype poses a significant challenge in evaluating study outcomes.^25,26 Even though the Orphan Drug Act accepts smaller patient cohorts for rare diseases, demonstrating clinical benefit in these limited and heterogeneous populations remains a critical requirement. Furthermore, due to the slowly progressive nature of the pulmonary or hepatic manifestations of AATD, extended observation periods are necessary. Finally, despite the financial incentives provided by the Orphan Drug Act, it can be assumed that the high costs of orphan drug development continue to discourage investment by many pharmaceutical companies.

Secondary endpoint: Orphan drug designations by the FDA and EMA

The human A1-PI was the first active substance to be granted orphan drug status for the treatment of AATD in 1984. From 1984 to 20th January 2025, the FDA granted orphan drug designations to 20 and the EMA to 9 active substances. Trudzinski et al. have already conducted a search for orphan drugs for the treatment of AATD until 16th July 2021. ⁷ Following their search, several new active substances were granted orphan drug designation. These include the oral neutrophil elastase inhibitor, the IgG4 Fc-bound recombinant human AAT, the HSV vector therapy and the A1AT modulator/protein folding stabiliser.

Alvelestat is a selective and reversible oral inhibitor of neutrophil elastase. In a multicentre, double-blind, placebo-controlled Phase II study (ASTRAEUS), alvelestat showed a statistically significant and consistent reduction in the three biomarkers studied (NE activity, Aα-val360 and desmosin) in the high dose group (240 mg twice daily) after 12 weeks of treatment with an acceptable safety profile. ²⁷ Alvelestat received orphan drug designation from the FDA in 2021 and from the EMA in 01/2025. Interestingly, a phase III trial design has been agreed in the US using the St. George’s Respiratory Questionnaire (SGRQ) total score as the primary endpoint. In Europe, however, a study design with lung density using computed tomography (CT) as the primary endpoint is planned. To evaluate the effectiveness of the therapy, an objective parameter such as the analysis of lung density on CT seems to be preferred.

In 2023, orphan drug designation was granted for protein folding stabilisers and AAT modulators, representing a novel class of drugs. This innovative therapeutic approach aims to optimise the folding process of AAT proteins in deficiency mutations, with the objective of preserving the functionality of the AAT proteins.

Vector therapy has played a role in the treatment of AATD since 2003. To date, there are two Adeno-associated vector therapies and one HSV-associated vector therapy with an orphan drug designation. Adeno-associated viral vectors have been widely used in gene therapy. The advantages of this therapy include low pathogenicity and a wide range of serotypes, allowing transduction into a variety of target organs. However, a limitation of the therapy is the low packing capacity of the genome of ~4.6 kb. ²⁸ In particular, adeno-associated vectors have been used in preclinical and clinical studies for the treatment of cystic fibrosis. However, despite a good safety profile, sufficient mRNA concentrations could not be achieved due to limited genomic packaging capacity. ²⁸ The potential of HSV vectors is difficult to assess due to the limited number of studies. In contrast to AAV vectors, they have a high genome packaging capacity (~152 kb). ²⁸

In 2015, an RNA interference therapeutic was granted orphan drug designation in the United States for the first time. Currently, two sponsors (Takeda and Dicerna) have each submitted an N-acetyl-galactosamine conjugated RNA interference therapeutic to the FDA and EMA with orphan drug designation. The RNA interference therapeutic ADS-001 is also known as Fazirsiran. It was developed for the treatment of liver involvement in AATD, which degrades the Z-AAT messenger RNA and thus reduces protein biosynthesis and the polymer formation of Z-AAT proteins. It was granted orphan drug status by the FDA in 2018, and in the placebo-controlled phase II study (SEQUOIA), the efficacy and safety of the drug were tested in a total of 40 patients with the Pi*ZZ genotype. ²⁹ The study demonstrated that Fazirsiran led to a sustained statistically significant reduction in the serum concentration of Z-AAT, which was found to be dose-dependent (primary endpoint). ²⁹ Furthermore, AATD-specific histological improvements were achieved, including a reduction in the Z-AAT content of the liver and the PAS+D globule load of liver biopsies. ²⁹ Subsequent to a successful phase II, a phase III trial (Redwood) has now been initiated. However, the disadvantage of treatment with RNA interference therapeutics is that the reduced AAT levels in the serum favour the progression of pulmonary emphysema.

Protein therapy has played the most significant role in clinical research to date, with a particular focus on human protein therapies that have already received approval. In addition to these, preclinical and clinical research are currently underway on a range of other protein therapies, including recombinant protein therapies and inhaled protein therapy. Notably, in 2022, a recombinant human AAT obtained orphan drug status. This consists of two recombinant human AAT molecules that are covalently bound to a human IgG4-Fc region, and was developed with the aim of enabling a longer half-life and higher functional AAT proteins as measured by NE inhibition. ³⁰ In a phase I study, good tolerability and a dose-dependent increase in functional AAT serum levels with a 2.5 to > 3 times longer half-life compared to human AAT were observed. ³⁰ It is also interesting to note that four sponsors were able to obtain a waiver in all age groups for all conditions or indications for their human alpha-1-proteinase inhibitor. The purpose of the waiver is to facilitate market access for medicines.

In addition to the aforementioned orphan drugs, recent literature also highlights novel gene therapy approaches based on advanced gene editing technologies such as CRISPR-Cas9 and prime editing, which enable precise modifications of genetic material at specific genomic loci. ³¹ CRISPR-Cas9 acts as a ‘gene scissors’ to induce a double-strand break in the DNA, which is then repaired by cellular mechanisms. ³² This can cause both desired and undesired genetic changes. ³² In contrast, prime editing is based on a single-strand break, in which a defined DNA sequence is incorporated directly into the DNA. This is done using an RNA template and a reverse transcriptase. ³²

The aim of these gene editing methods in current studies for the treatment of AATD is to correct the most common pathogenic Z mutation, which is caused by a single nucleotide polymorphism (Glu342Lys).^33–35

Limitations

A comprehensive search of the FDA and EMA databases for orphan drugs to treat AATD was conducted. However, it cannot be ruled out that there are other compounds in clinical development that the companies have not disclosed for strategic reasons. Publication could jeopardise the market position by encouraging other competitors to develop similar compounds. Another reason for not disclosing an early-stage compound may be that it would jeopardise the granting of patents or make it more difficult to attract investors due to insufficient data. Moreover, the clinical development of drugs for the treatment of AATD is a dynamic and constantly evolving field. Drugs that were added to the databases after the specified cut-off date could not be included due to the methodology used. In addition, it is possible that some drugs are listed in the databases but were not captured by the selected search terms.

Conclusion

The development of pharmaceuticals for the treatment of AATD has spanned over four decades. To date, the only group of active substances that has been approved by the FDA and EMA for the treatment of AATD is that of human alpha-1-proteinase inhibitors. There are currently five approved human alpha-1 proteinase inhibitors listed in the FDA’s drug labelling database, which differ in terms of their galenics and composition. Only the first of these compounds has been approved through the orphan drug process. Two human alpha-1 proteinase inhibitors have been approved for use in Europe. One of these compounds, known as Respreeza, is listed in the EMA drug label database, while the other, Prolastin, has been listed by the Paul Ehrlich Institute in Germany since the 1980s. This is attributable to the fact that the EMA was only founded in 1995.

The aim of these inhibitors is to slow the progression of pulmonary emphysema. There is currently no specific therapy that has been approved for the treatment of extrapulmonary manifestations of AATD. In recent years, a number of new classes of drugs have been granted orphan drug status, some of which have already shown positive results in phase I and phase II trials. Clinical development of RNA interference therapeutics has also made progress in recent years. If their clinical development remains successful, the future may also hold the prospect of combination therapy, combining the aforementioned drug groups to provide potentially better treatment for AATD.