Clinical Trial

. 2025 Dec 18;66(6):2501019.

doi: 10.1183/13993003.01019-2025. Print 2025 Dec.

Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency

J Michael Wells^{1

2

3}, Ingrid L Titlestad^{4

5}, Hanan Tanash⁶, Alice M Turner⁷, Kenneth R Chapman⁸, Umur Ş Hatipoğlu⁹, Monica P Goldklang¹⁰, Jeanine M D'Armiento¹⁰, Cheryl S Pirozzi¹¹, M Bradley Drummond¹², Igor Z Barjaktarevic¹³, Wissam M Chatila¹⁴, Megan S Devine¹⁵, Charlie Strange¹⁶, Robert A Sandhaus¹⁷, Jacqueline M Parkin¹⁸, Elizabeth Westfall^{19

2}, Vivian Y Lin^{19

2}, Robin Parks²⁰, Hui-Chien Kuo²⁰, Adzoa Ekue¹⁸, Kelly L Moffitt²¹, Jamie Inshaw²², Inmaculada Aban²⁰, Mark T Dransfield^{19

2

3

23}, Robert A Stockley^{24

23}

Affiliations

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA jmwells@uabmc.edu.
² UAB Lung Health Center, Birmingham, AL, USA.
³ Birmingham VA Healthcare System, Department of Veterans Affairs, Birmingham, AL, USA.
⁴ Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark.
⁵ Odin Respiratory Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁶ Department of Respiratory Medicine, Skåne University Hospital, Malmö, Sweden.
⁷ School of Health Sciences, University of Birmingham, Birmingham, UK.
⁸ Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁹ Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Department of Anesthesiology, Columbia University, New York, NY, USA.
¹¹ Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah, Salt Lake City, UT, USA.
¹² Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina, Chapel Hill, NC, USA.
¹³ Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
¹⁵ UT Health Science Center Tyler, Tyler, TX, USA.
¹⁶ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA.
¹⁷ Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.
¹⁸ Mereo BioPharma Group plc, London, UK.
¹⁹ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁰ School of Public Health, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
²¹ ProAxsis Ltd, Belfast, UK.
²² Exploristics Ltd, Belfast, UK.
²³ These authors contributed equally.
²⁴ University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

PMID: 40967767
PMCID: PMC12713387
DOI: 10.1183/13993003.01019-2025

Clinical Trial

Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency

J Michael Wells et al. Eur Respir J. 2025.

. 2025 Dec 18;66(6):2501019.

doi: 10.1183/13993003.01019-2025. Print 2025 Dec.

Authors

Affiliations

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA jmwells@uabmc.edu.
² UAB Lung Health Center, Birmingham, AL, USA.
³ Birmingham VA Healthcare System, Department of Veterans Affairs, Birmingham, AL, USA.
⁴ Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark.
⁵ Odin Respiratory Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁶ Department of Respiratory Medicine, Skåne University Hospital, Malmö, Sweden.
⁷ School of Health Sciences, University of Birmingham, Birmingham, UK.
⁸ Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁹ Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Department of Anesthesiology, Columbia University, New York, NY, USA.
¹¹ Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah, Salt Lake City, UT, USA.
¹² Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina, Chapel Hill, NC, USA.
¹³ Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
¹⁵ UT Health Science Center Tyler, Tyler, TX, USA.
¹⁶ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA.
¹⁷ Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.
¹⁸ Mereo BioPharma Group plc, London, UK.
¹⁹ Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁰ School of Public Health, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
²¹ ProAxsis Ltd, Belfast, UK.
²² Exploristics Ltd, Belfast, UK.
²³ These authors contributed equally.
²⁴ University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

PMID: 40967767
PMCID: PMC12713387
DOI: 10.1183/13993003.01019-2025

Abstract

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the alpha-1 antitrypsin (AAT) serpin antiprotease, leading to protease-antiprotease imbalance. Weekly intravenous AAT therapy (augmentation) is the only specific treatment available. Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy. Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD.

Methods: We conducted two complementary, double-blind, randomised, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 and 240 mg twice daily without augmentation. Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (Aα-Val³⁶⁰ and desmosine/isodesmosine) as well as safety and tolerability.

Results: We enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS). Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at alvelestat 240 mg twice daily. There was no effect of alvelestat 120 mg on disease activity biomarkers, while 240 mg demonstrated significant reduction in Aα-Val³⁶⁰ and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected.

Conclusions: Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice-daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice-daily dose into a clinical end-point study.

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Conflict of interest statement

Conflict of interest: J.M. Wells reports support for the present study from NIH/NCATS and Mereo BioPharma plc, grants from NIH/NHLBI, Department of Veteran Affairs, ARCUS-Med, Medscape, Verona Pharma, Grifols, Alpha-1 Foundation, Inhibrx and American Lung Association, patents planned, issued or pending with Mereo BioPharma (PCT/GB2021/050658), participation on a data safety monitoring board or advisory board with AstraZeneca, Takeda, GSK, Bavarian Nordic, Krystal Biotech, Sanofi and Verona Pharma, stock or stock options with Alveolus Bio, and support for medical writing from Takeda, GSK and Verona Pharma. A.M. Turner reports grants from CSL Behring, Grifols, Vertex, Takeda, GSK and Chiesi, consultancy fees from CSL Behring, AstraZeneca, Beam and AiRNA, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Takeda, and support for attending meetings from Grifols and CSL Behring. K.R. Chapman reports support for the present study from Mereo BioPharma, grants from Sanofi, GSK, Insmed, AstraZeneca, Boehringer Ingelheim, Bellus, Grifols, Inhibrx, Novartis, Regeneron, Takeda and Vertex, consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, GSK, Grifols, Inhibrx, Kamada, Merck, Frosst, Novartis, Regeneron, Roche, Sanofi, Takeda and Valeo, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Grifols, GSK, Merck Frosst, Novartis, Regeneron, Sanofi and Valeo, and a leadership role with AlphaNet Canada. U.Ş. Hatipoğlu reports royalties or licences from UpToDate and consultancy fees from CITI Pharma. M.P. Goldklang reports grants from Mereo, Takeda, Arrowhead, Vertex and Inhibrx, consultancy fees from Sanofi, GSK and Bridge Bio, and participation on a data safety monitoring board or advisory board with Korro Bio, Inhibrx and Takeda. J.M. D'Armiento reports grants from Mereo, Takeda, Arrowhead, Vertex and Inhibrx, consultancy fees from Sanofi and Bridge Bio, and participation on a data safety monitoring board or advisory board with Sanofi and Takeda. C.S. Pirozzi reports support for the present study from ATALANTa, grants from NIH, Alpha-1 Foundation, Inhibrx Inc, Vertex and AstraZeneca, consultancy fees from Takeda, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Medscape, AKH Inc., Academy for Continued Healthcare Learning (ACHL), Medscape Education, Cleveland Clinic and Alpha-1 Foundation. M.B. Drummond reports support for the present study from NIH, grants from PCORI, Vertex Pharma, Teva Pharmaceuticals, American Lung Association, Boehringer Ingelheim, Midmark and NIH/NHLBI, consultancy fees from AstraZeneca, Verona, Takeda, Becker Pharma, GSK, Stratos, Genentech and Amgen, participation on a data safety monitoring board or advisory board with Chiesi and NIH, and leadership roles with the COPD Foundation Medical and Scientific Advisory Board and Alpha-1 Foundation Medical and Scientific Advisory Board. I.Z. Barjaktarevic reports grants from Theravance, Viatris, Aerogen, Alpha-1 Foundation, Johnny Carson's Foundation, Takeda and Amgen, consultancy fees from AstraZeneca, Sanofi/Regeneron, Grifols, Verona Pharma, Inhibrx, Takeda, Genentech, Aerogen, Theravance and Viatris, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Sanofi/Regeneron, Grifols, Verona Pharma, Inhibrx, Takeda, Genentech, Aerogen, Theravance and Viatris. W.M. Chatila reports support for the present study from the ATALANTa trial and grants from NIH UG3/UH3 TR002450. C. Strange reports grants from NIH/NHLBI UG3 TR002450 and Mereo BioPharma 4 Ltd, and a leadership role with AlphaNet. R.A. Sandhaus reports funding for the present study from NIH, grants from Inhibrx/Sanofi, NIH and Alpha-1 Foundation, consultancy fees from Grifols, CSL Behring, Takeda, Korobio, Beam, Wave and Biomarin, support for meetings from AlphaNet, a patent pending for analysis of chest CTs with National Jewish Health, participation on a data safety monitoring board or advisory board with Takeda and Beam, and leadership roles with Alpha-1 Foundation and AlphaNet. J.M. Parkin reports support for the present study from Mereo BioPharma Group plc, Alpha-1 Foundation (The Alpha-1 Project), Acadustri Ltd UK, NIH (NCATS), Syneos Contract Research Organization, ProAxsis, University of Birmingham at Alabama, University of Birmingham UK, University of Dundee and Exploristics, patents planned, issued or pending (method of treatment using alvelestat in combination with alpha-1 antitrypsin augmentation therapy) with Mereo BioPharma 4 Ltd and University of Alabama at Birmingham, participation on a data safety monitoring board or advisory board with ASTRAEUS, and stock (or stock options) with Mereo BioPharma Group plc. V.Y. Lin reports support for the present study from NIH (NCATS). A. Ekue reports support for the present study from Mereo BioPharma and stock (or stock options) as an employee of Mereo BioPharma. K.L. Moffitt reports support for the present study from ProAxsis Ltd. J. Inshaw is an employee of Exploristics, a for-profit company providing statistical consultancy for Mereo and assistance in manuscript review. I. Aban reports grants from Myasthenia Gravis Foundation of America, Ra/UCB Pharmaceutical, Alexion, Argenx, Catalyst and Verona Pharmaceutical, consultancy fees from Roche, and participation on a data safety monitoring board or advisory board with NIH and Cleveland Clinic. M.T. Dransfield reports support for the present study from NIH, grants from Department of Defense, American Lung Association and NIH, royalties or licences from UpToDate, consultancy fees from Aer Therapeutics, Apreo, AstraZeneca, Genentech, GSK, Novartis, Pulmonx and Teva, support for attending meetings from GSK, and a leadership role with the COPD Foundation. R.A. Stockley reports grants from CSL Behring and Mereo BioPharma, consultancy fees from Mereo BioPharma, CSL Behring, Vertex and Grifols, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, participation on a data safety monitoring board or advisory board with Kamada and Aramata, and a leadership role with GOLD Scientific Committee. The remaining authors have no potential conflicts of interest to disclose.

Figures

None — Overview of the study. NE: neutrophil elastase; AATD: alpha-1 antitrypsin deficiency; CT: computed tomography; FEV₁: forced expiratory volume in 1 s; SGRQ: St George's Respiratory Questionnaire; AAT: alpha-1 antitrypsin. The plots show change from baseline (BL) in blood biomarkers by treatment group at week 12: neutrophil elastase (NE) (median (interquartile range)), Aα-Val³⁶⁰ (least squares mean (95% CI)) and desmosine/isodesmosine (least squares mean (95% CI)). ^#: twice daily.

**FIGURE 1**
Change from baseline (BL) in blood biomarkers in ASTRAEUS and ATALANTa by treatment group at week 12: a) neutrophil elastase (NE) (median (interquartile range)), b) Aα-Val³⁶⁰ (least squares mean (95% CI)) and c) desmosine/isodesmosine (least squares mean (95% CI)). *: p<0.01; **: p<0.006; ***: p<0.001.

**FIGURE 2**
Change from baseline in patient-reported outcomes in ATALANTa at weeks 4, 8 and 12: a) St George's Respiratory Questionnaire (SGRQ) score, b) COPD Assessment Test (CAT) score, c) Shortness of Breath Questionnaire (SOBQ) score and d) modified Medical Research Council (mMRC) dyspnoea scale.

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Comment in

Alvelestat for alpha-1 antitrypsin deficiency-associated emphysema: the hope for an oral treatment.
Singh D, Miravitlles M. Singh D, et al. Eur Respir J. 2025 Dec 18;66(6):2502003. doi: 10.1183/13993003.02003-2025. Print 2025 Dec. Eur Respir J. 2025. PMID: 41412714 No abstract available.

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Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency

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Two randomised controlled phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency

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Abstract

Conflict of interest statement

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