Efficacy and safety of inhaled alpha-1-antitrypsin in patients with severe alpha-1-antitrypsin deficiency and frequent exacerbations of Chronic Obstructive Pulmonary Disease

  1. Jan Stolk1⇑,
  2. Naveh Tov2,
  3. Kenneth R. Chapman3,
  4. Pablo Fernandez4,
  5. William MacNee5,
  6. Nicholas S. Hopkinson6,
  7. Eeva Piitulainen7,
  8. Niels Seersholm8,
  9. Claus F. Vogelmeier9,
  10. Robert Bals10,
  11. Gerry McElvaney11 and
  12. Robert A. Stockley12
  1. 1Department of Pulmonology, member of European Reference Network LUNG, Leiden University Medical Centre, Leiden, NL
  2. 2Department of Clinical Development, Kamada Ltd, Rehovot, Israel
  3. 3Department of Medicine, University of Toronto, Toronto, ON, Canada
  4. 4Independent consultant, Penn, UK
  5. 5University of Edinburgh, Edinburgh, United Kingdom
  6. 6National Heart and Lung Institute, Imperial College, London, UK
  7. 7Department of Respiratory Medicine and Allergology Malmö, Skane University Hospital, Lund University, Sweden
  8. 8Department of Respiratory Medicine Y, Gentofte University Hospital, Copenhagen, Denmark
  9. 9Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Diseases (DZL), University Medical Centre Giessen and Marburg, Philipps-University Marburg, Marburg, Germany
  10. 10Hospital of the University of the Saarland, Internal Medicine V - Pulmonology, Member of the German Center for Lung Diseases (DZL), Homburg, Germany
  11. 11Department of Respiratory Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland
  12. 12Queen Elizabeth Hospital, Birmingham, United Kingdom
  1. Dr J. Stolk, Department of Pulmonology, member of European Reference Network LUNG, Leiden University Medical Centre, Leiden, NL. E-mail: j.stolk{at}lumc.nl

Abstract

Patients with inherited alpha-1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently suffer from exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.

We randomly assigned 168 patients to receive twice daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an eDiary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary end-points included change in the nature of the exacerbation by the Anthonisen criteria. Safety was also assessed.

Time to first moderate or severe exacerbation was at median 112 days (IQR 40, 211) for AAT and 140 days (IQR 72, 142) for placebo, p=0·0952. The mean yearly rate of all exacerbations in the AAT and placebo groups was 3.12 and 2.67 (p=0.31), respectively. More patients receiving AAT reported treatment-related TEAEs (Treatment Emergent Adverse Events) compared to placebo (57·5% versus 46·9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, the rate of safety events in the AAT treated group dropped to that of the placebo group.

We conclude that in AATD patients with severe COPD and frequent exacerbations AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.

Footnotes

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Conflict of interest: Dr. Stolk reports personal fees from Kamada Ltd, during the conduct of the study; grants from CSL Behring, outside the submitted work.

Conflict of interest: Dr. Tov reports personal fees from KAMADA LTD, during the conduct of the study; personal fees from KAMADA LTD, outside the submitted work.

Conflict of interest: Dr. Chapman reports personal fees from Kamada, during the conduct of the study; grants from CSL Behring, grants from Grifols, outside the submitted work.

Conflict of interest: Dr. Fernandez reports receiving consultancy fees from Kamada, during the planning, design, conduct and reporting of the study.

Conflict of interest: Dr. MacNee reports other from Kamada, during the conduct of the study; personal fees from Boehringer Ingleheim, grants and personal fees from Pfizer, grants and personal fees from GSK, personal fees from Astra Zeneca, personal fees from Novartis, personal fees from Zambon, from Chiesi, outside the submitted work.

Conflict of interest: Dr. Hopkinson has nothing to disclose.

Conflict of interest: Dr. Piitulainen has nothing to disclose.

Conflict of interest: Dr. Seersholm has nothing to disclose.

Conflict of interest: Dr. Vogelmeier reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, grants and personal fees from Grifols, personal fees from Menarini, personal fees from Mundipharma, grants and personal fees from Novartis, personal fees from Teva, from Cipla, outside the submitted work.

Conflict of interest: Dr. Bals reports grants from Kamada, during the conduct of the study; grants from BMBF, DFG, Schwiete Stiftung, Sander-Stiftung, grants from Boehringer Ingelheim, personal fees from GSK, CSL Behring, Boehringer Ingelheim, Grifols, AstraZeneca, Novartis, outside the submitted work.

Conflict of interest: Dr. McElvaney reports personal fees from CSL Behring, grants and personal fees from Grifols, grants from Chiesi, outside the submitted work.

Conflict of interest: Dr. Stockley reports personal fees from Kamada, during the conduct of the study; personal fees from AstraZeneca, personal fees from Medimmune, personal fees from Almirall, personal fees from Nycomed, personal fees from Takeda, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Baxter, personal fees from Chiesi, personal fees from Polyphor, outside the submitted work.

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