Phase II trial to assess the biochemical efficacy of transgenic alpha1-anti-trypsin as an effective treatment of cystic fibrosis

L. Martin*, D. Downey, J. S. Elborn, D. Bilton, M. T. Keogan, J. Edgar

*Corresponding author for this work

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1 Citation (Scopus)


Chronic inflammation and infection in patients with cystic fibrosis (CF) is associated with high levels of airway neutrophil elastase (NE), neutralised in normal individuals by alpha1-anti-trypsin (AAT). In CF the amount of free NE present overwhelms AAT leading to lung destruction and a reduced host immune defence system. McElvaney et al. (1991) Lancet 337, 392-384, showed that delivery of plasma-derived AAT to CF airways resulted in inhibition of NE activity in lavage fluid. These studies were not extended due to availability and cost of the plasma-derived protein. Using transgenic technology, human AAT (tg-hAAT) is produced in the milk of sheep allowing economic, high volume production. In a double-blind, randomised, placebo-controlled study the effect of tg-hAAT (500 mg, 250 mg and 125 mg) and placebo were compared. Sputum NE, other markers of disease activity and safety parameters were examined. 39 patients were randomised to receive nebulised treatment once daily for 4 weeks, followed by 2-4 weeks with no study treatment, then a 2 week rechallenge phase. A trend towards a reduction in sputum NE activity was observed in patients treated wim 500 mg (50% decrease) and 250 mg (89% decrease) compared to placebo (2.53% increase). This was not statistically significant due to large intraand inter-patient variability and low sputum elastase in patients receiving 500 mg of tg-hAAT. Sputum NE/AAT complex and myeloperoxidase (MPO) levels were generally lower on active treatment, with statistical significance for complexes at 125 mg (p=0.05) and MPO at 500 mg (p=0.04). No increase in pulmonary exacerbations, major adverse events or allergic reactions to tg-hAAT were observed. In conclusion, although there was no statistically significant difference between tg-hAAT treatment and placebo for free sputum NE levels, positive results were found for some of the secondary efficacy variables. This study also demonstrated that tg-hAAT is well tolerated.

Original languageEnglish
Issue numberSUPPL. 3
Publication statusPublished - 01 Dec 1999
Externally publishedYes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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