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Chronic Obstr Pulm Dis. 2016 Nov 18;4(1):34-44. doi: 10.15326/jcopdf.4.1.2016.0156.

The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials.

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James P. Mara Center for Lung Disease at Mt. Sinai, Department of Medicine, St. Luke's-Roosevelt Hospital, New York, New York.
Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado.
Clinical Strategy and Development, CSL Behring, King of Prussia, Pennsylvania.
Department of Respiratory Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.


The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; p=0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; p=0.026), 12 (-0.040; 95% CI -0.055, 0.025; p<0.001), and 24 (-0.052; 95% CI -0.070, 0.034; p<0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 (p<0.001) and 48 (p<0.001). Reduced elastin degradation was associated with slower lung density decline (p=0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response.


alpha-1 antitrypsin deficiency; desmosine; elastin biomarkers; isodesmosine; lung density

Conflict of interest statement

GMT reports grants from CSL Behring during the conduct of the study. JOC has a patent (USPTO 7166437) licensed to MatRx Pharm. KRC reports grants from CSL Behring during the conduct of the study, and grants for other work from AstraZeneca, GlaxoSmithKline, Novartis, Genentech, Grifols, Sanofi, Kamada, Merck, Amgen, Roche and Boehringer Ingelheim. RAS reports grants from CSL Behring during the conduct of the study, and is employed part-time by the Alpha-1 Foundation and AlphaNet, 2 not-for-profit entities that support research and health management in Alpha-1 and that receive part of their funding from pharmaceutical industry sources. NGM reports grants and personal fees from CSL Behring during the conduct of the study. MF is an employee of CSL Behring. JME was employed by CSL Behring at the time of the study. All other authors have nothing to disclose.

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