Mesa 4. Lo que viene en EPOC
Dr. Jose Luis López-Campos.
Hospital Universitario Virgen del Rocio. Sevilla
Elevated Matrix Metalloprotease 9 In Moderate To Severe COPD: Results From Spiromics And Eclipse
J. M. Wells, Margaret Parker, Robert A. Oster, Russell P. Bowler, Mark T. Dransfield, Michael H. Cho, Prescott G. Woodruff, Victor Kim, Jeffrey L. Curtis, Fernando J. Martinez , Robert Paine, R. G. Barr, MeiLan K. Han, Wanda K. O’Neal, Peter J. Castaldi, Amit Gaggar
Abstract
Rationale: Matrix metalloprotease (MMP)-9 couples cigarette smoke to inflammation, airway remodeling, and emphysema development – all hallmarks of COPD. However, no study has characterized individuals with COPD and elevated MMP-9 nor evaluated its impact on outcomes including COPD exacerbations (AECOPD).
Methods: We used demographic, clinical, physiologic, and CT data from the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE) studies. We included individuals with GOLD Stage 2-4 COPD that had plasma MMP-9 values and prospective AECOPD data recorded. High MMP-9 was defined as plasma MMP-9 459ng/m1 (>90th percentile value measured in a control population) measured by RBM-Myriad’s multiplex-platform at baseline.
An AECOPD was defined as an unscheduled healthcare visit or by antibiotic and/or systemic glucocorticoid treatment. We used logistic regression models to identify associations between clinical characteristics and high MMP-9, with or without prospective AECOPDs; zero-inflated negative binomial regression to assess associations with AECOPD frequency; and Cox proportional hazards models to determine time-to-first-AECOPD.
Results: We analyzed data from 200 ECLIPSE participants and 796 individuals from SPIROMICS. Participants from SPIROMICS had more current smokers (33% versus 2.5%) and higher FEVi (53±17% versus 44±17%) compared to ECLIPSE. Baseline plasma MMP-9 levels were 279±191 ng/mI and 223±183 ng/ml in the ECLIPSE and SPIROMICS cohorts, respectively. High MMP-9 was present in 20 (10%) of ECLIPSE and 78 (9.7%) of SPIROMICS subjects.
AECOPD occurred during follow-up in 162 (81%) in ECLIPSE when followed for 1085 (IQR=720-1115) days and in 453 (58%) in SPIROMICS when followed for 1022 (IQR=739-1119) days. In both cohorts, we found positive associations between high MMP-9 and FEVi as well as high MMP-9 and plasma white blood cell count. Using logistic regression models adjusting for age, sex, smoking status, pack-year, FEV.I, chronic bronchitis, asthma, GERD, and AECOPD within the last year, high MMP-9 (OR 3.2, 95%Cl 1.0-10.0, P=0.04 – ECLIPSE; OR 2.27, 95%CI 1.27-4.05, P=0.006 – SPIROMICS) was associated with at least one AECOPD during follow-up.
In SPIROMICS, the high MMP-9 subgroup had a higher rate of AECOPD (rate ratio 1.86, 95%CI 1.44-5.05, P=0.002) and a shorter time to first event (577 vs 734 days, HR 1.36, 95%CI 1.01-1.84, P=0.043) compared to the non-elevated-MMP-9 subgroup.
Conclusions: Systemic MMP-9 is reliably measured in two well-characterized COPD cohorts, is associated with FEVi and plasma WBC count, and independently predicts future exacerbations. These findings provide strong evidence for plasma MMP-9 as a COPD biomarker.
A randomized placebo and active controlled trial of AZD8871 a novel dual acting bronchodilator in COPD patients
D. Singh (Manchester, United Kingdom)
Abstract
AZD8871 is an inhaled long acting dual muscarinic antagonist/β2 adrenoceptor agonist (MABA) under development for treatment of COPD and asthma. This 5-way complete crossover trial was designed to test efficacy, pharmacokinetics, safety and tolerability of AZD8871 in patients with COPD.
Moderate to severe COPD patients ≥40 years of age (females of non-childbearing potential and males) were randomized. Patients received single doses of AZD8871 400 or 1800 µg, or placebo in a double blind fashion, or open label indacaterol 150 µg or tiotropium 18 µg, in a randomized order. Each treatment was followed by a wash out period of 7-21 days. 38 patients were randomized and 28 patients completed all treatments. Mean (SD) %predicted FEV1 at baseline was 52(12.5)% and 20(13.7)% patients were reversible. AZD8871 pharmacokinetics were assessed in subset of 18 patients.
AZD8871 demonstrated very quick onset of action, within 5 min of dosing, at both doses. A sustained bronchodilation over 36 hours was observed with both doses of AZD8871. LS mean (SEM) differences in Trough FEV1 for AZD8871 400 µg & 1800 µg, indacaterol and tiotropium versus placebo were 107(24), 210(24), 153(24), 138(24) mL, respectively. AZD8871 1800 µg showed greater bronchodilation than both indacaterol and tiotropium for both peak and trough FEV1. Few adverse events were observed: headache (31.6%) and nasopharyngitis (13.2%) were the most common and there was no dose response observed with any adverse event.
Overall, both dose levels of AZD8871 delivered significant and sustained bronchodilation, superior to placebo and at the highest dose superior to both reference agents, with no emerging safety concerns.
