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Introduction: Revefenacin (REV), a novel, lung-selective, LAMA delivered via nebulizer, is well tolerated and demonstrated increased trough FEV1 in patients with moderate to very severe COPD over 12 weeks. Objectives: Assess COPD exacerbation data associated with once-daily REV (88 µg & 175 µg) in patients with moderate to very severe COPD participating in a phase 3 REV clinical trial program. Methods: Once-daily REV was administered via a standard jet nebulizer in 2 replicate, 12-wk, randomized, double-blind, placebo-controlled, parallel-group, ph3 trials (0126 & 0127), and a 52-wk, randomized, double-blind (REV arms), active control (tiotropium [TIO] arm), parallel-group ph3 trial (0128). The studies weren’t enriched for patients with frequent exacerbations. Results: Pooled data analysis from Studies 0126 and 0127 showed REV nominally reduced COPD exacerbation burden by 15%–18% vs placebo. In Study 0128, REV 175 µg was associated with numerically fewer COPD exacerbations (moderate & severe COPD exacerbations) than REV 88 µg and TIO 18 µg. Conclusions: Analyses of ph3 data indicate that once-daily REV for up to 52 wks was associated with a reduction in COPD exacerbation in patients with moderate to very severe COPD, with REV providing additional benefit over TIO. The absence of selection for exacerbation-prone patients, small sample sizes, and therefore the lack of statistical power must be accounted for when interpreting these positive trends.

Background: Aclidinium bromide (AB) and tiotropium (TIO) are long-acting anti-muscarinic COPD maintenance therapies. AB has not been compared with TIO beyond 6 weeks (wks). Aim: To compare efficacy and safety of AB vs TIO at 24 wks in symptomatic patients (pts) with COPD. Methods: AMPLIFY (NCT02796677) was a Phase 3, 24-wk, double-blind, active-controlled study. Pts with moderate to very severe COPD and CAT score ≥10 were randomized to twice-daily AB/formoterol fumarate (FF) 400/12 µg, AB 400 µg or FF 12 µg or once-daily TIO 18 µg. The primary non-inferiority endpoint (AB vs TIO; per protocol [PP] population) was change from baseline (Δ) in morning pre-dose (trough) FEV1 at Wk 24 (treatment difference lower 95% confidence interval [CI] > –50 mL). AB/FF data are shown elsewhere. A subset of pts entered a 24-h spirometry sub-study. Results: The intent-to-treat population (AB and TIO arms) included 950 pts (Table). At Wk 24, Δtrough FEV1 for AB vs TIO was within the non-inferiority limit (Δ7 mL [95% CI –21, 35 mL]; PP population [n=842]). Other bronchodilation outcomes were significantly improved for AB vs TIO on Day 1; differences at Wk 24 were not statistically significant (Table). Health-related quality of life (QoL) improvements and treatment-emergent adverse events were similar between groups (Table). Conclusions: In pts with COPD, AB was non-inferior to TIO in improving trough FEV1 and had similar efficacy for other bronchodilation and QoL outcomes at Wk 24.

Introduction: Studies suggest that high blood EOS count may be a marker of increased exacerbation risk in COPD patients (pts) with a history of exacerbations. We investigated the effect of blood EOS count on the efficacy of roflumilast (ROF) on COPD exacerbation rate. Methods: A post-hoc analysis was performed on two trials (REACT [NCT01329029], RE2SPOND [NCT01443845]) in which pts with severe COPD and ≥2 exacerbations in the previous year were randomised to ROF 500μg od or placebo (PBO) added to ICS/LABA±LAMA for 52 weeks. Primary endpoint was rate of moderate or severe COPD exacerbations/pt/year. Exacerbation rates were analysed by baseline EOS cell count strata ( Results: Of 4287 pts, 2146 had an EOS count ≥150 cells/mm3 at entry. ROF reduced moderate or severe exacerbations rates by 19.1% (p=0.002) in pts with EOS ≥150 cells/mm3 and by 3.8% (p=0.605) in pts with EOS Conclusions: In this post-hoc analysis, PBO-treated COPD pts with higher blood baseline EOS counts had more exacerbations. Pts with higher blood baseline EOS counts derived greater benefit from ROF in exacerbation risk reduction compared to PBO.

Rationale: COPD patients have a high risk of community-acquired pneumonia (CAP). We studied Streptococcus pneumoniae (SP) and non-typeable Haemophilus influenzae (NTHI) effects on COPD macrophage responses and how budesonide (BUD) and fluticasone propionate (FP) alter host-pathogen interactions. Methods: Blood monocytes from 10 controls, 20 healthy smokers and moderate-severe COPD [19 current smokers (CS), 21 ex-smokers (ES)] were cultured with GM-CSF to generate monocyte-derived macrophages (MDM). MDM were pre-treated with 10nM BUD, FP or vehicle for 24h and exposed to live SP or NTHI. After 24h cell surface bacterial recognition receptor expression was analyzed by flow cytometry and supernatant cytokines by bead array. Data at p≤0.05 (2-sided paired t-test) are shown. Results: SP and NTHI reduced receptor expression on MDM from COPD (mainly in ES) and healthy smokers but not controls. SP and NTHI reduced SRA-1 in CS & ES and MARCO in ES. SP also reduced CD1d, TLR2 and TLR4 in CS & ES and CD93 in ES. NTHI also reduced CD11b in CS & ES and CD35 and CD206 in ES. BUD prevented reductions by SP on SRA-1 and by NTHI on CD206, both in ES. FP prevented SP reductions of TLR2 in CS & ES and TLR4 in ES but had no effect on reductions by NTHI. BUD and FP inhibited NTHI- and SP-induced cytokines. Conclusions: Reduction of bacterial recognition receptors on macrophages may be part of the enhanced risk of CAP in COPD. BUD prevented receptor reductions induced in ex-smokers by both SP and NTHI while FP affected only SP-induced reductions. These differential effects may contribute to the difference in pneumonia risk between inhaled BUD and FP treatments in COPD. Support: AstraZeneca.

Introduction: IL-17A is associated to chronic obstructive pulmonary disease (COPD). The expression and role of IL-17A in acute exacerbation of COPD (AECOPD) and end-stage disease is, however, unknown. Aim: Characterize the expression and functional role of IL-17A in AECOPD, and relevance to disease progression. Methods: IL-17A was measured in sputum before, during and after nontypable Haemophilus influenzae (NTHi)-associated, culture positive and culture negative AECOPD, and in lung tissue specimens from GOLD I-IV COPD patients and asymptomatic smokers/never smokers. Cigarette smoke exposure of gene-targeted mice was used in conjunction with NTHi infection to establish the functional relevance of IL-17A. Results: IL-17A was elevated in sputum during NTHi-associated AECOPD, compared to before or after the event, but not during culture negative AECOPD, or AECOPD associated with bacteria other than NTHi. IL-17A was, however, increased in a pooled analysis of all AECOPD. Functionally, IL-1 receptor 1 dependent IL-17A was required for NTHi-exacerbated neutrophilia in cigarette smoke-exposed mice. Alveolar macrophages were identified as a potential source of IL-17A. Lastly, lung tissue expression of IL-17A was significantly increased in end-stage COPD compared to asymptomatic smokers. Conclusion: IL-17A is specifically increased during NTHi-associated AECOPD and in end-stage disease. Functionally, IL-17A is required for NTHi-exacerbated inflammation over the background of cigarette smoke. As AECOPD accelerates COPD, IL-17A may participate in driving the progression of COPD by promoting neutrophil accumulation in lung tissue.