Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD

Abstract

BackgroundAs chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.MethodsThe datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.ResultsThe pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).ConclusionsThis post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.Trials registrationClinicalTrials.gov identifiers: NCT00076089 and NCT00430729.

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…2007b; Rennard et al. 2011), few studies have investigated the effects of PDE4 inhibitors in the control of virus‐induced inflammation (Ikemura et al. 2000; Van Ly et al.…”

The Importance of Chronic Bronchitis in Chronic Obstructive Pulmonary Disease

“…There have been trials of PDE4 inhibitors in COPD (169)(170)(171), that have confirmed a modest but significant improvement in spirometry in COPD, and quality of life scores and a reduction in the number of exacerbations experienced. There is evidence that Roflumilast may be particularly beneficial in patients with COPD and chronic bronchitis (172), but it is unclear if this drug is effective in chronic bronchitis without airflow obstruction, and further trials are awaited. PDE4 inhibitors appear to reduce the number of neutrophils recruited to the airways, with a reduction of between 30 -50%, which could explain their clinical efficacy (168).…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Moderate to severe COPD exacerbation and exacerbation requiring corticosteroid were significantly reduced in roflumilasttreated COPD patients. The maximal benefit of roflumilast for reducing exacerbation was noted in ICS-treated COPD patients and in those with chronic bronchitis, compared with those without ICS treatment and those without chronic bronchitis (54). Findings from subgroup analysis confirm the benefit of roflumilast in personalized medicine for specific COPD phenotypes.…”

“…Despite that chronic cough and sputum production are characteristics of bronchiectasis, they have been suggested as a risk factor for exacerbations of COPD (68,69). Roflumilast has been shown benefit for inhibiting neutrophilic airway inflammation in COPD and preventing exacerbation in COPD with chronic bronchitis (46,54). In addition, neutrophils are prominent cell type involved in bronchiectasis and neutrophilic inflammation is key pathogenesis of COPD (70)(71)(72).…”