Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: the PIONEER study

Abstract

Background This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). Methods Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% predicted, and history of ≥1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 μg twice daily (BID), budesonide, or placebo for 24 weeks. Primary objectives: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. Results Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV1 at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment–placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13–28% (non-significant). In post-hoc analyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24–37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/μL (49–73%, statistically significant for CHF6001 800 and 1600 μg BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). Conclusions CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001. Trial registration ClinicalTrials.gov (NCT02986321). Registered 8 Dec 2016.

COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum

“…These findings suggest that T2 and PDE4 overexpression in COPD patients with higher sputum eosinophil counts contributes to the differential clinical response to PDE4 inhibitors observed in previous clinical trials. 4,10 The presence of T2 mediators in the airways of COPD patients has been previously shown in different studies measuring protein levels, [24][25][26] and gene expression in bronchial epithelial brush. 27,28 We now build on these previous findings using an unbiased approach in sputum cells, specifically studying patients with chronic bronchi- Differentially expressed genes (DEGs) in common between the primary and validation analyses.…”

“…In conclusion, recent studies showed that the effect of oral and inhaled PDE4 inhibitors on exacerbations in COPD patients with chronic bronchitis appears to be greater at higher blood eosinophil counts. 4,10 Furthermore, we recently showed that tanimilast significantly reduced sputum eosinophil numbers in the eosinophilhigh group. 12 These previous results coupled with our current data strongly suggest that differential responses to PDE4 inhibition may relate to an increased presence of features of T2 inflammation and PDE4-related pathways in the eosinophilic COPD phenotype.…”

“…consistently and significantly reduced in the eosinophil high population and the overall population by both tanimilast doses but with a more pronounced effect in the eosinophilic group. It has previously been reported that PDE4 inhibitors have a greater effect in COPD patients with higher eosinophil counts 4,10 and that PDE4…”

“…6 In preclinical studies and RCTs, tanimilast showed a potent topical anti-inflammatory effect which was devoid of class-related systemic adverse effects. [5][6][7][8][9][10] In recent post hoc analyses, it was shown that tanimilast significantly reduced the exacerbation rate in the subgroup of COPD patients with chronic bronchitis and eosinophil count ≥ 150cells/µl after 24 weeks of treatment. 10 In a biomarker RCT conducted in COPD patients with chronic bronchitis receiving triple therapy (ICS/ long-acting β 2 agonist therapy (LABA) / long-acting muscarinic antagonist (LAMA)), tanimilast showed clear anti-inflammatory effects by modulating a range of airway biomarkers and inflammation pathways after 32 days of treatment.…”

“…[5][6][7][8][9][10] In recent post hoc analyses, it was shown that tanimilast significantly reduced the exacerbation rate in the subgroup of COPD patients with chronic bronchitis and eosinophil count ≥ 150cells/µl after 24 weeks of treatment. 10 In a biomarker RCT conducted in COPD patients with chronic bronchitis receiving triple therapy (ICS/ long-acting β 2 agonist therapy (LABA) / long-acting muscarinic antagonist (LAMA)), tanimilast showed clear anti-inflammatory effects by modulating a range of airway biomarkers and inflammation pathways after 32 days of treatment. 8,11 Moreover, the ability of tanimilast to reduce sputum eosinophil counts was increased in patients with higher eosinophils levels in sputum (≥3%).…”