Table 7.
Developmental status of modulators of mucus-mediated airway obstruction for COPD
| Mediator | Role in COPD | Drug | Clinical development | References |
|---|---|---|---|---|
| Epidermal growth factor receptor (EGFR) | EGFR regulates mucin stores in airway epithelium, which are significantly increased in COPD. | BIBW 2948 (inhibits EGFR autophosphorylation) | Inhalation of BIBW 2948 (4-week treatment) in DBPCRT (NCT00423137) reduced internalization of EGFR but did not reduce mucin stores; BIBW 2948 treatment was associated with higher discontinuation rate (24%) than placebo (4.3%). FEV1 in the higher dose group significantly declined by visit 5 but returned to baseline by visit 7. | 134 |
| Myristoylated alanine-rich C kinase substrate (MARCKS) | Mediates movement of mucin granules to the apical membrane as part of mucin exocytosis. | BIO-11006 | A 21-day phase II DBPCRT of BIO-11006 (inhaled) in COPD (NCT00648245) has been completed; a 2011 abstract reported improved lung function and reduced mucus hypersecretion. | 98, 135, 136 |
| Epithelial sodium channel | Role in homeostasis of mucus hydration, ciliary beating, and clearance of mucus. | GS-5737; compound A | Study of effects of GS-5737 on ciliary action in healthy controls (NCT01793649) was terminated. Preclinical study of compound A shows improved ciliary movement, mucus clearance, and airway hydration. | 137 |
| Multiple mechanisms | ||||
| Anti-inflammatory and mucolytic | Inflammation, oxidative stress and mucus hypersecretion are well-established in COPD. | N-acetylcysteine (NAC) | The 1-year DBPCRT PANTHEON trial found 600 mg bid NAC reduced exacerbations in patients with GOLD II–III COPD (Chinese Clinical Trials Registry TRC-09000460), as did a smaller study (NCT01136239) that found a reduction only in high-risk patients but also observed improvement in airway function. However, two lower dose studies (600 mg/day) (NCT00184977; not registered) found no benefit while another (not registered) did. | 12, 90–94, 138, 139 |
| Mucolytic, anti-inflammatory, antioxidant, promotes activity of antibiotics | Inflammation, oxidative stress, and mucus hypersecretion are well-established in COPD. | Erdosteine | DBPCRT (NCT00338507) to test daily erdosteine for 28 days. After 4 weeks, erdosteine treatment significantly reduced plasma oxidant levels and increased %FEV1 reversibility by salbutamol treatment. In other reported studies, addition of erdosteine for 7–10 days reduced duration of acute exacerbations, while long-term treatment in stable COPD reduced exacerbations and improved quality of life. | 88, 89 |
| Cystic fibrosis transmembrane conductance regulator (CFTR) | One study found that CFTR is downregulated in smokers with and without COPD; another found that expression of CFTR inversely correlated with emphysema severity. | Ivacaftor potentiates chloride transport | A pilot DBPCRT of ivacaftor (NCT02135432) (treatment up to 2 weeks) with outcome assessed by sweat chloride has been completed. | 140, 141 |
Abbreviations: DBPCRT, double-blind, placebo-controlled, randomized trial; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease.