Table 2.
Developmental status of cytokine inhibitors for COPD
| Mediator | Role in COPD | Drug | Clinical development | References |
|---|---|---|---|---|
| IL-1 | Promotes proinflammatory responses. Elevated in stable COPD and further increased in exacerbations. | Canakinumab, a human anti-IL-1β monoclonal antibody | A phase I/II RDBPCES of canakinumab (NCT00581945) (45-week treatment), no statistical analysis provided for lung function changes. | 49, 50 |
| IL-5 | Mediates eosinophil maturation and mobilization; eosinophils increased during some exacerbations. | Mepolizumab (MAb against IL-5), benralizumab (MEDI-563; MAb against IL-5Rα) | Mepolizumab (26–52-week treatment) tested as adjunct in DBPCRT targeting COPD exacerbation rate, studies completed, but results not posted (NCT02105948, NCT01463644, and NCT02105961). Benralizumab (≤56-week treatment) has completed a trial for moderate-to-severe COPD (NCT01227278), but no evidence of efficacy was observed; studies for exacerbation reduction and other effectiveness measures (NCT02155660 and NCT02138916) are ongoing. | 9, 51 |
| IL-13 | Plasma but not sputum concentrations inversely correlated with FEV1 in COPD. IL-13 induces goblet cell hyperplasia and mucus hypersecretion. | Lebrikizumab, a humanized anti-IL-13 MAb | There is a study of lebrikizumab (24-week treatment) for decline in frequency of COPD exacerbations and lung function (NCT02546700). | 100–102 |
| IL-17A | One study found IL-17 reduced in sputum of severe COPD patients but another found numbers of CD4+ Th17 cells in the airways correlated with airflow limitations. | CNTO6785 | CNTO6785 (12-week treatment) is being investigated in moderate-to-severe COPD in DBPCRT (NCT01966549). No results reported yet. | 43, 53, 58 |
| Tumor necrosis factor | Higher levels in sputum and serum of COPD patients; augments inflammation. | Infliximab, etanercept | Infliximab (6-month treatment) (NCT00056264) showed no clinical benefit but toxicity – higher rate of pneumonia and malignancies; however, difference in malignancy rate diminished greatly on long-term follow-up (NCT00380796), making the results difficult to interpret. Etanercept (90-day treatment) (NCT00789997) was not more efficacious than prednisone for the treatment of exacerbations. | 28, 103–105 |
Abbreviations: IL, interleukin; RDBPCES, randomized, double-blind, placebo-controlled, exploratory study; MAb, monoclonal antibody; DBPCRT, double-blind, placebo-controlled, randomized trial; FEV1, forced expiratory volume in 1 second; Th17, T helper 17.