Emerging pharmaceutical therapies for COPD

Figures & data

Table 1 Developmental status of chemokine receptor inhibitors for COPD

Mediator	Role in COPD	Drug	Clinical development	References
CCR1	Receptor for CCL3 (MIP-1α) and chemoattractant for inflammatory cells. CCR1 is also among receptors binding CCL5 and CCL7.	AZD4818	AZD4818 (4-week treatment) provided no significant benefit to COPD patients (NCT0629239).	^Citation46
CCR2	Receptor for CCL2 (MCP-1), which recruits inflammatory cells to lungs in COPD. Increases synthesis of MUC5AC and MUC5B.	AZD2423	AZD2423 (28-day treatment) in DBPCRT (NCT1215279); study has completed but statistical analysis not released.	^Citation47, ^Citation48
CXCR2 (IL8RB)	Activated by CXCL8 (IL-8), which is higher in BAL and sputum of COPD patients. CXCL8 is chemotactic for neutrophils.	Navarixin (MK-7123); AZD5069	MK-7123 (navarixin; 6-month treatment) in DBPCRT showed statistically significant improvement in postbronchodilator FEV1 (NCT1006616 and NCT0441701). AZD5069 (4-week treatment) in DBPCRT in patients with moderate-to-severe COPD reduced blood neutrophil counts with no increased infection (NCT1233232).	^Citation44, ^Citation45

Abbreviations: DBPCRT, double-blind, placebo-controlled, randomized trial; IL-8, interleukin 8.

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 (NCT0581945) (45-week treatment), no statistical analysis provided for lung function changes.	^Citation49, ^Citation50
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 (NCT2105948, NCT1463644, and NCT2105961). Benralizumab (≤56-week treatment) has completed a trial for moderate-to-severe COPD (NCT1227278), but no evidence of efficacy was observed; studies for exacerbation reduction and other effectiveness measures (NCT2155660 and NCT2138916) are ongoing.	^Citation9, ^Citation51
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 (NCT2546700).	^Citation100–Citation102
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 (NCT1966549). No results reported yet.	^Citation43, ^Citation53, ^Citation58
Tumor necrosis factor	Higher levels in sputum and serum of COPD patients; augments inflammation.	Infliximab, etanercept	Infliximab (6-month treatment) (NCT0056264) showed no clinical benefit but toxicity – higher rate of pneumonia and malignancies; however, difference in malignancy rate diminished greatly on long-term follow-up (NCT0380796), making the results difficult to interpret. Etanercept (90-day treatment) (NCT0789997) was not more efficacious than prednisone for the treatment of exacerbations.	^Citation28, ^Citation103–Citation105

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.

Table 3 Developmental status of proinflammatory signaling pathway inhibitors for COPD

Mediator	Role in COPD	Drug	Clinical development	References
MAPK (p38 mitogen-activated protein kinase)	Higher MAPK in lungs activates proinflammatory response in AMs and lymphocytes.	Acumapimod, dilmapimod (SB-681323), losmapimod, PH-797804, GSK-610677, AZD-7624	Acumapimod (BCT197A2201) reportedly remains in active development, although phase II results have not been reported and there are no current clinical trials. Dilmapimod (SB-681323) significantly reduced TNF-α production in COPD (NCT0144859) but its development was discontinued. Losmapimod did not induce a significant improvement in exercise tolerance or lung function (NCT1218126) and was discontinued. PH-797804 (6-week treatment) (NCT0559910) significantly improved lung function and dyspnea in moderate-to-severe COPD in DBPCRT but was discontinued. Development of GSK-610677 was discontinued following an unreported phase I trial (NCT0694902). Results of a phase II study of AZD-7624 (NCT2238483) have not been reported.	^Citation64, ^Citation106–Citation109
Narrow spectrum kinase inhibitors	p38α and Src family kinases such as Hck are involved in the production of proinflammatory cytokines from macrophages, smooth muscle cells, and human airway epithelial cells. Cigarette smoke activates c-Src and augments airway inflammation and destruction of lung tissue.	JNJ49095397/RV568	RV568 (14-day inhaled treatment) significantly increased FEV1 and reduced sputum malondialdehyde and serum myeloperoxidase in COPD patients. A recent conference report, however, in over 200 COPD patients showed no benefit with RV568 for 12 weeks with respect to lung function or EXACT-PRO (NCT1867762, NCT1475292, and NCT1661244).	^Citation64, ^Citation66, ^Citation110
PI3Kδ (phosphoinositide-3-kinase δ)	Involved in maturation and effector functions of B cells and other leukocytes.	GSK2269557, RV1729	GSK2269557 (treatment up to 84 days in NCT2522299 or 28 days in NCT2294734) DBPCRTs in patients with acute exacerbations of COPD in progress. RV1729 (treatment up to 28 days) is being tested in NCT2140346 with limited efficacy data being gathered in a predominantly phase I study.	^Citation66, ^Citation67
IKK (inhibitor of nuclear factor kappa-B kinase)	IKK is an upstream activator of the proinflammatory transcription factor NF-κB. IKKα and IKKβ activity is elevated in patients with COPD.	IMD-1041, an IKKβ inhibitor	IMD-1041 in DBPCRT (NCT0883584) has no follow-up information posted since April 2009; unclear whether study was performed.	^Citation111
LTB4 receptor	LTB4 levels are elevated in sputum, breath, and BAL of COPD patients; highest LTB4 levels seen in exacerbations. LTB4 is chemotactic for neutrophils and T cells. AMs bearing the BLT1 receptor are more common in COPD patients.	BIIL 284	BIIL 284 (12-week treatment) was assessed for effects on lung function, exercise endurance, sputum, and safety in COPD patients (NCT2249247); a 14-day study assessed effects on biomarkers (NCT2249338) – results of neither study have yet been published. Other LTB4 receptor antagonists have not demonstrated beneficial results.	^Citation4, ^Citation112
5-LO (5-lipoxygenase)	Involved in synthesis of leukotrienes.	5-Lipoxygenase inhibitor (zileuton) used clinically for asthma	Zileuton (14-day treatment) reduced urinary LTE4 levels in hospitalized COPD patients with acute exacerbations in DBPCRT (NCT0493974) but did not significantly shorten stay or reduce treatment failure.	^Citation113
Prostaglandin D2 receptor or chemoattractant receptor-homologous molecule expressed on Th2 (CRTh2) receptor	Highly expressed on eosinophils, basophils, Th2 (not Th1) lymphocytes, and subset of monocytes. Blocking this receptor inhibits chemotaxis of these cells. CRTh2 is expressed on mucosal epithelia and mononuclear infiltrates from COPD lungs.	AZD1981	AZD1981 (4-week treatment) did not induce significant differences in lung function, quality of life variables, nor use of reliever medication in COPD patients in DBPCRT (NCT0690482).	^Citation114
Adenosine A2A receptor	Inhibits neutrophil superoxide production, phagocytosis, adhesion, and cytokine release.	UK-432097 (agonist)	UK-432097 (6-week inhaled treatment) in DBPCRT (NCT0430300) showed no significant differences in FEV1, use of rescue bronchodilator, or quality of life parameters.	^Citation115
Selectins	Involved in migration of leukocytes from blood to surrounding tissues. Overexpressed in lung tissue of COPD patients.	Bimosiamose	Inhalation of bimosiamose (28-day treatment) attenuated inflammation by significantly reducing numbers of macrophages and concentrations of CXCL8 in sputum of COPD patients in DBPCRT (NCT1108913). Adverse events were similar between the groups.	^Citation68
Vasoactive intestinal peptide (VIP)	Bronchodilatory and immunomodulatory effects in the lungs. Anti-inflammatory activity requires activation of both VPAC1 and VPAC2 receptors, With VPAC1 being particularly elevated in AMs of COPD patients.	VIP; available derivatives have not been tested in human COPD	VIP (3-month inhaled treatment) was tested in DBPCRT in severe COPD patients (NCT0464932). Study was completed in 2006 but no results are available.	^Citation116–Citation119

Abbreviations: AM, alveolar macrophage; TNF-α, tumor necrosis factor α; DBPCRT, double-blind, placebo-controlled, randomized trial; FEV₁, forced expiratory volume in 1 second; NF-κB, nuclear factor-κB; Th, T helper.

Table 4 Developmental status of miscellaneous inflammatory modulators for COPD

Mediator	Role in COPD	Drug	Clinical development	References
PPARγ (peroxisome proliferator-activated receptor γ)	Cigarette smoke downregulates PPARγ. Reduced PPARγ expression and activity seen in COPD.	Thiazolidinediones: rosiglitazone and pioglitazone	Retrospective cohort study of patients with diabetes and COPD showed that patients who filled ≥2 thiazolidinedione prescriptions (97.1% rosiglitazone) had a significantly lower number of COPD exacerbations than those receiving other diabetic medications.	^Citation69, ^Citation72
IgE activity	The high affinity IgE receptor is overexpressed on myeloid and plasmacytoid dendritic cells (DCs) of current smokers. Expression on plasmacytoid DCs correlates with COPD stage.	Omalizumab	The clinical trial of omalizumab (NCT0851370) was withdrawn due to lack of patients meeting inclusion criteria (elevated IgE and positive skin prick test to environmental allergens).	^Citation120
RARγ (retinoic acid receptor γ)	Regulates function of multiple cells of the immune system.	Palovarotene	RARγ agonist (2 year treatment) was tested for ability to improve lung function in patients with emphysema in DBPCRT (NCT0413205); in patients with lower lobe emphysema, palovarotene significantly reduced the decline in lung function (from conference report). In another study, over 1 year, palovarotene failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe alpha-1 antitrypsin deficiency.	^Citation121, ^Citation142, ^Citation143
Angiotensin receptor	Angiotensin II receptor blockers reduce in-hospital mortality during first COPD exacerbation.	Losartan	Open-label clinical trial of losartan (4-week treatment) (NCT2416102) to assess effects on mucociliary dysfunction (nasal potential difference, IL-8 and TGF-β in nasal discharge) in COPD patients is recruiting; a 4-year study of losartan for prevention of emphysema progression (NCT2696564) is not yet recruiting.	^Citation122
Endothelin	Vasoconstrictor, contributes to pulmonary hypertension in COPD.	Bosentan	Bosentan (18-month treatment) halted progression of PH and led to improvements in most patients, especially those in GOLD grades III and IV. A study of bosentan effects on acute exacerbations and lung function in patients with GOLD III or IV COPD and pulmonary hypertension was initiated but status is unknown (NCT2093195).	^Citation73–Citation75
Statins	Statins exert anti-inflammatory effects by several mechanisms independent of cholesterol lowering.	Simvastatin, rosuvastatin	Although retrospective studies suggested that statins may reduce frequency of exacerbations, hospitalization, and mortality in COPD patients, a recent prospective large randomized trial of simvastatin in COPD patients (NCT1061671) did not detect significant differences. Another 3-month study of simvastatin found no effect in inflammatory biomarkers. Rosuvastatin (12-week treatment) in DBPCRT (NCT0929734) reduced biomarkers of systemic inflammation and improved endothelial function in a prespecified subgroup (patients with supramedian circulating hsCRP levels).	^Citation77, ^Citation78, ^Citation123, ^Citation124
T cells	T cells infiltrate airways, and are key mediators in the immune response; numbers of senescent cells, which produce increased amounts of proinflammatory and cytotoxic mediators and are relatively resistant to GC treatment, are elevated in blood and lungs of COPD patients.	Cyclosporine, an immunosuppressant affecting T-cell responses	A phase I dose-escalation study of inhaled cyclosporine (28-day treatment) in severe COPD patients (NCT0783107) also evaluated inflammatory biomarkers; no results of 2009 study are available. An ongoing phase II DBPCRT (16-week treatment) (NCT0974142) is evaluating oral cyclosporine in severe COPD.	^Citation125, ^Citation126

Abbreviations: Ig, immunoglobulin; IL, interleukin; TGF-β, transforming growth factor β; GOLD, Global Initiative for Chronic Obstructive Lung Disease; DBPCRT, double-blind, placebo-controlled, randomized trial; hsCRP, high-sensitivity C-reactive protein.

Table 5 Developmental status of cAMP and cGMP phosphodiesterase inhibitors

Mediator	Role in COPD	Drug	Clinical development	References
PDE4 (phosphodiesterase subtype 4)	Hydrolyzes cAMP, an inhibitor of inflammatory pathways; expressed in a wide variety of cells.	Roflumilast, a selective PDE4 inhibitor; GSK-256066; CHF6001; MK0359; MK-0873; tofimilast; UK-500,001; tetomilast (OPC-6535, PDE4 inhibitor with modest PDE3 inhibitory activity); oglemilast; QAK423A; TPI 1100.	Roflumilast is only US FDA approved PDE4 inhibitor; it reduced exacerbation frequency and also produced clinically significant improvements in dyspnea. GSK-256066 (4-week inhaled treatment) in DBPCRT (NCT0549679) improved residual volume and showed a nonsignificant trend toward augmenting postbronchodilator FEV1. Preclinical testing of CHF6001 (inhaled) shows efficacy and low toxicity in several rat models of pulmonary inflammation. It is in clinical testing (28-day treatment) (NCT1730404) but no results have been reported. Numerous other PDE inhibitors are in clinical testing, including MK-0359 (NCT0482235); MK-0873 (NCT0132730); tofimilast (NCT0219622); UK-500,001 (NCT0263874); tetomilast (OPC-6535) (NCT0874497), terminated, NCT0917150); oglemilast (NCT0671073); QAK423A (NCT1197287); and TPI 1100 (NCT0914433).	^Citation10, ^Citation42, ^Citation80, ^Citation99, ^Citation127–Citation129
PDE3/PDE4	PDE3 degrades both cAMP and cGMP. It is expressed on airway smooth muscle cells and acts as a bronchoconstrictor. Combined PDE3/PDE4 inhibition is often additive or synergistic.	RPL554	RPL554 (up to 94-day treatment) is being investigated as an adjunct to salbutamol and ipratropium in COPD patients in DBPCRT (NCT2542254).	^Citation10
PDE5	PDE5 promotes pulmonary arterial vasoconstriction and vessel wall hypertrophy.	Tadalafil (inhibits PDE5)	Tadalafil, which is approved for pulmonary arterial hypertension, in DBPCRT (12-week treatment) (NCT1197469) did not improve exercise capability or quality of life. Another study (NCT1862536) is in progress.	^Citation130

Abbreviations: FEV₁, forced expiratory volume in 1 second; DBPCRT, double-blind, placebo-controlled, randomized trial; FDA, Food and Drug Administration.

Table 6 Developmental status of elastin-degrading protease inhibitors for COPD

Mediator	Role in COPD	Drug	Clinical development	References
Neutrophil elastase	Abundant in neutrophils; can degrade extracellular matrix and damage/destroy lung parenchyma; affects mucus secretion.	AZD9668 AZD6553	AZD9668 (12-week treatment) showed no effect on pulmonary function or quality of life when combined with tiotropium (NCT0949975) or budesonide/formoterol (NCT1023516); there was likewise no effect on airway remodeling (NCT1054170) and studies found no decrease in degradation as assessed by urinary desmosine. AZD6553 clinical trial (NCT1068184) was terminated due to PK inconsistent with pharmaceutical properties.	^Citation131, ^Citation132
Matrix metalloproteinases (MMPs)	Higher levels of multiple MMPs in lungs of COPD patients; involved in matrix breakdown and tissue remodeling.	AZD1236 (anti-MMP-9 and -12); GS-5745 (anti-MMP-9)	In a 6-week DBPCRT (NCT0758706) of AZD1236 (anti-MMP-9 and -12) in moderate-to-severe COPD patients, reduction in urinary desmosine did not reach statistical significance and there was no effect on COPD clinical symptoms. Another study (NCT0758459) has completed but statistical analysis not released. A 28-day safety and PK study of GS-5745 in COPD patients (NCT2077465) has been completed.	^Citation82, ^Citation133

Abbreviations: PK, pharmacokinetics; DBPCRT, double-blind, placebo-controlled, randomized trial.

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 (NCT0423137) 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.	^Citation134
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 (NCT0648245) has been completed; a 2011 abstract reported improved lung function and reduced mucus hypersecretion.	^Citation98, ^Citation135, ^Citation136
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 (NCT1793649) was terminated. Preclinical study of compound A shows improved ciliary movement, mucus clearance, and airway hydration.	^Citation137
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 (NCT1136239) that found a reduction only in high-risk patients but also observed improvement in airway function. However, two lower dose studies (600 mg/day) (NCT0184977; not registered) found no benefit while another (not registered) did.	^Citation12, ^Citation90–Citation94, ^Citation138, ^Citation139
Mucolytic, anti-inflammatory, antioxidant, promotes activity of antibiotics	Inflammation, oxidative stress, and mucus hypersecretion are well-established in COPD.	Erdosteine	DBPCRT (NCT0338507) 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.	^Citation88, ^Citation89
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 (NCT2135432) (treatment up to 2 weeks) with outcome assessed by sweat chloride has been completed.	^Citation140, ^Citation141

Abbreviations: DBPCRT, double-blind, placebo-controlled, randomized trial; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

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