Current Perspectives on Biological Therapy for COPD

Figures & data

Figure 1. The inflammatory process in the pathogenesis of COPD.

(MMP9:matrix metalloproteinase-9, COB: chronic obstructive bronchitis, ROS: reactive oxygen species, CTGF: connective tissue growth factor, TGF-β:transforming growth factor beta, CCR2: cc chemokine receptor2)

Table 1. Clinical trials that have evaluated biologics in the management of COPD.

Class of biologics	Drug	Type of study	No. of participants	Status	Results	Author/Year	Remarks/Reference
Anti-TNF alpha	Infliximab	1. Exploratory double-blind placebo-controlled randomized trial	Total =22 Infliximab treatment group = 14 Placebo = 8	Completed	No clinically beneficial effects of infliximab were observed	van der Vaart, H., et al./2005	[77]
		2. Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial	Total =234 Infliximab 3 mg/kg = 78 Infliximab 5 mg/kg = 79Placebo = 77	Completed	Patients with moderate to severe COPD did not benefit from treatment with infliximab	Rennard, S.I., et al./2007	[79]
		3. A pilot randomized controlled trial	Infliximab 5 mg/kg = 16Placebo = 25	Completed	No observable reduction in local and systemic inflammation as a result of infliximab on COPD patients	Dentener et al./2008	[78]
	Etanercept	1. Observational cohort study	Total = 15771	Completed	Reduction in COPD-related hospitalization	Suissa et al./2008	[80]
		2. Randomized double-blind placebo controlled pilot trial	Total = 81 Etanercept treatment group:41 prednisolone placebo group:40	Completed	Etanercept was not more effective than prednisone for the treatment of AECOPD	Aaron et al./2013	[81]
Anti-IL-8 & Anti CXCR	ABX IL-8	Randomized, double-blind, parallel-group, placebo-controlled trial	Total = 109ABX IL-8 treatment group = 56Placebo = 53	Completed	Neutralization of IL-8 with ABX IL-8 may improve dyspnea in patients with COPD	Mahler et al./2004	[96]
Anti-IL-17	CNTO 6785	Phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study	Total:187CNTO6785 treatment group:93Placebo:94	Completed	A small improvement in FEV1% predicted in moderate to severe COPD patients however there was no statistically significant variation.	Eich et al./2017	[104]
Anti-IL-5& IL-5R	Benralizumab	1. Randomized, double-blind, placebo-controlled, phase 2a study	Total = 101 benralizumab = 51 placebo = 50	Completed	A significant increase in FEV1% predicted although no improvement in the annual rate of AECOPD	Brightling et al./2014	[111]
		2. Randomized, double-blind, placebo-controlled, phase 3(GALATHEA)	Total = 1656,benralizumab 30 mg group = 554,benralizumab100mg group = 552,placebo = 550	Completed	Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD	Criner et al./2019	[112]
		3. Randomized, double-blind, placebo-controlled, phase 3(TERRANOVA)	Total = 2255,benralizumab10mg group = 562,benralizumab30mg group = 562,benralizumab 100 mg group = 562, placebo = 568	Completed	Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD	Criner et al./2019	[112]
	Mepolizumab	1. Single-center, randomized, placebo-controlled, parallel-group, double-blinded pilot study	Total = 18 Mepolizumab treatment group = 8 Placebo = 10	Completed	Sputum eosinophil count decreased in those receiving mepolizumab versus placebo	Dasgupta et al./2017	[113]
		2. Multi-center, randomized, placebo-controlled, double-blind, parallel-group trial	Total = 836 Mepolizumab treatment group = 417 Placebo = 419	Completed	Mepolizumab reduces exacerbations in patients with eosinophil-associated COPD.	Pavord et al./2017	[114]
		3. Multi-center, randomized, placebo-controlled, double-blind, parallel-group trial	Total = 674 Mepolizumab 100 mg treatment group = 223 Mepolizumab 300 mg treatment group = 225 Placebo = 226	Completed	No significant differences in annualized exacerbation rate among all three group	Pavord et al./2017	[114]
Anti-IL13/Anti-IL4	Lebrikizumab	Phase II, randomized, double-blind, placebo-controlled, parallel-group clinical trial	Total =309	Completed	Preliminary results show no influence of lebrikizumab on AECOD		Full results are yet to be published [107]
Anti-IL-33/Anti st2	Itepekimab	1. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Proof-of-Concept Study	Total = 343 Itepekimab treatment group = 172 Placebo = 171	Completed	Subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD.	Rabe et al./2021	[120]
	MSTT1041A/Astegolimab	Single-centre, double-blinded, placebo-controlled, phase2a, randomized controlled trial(NCT03615040)	Total = 81 Astegolimab treatment group = 42 Placebo = 39	Completed	Improvement in the overall health status of the treatment group but failed to reduce exacerbation rate significantly when tested on moderate to severe COPD.	Yousuf et al./2022	[121]
Anti-IL-1	MEDI8968	Phase II, randomized, double-blind, placebo-controlled, parallel-group study	Total = 324MEDI8968 treatment group = 160placebo = 164	Completed	MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function, or quality of life.	Calverley/2017	[131]
	Canakinumab	Randomized, Double-blind, Placebo-Controlled exploratory study	Total = 147 Canakinumab treatment group = 74Placebo = 73	Completed	Not effective in reducing the risk of AECOPD and improving lung function or health status	No publication	NCT00581945

Table 2. Clinical trials that are evaluating biologics in the management of COPD.

Class of biologics	Drug	Type of study	No. of participants	Status	Trials identifier	Remarks
Anti-IL-5& IL-5R	Benralizumab	1. Multicenter, randomized, double-blind parallel-group placebo control phase 3 study	Estimated total = 642	ongoing	NCT04053634	This ongoing study is evaluating the efficacy and safety of benralizumab in eosinophilic COPD
		2. Phase 2 double-blind randomized parallel assigned study	Estimated total = 158	ongoing	NCT04098718	This study is evaluating the effect of benralizumab alone or with prednisone in COPD patients with raised eosinophils at the time of exacerbations
	Mepolizumab	1. Multi-center, randomized, placebo-controlled, double-blind, parallel-group study	Estimated total = 800	ongoing	NCT04133909	Designed to confirm the benefits of mepolizumab treatment on moderate or severe exacerbations in COPD when given as an add-on therapy
		2. Single-center, double-blinded, randomized, placebo-controlled trial	Estimated total = 238	ongoing	NCT04075331	This study is evaluating the efficacy of mepolizumab on future hospitalization or death in those with severe eosinophilic AECOPD
Anti-IL13/Anti-IL4	Dupilumab	1. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pivotal Study	Total = 939	ongoing	NCT03930732	Assessing the Efficacy, Safety, and Tolerability of Dupilumab in COPD with type 2 inflammation
		2. A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal Study	Estimated total = 924	ongoing	NCT04456673	Assessing the Efficacy, Safety, and Tolerability of Dupilumab in COPD with type 2 inflammation
Anti-IL-33/Anti st2	Itepekimab	1. Randomized, Double-blind, Placebo-controlled, Parallel Group Phase 3 Study	Estimated total = 930	ongoing	NCT04701983	Evaluating the Efficacy of Itepekimab on an annualized rate of AECOPD in former smokers
		2. Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 3 Study	Estimated total = 1170	ongoing	NCT04751487	The annualized rate of moderate or severe acute exacerbation of COPD (AECOPD) in former smokers
	MEDI3506	Phase II, Randomized, Double-blind, Placebo-controlled Study	Estimated total = 144	ongoing	NCT04631016	Assessing the Efficacy, Safety, and Tolerability of MEDI3506 in Participants With Moderate to Severe COPD and Chronic Bronchitis (FRONTIER 4)
Anti TSLP	Tezepelumab	A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Phase 2a Study	Estimated total = 338	ongoing	NCT04039113	Exploring the Efficacy and Safety of Tezepelumab in Patients With Moderate to Very Severe COPD

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