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Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease

Authors Burkes RM, Panos RJ

Received 23 September 2020

Accepted for publication 24 November 2020

Published 14 December 2020 Volume 2020:12 Pages 589—602

DOI https://doi.org/10.2147/JEP.S259328

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Professor Bal Lokeshwar

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Robert M Burkes,1,2 Ralph J Panos1,2

1University of Cincinnati Division of Pulmonary, Critical Care, and Sleep Medicine, Cincinnati, OH, USA; 2Department of Pulmonary, Critical Care, and Sleep Medicine, Cincinnati Veterans’ Affairs Medical Center, Cincinnati, OH, USA

Correspondence: Ralph J Panos
Cincinnati Veterans’ Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA
Tel +1 513-861-3100 x 7002
Email [email protected]

Introduction: Inhaled β-agonists have been foundational medications for maintenance COPD management for decades. Through activation of cyclic adenosine monophosphate pathways, these agents relax airway smooth muscle and improve expiratory airflow by relieving bronchospasm and alleviating air trapping and dynamic hyperinflation improving breathlessness, exertional capabilities, and quality of life. β-agonist drug development has discovered drugs with increasing longer durations of action: short acting (SABA) (4– 6 h), long acting (LABA) (6– 12 h), and ultra-long acting (ULABA) (24 h). Three ULABAs, indacaterol, olodaterol, and vilanterol, are approved for clinical treatment of COPD.
Purpose: This article reviews both clinically approved ULABAs and ULABAs in development.
Conclusion: Indacaterol and olodaterol were originally approved for clinical use as monotherapies for COPD. Vilanterol is the first ULABA to be approved only in combination with other respiratory medications. Although there are many other ULABA’s in various stages of development, most clinical testing of these novel agents is suspended or proceeding slowly. The three approved ULABAs are being combined with antimuscarinic agents and corticosteroids as dual and triple agent treatments that are being tested for clinical use and efficacy. Increasingly, these clinical trials are using specific COPD clinical characteristics to define study populations and to begin to develop therapies that are trait-specific.

Keywords: chronic obstructive pulmonary disease, COPD, β-agonist, long-acting β-agonist, LABA, ultra long-acting β-agonist, ULABA

Introduction

Bronchodilating β-agonists have been lynchpins of chronic obstructive pulmonary disease treatment for decades.1–3 Therapeutic β-agonists preferentially bind β2 receptors that are expressed abundantly by airway smooth muscle cells.4 Activation of the β2 receptor stimulates smooth muscle relaxation and bronchodilation via a cyclic adenosine monophosphate pathway.5,6 Based upon their therapeutic duration of action, β-agonists are classified as short acting (SABA) (4–6 h), long acting (LABA) (6–12 h), and ultra-long acting (ULABA) (24 h) (Box 1).7 Ultra-long-acting β-agonists (ULABAs) are of particular interest due to more convenient dosing patterns, the advent of a growing number of nebulized medications, and the ability to use these agents in combination drug therapy.7,8 The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines recommend daily use of these agents for any patient with active daily COPD symptoms and/or a history of acute exacerbations of COPD (AECOPD).1 More recently, work has focused on developing therapies specific to clinical COPD phenotypes by utilizing ULABAs in combination with other types of respiratory medications, including muscarinic antagonists and inhaled corticosteroids.9,10 Additionally, new and innovative delivery systems are being developed to optimize drug delivery to the lungs and improve ease of use.11,12

Box 1 List of β-Agonists Based Upon Duration of Action

This review will focus on translational and clinical studies that are helping to create a patient-centered approach to COPD treatment. Although several efficacious ULABA formulations are approved and available (indacaterol, olodaterol, and vilanterol), medical chemists continue to design new β-agonist molecules that are being evaluated for possible clinical testing. Another promising area is the development of molecules with both β-agonist and muscarinic antagonist properties. We will begin with an overview of current guidelines which will provide the framework for future drug discovery and salient clinical outcomes expected of ULABAs, discuss the most recent work being performed with ULABAs, including combination therapies, discuss the role of drug delivery in the development of ULABA therapy, and, finally, biochemical advances that may be utilized in the next wave of ULABA agents. Understanding the breadth of science, from bench-side-to-translational-to-clinical will refine how these agents may be used in COPD management.

Guideline Based Utilization of ULABAs for COPD

The GOLD guidelines are the preeminent global clinical guidelines for the treatment of COPD.1 The GOLD guidelines classify ULABAs as long-acting-daily COPD medications for symptomatic patients and/or patients predisposed to COPD exacerbations and do not distinguish ULABA from LABA. The utilization of either LABA or ULABA should not preclude the use of short-acting β-agonists (SABA) for symptomatic control.1 However, GOLD does not make specific recommendations for the utilization of long-acting β-agonists outside of recommending prescribing drugs that are best tolerated, provide optimal convenience, and are the most efficacious for any given patient. Certainly, the use of a once daily medication, if drug delivery is optimized, is a boon to COPD therapy. Long-acting β-agonists (LABA and ULABA) have been combined with either anticholinergics or corticosteroids in dual combination devices and with both anticholinergics and corticosteroids in triple combination devices.13 ULABA monotherapy and combination therapy in COPD have been extensively studied and will be reviewed.

As a class, LABA and ULABA therapy in COPD has been shown to improve quality of life metrics and reduce hospitalizations relative to placebo, while seemingly having no effect on exacerbations-as-a-whole and mortality in a combination of 26 studies with approximately 15,000 participants.14 It should be noted that visual appraisal of the funnel plot in this review suggests that there is some bias towards statistically significant findings in publications as well as reported inconsistencies in the definition of “exacerbation” across studies. Further, the studies mainly focused on salmeterol and formoterol as interventions, which are not ULABAs.14 Studies of other ULABAs present generally similar but not entirely analogous findings:

Indacaterol

Indacaterol is a ULABA developed by medicinal chemists at Novartis and approved for clinical use by the Federal Drug Administration (FDA) in July 2011. The development, pharmacology, clinical efficacy, and safety profile of indacaterol were reviewed extensively in our previous review of ULABA’s.15 Initial studies in 2006 showed that after 28 days of indacaterol therapy, participants receiving indacaterol (400 mcg and 800 mcg) had a 200 mL to 260 mL, respectively, increase in forced expiratory volume in one second (FEV1) compared with placebo.16 Further, in this initial study, indacaterol had no effect on electrocardiographic parameters, adverse events, or tachycardia, with only a mild increase in serum potassium, glucose, and blood pressure. Other pre-clinical and early clinical trials of indacaterol have been reviewed.17 Indacaterol improved breathlessness in a meta-analysis of six trials.18,19 A Cochrane systemic review analyzed 13 trials comparing indacaterol with either placebo or twice daily β-agonist in the treatment of COPD and demonstrated that indacaterol produced statistically and clinically meaningful increases in both lung function and quality of life compared with placebo.20 A network meta-analysis comparison of monotherapy with LABA’s or ULABA’s in individuals with COPD showed that indacaterol was the most effective β-agonist monotherapy for moderate-to-severe COPD based upon the effects on spirometry, breathlessness, and COPD exacerbation rates.21 A similar network meta-analysis of 40 randomized controlled trials showed that indacaterol treatment was associated with a reduction in mortality in fixed (HR 0.28; 95% CI 0.08–0.85) and random effects (HR 0.29; 95% CI 0.08–0.89) models compared with placebo.22 Indacaterol’s safety profile is similar to placebo but side effects may occur with prolonged use.23

Dual drug combinations incorporating indacaterol have been examined in the management of COPD. With less frequent medication administration, these combinations seek to improve patient adherence and ease of use. Once daily treatment with indacaterol/glycopyrronium (110/50 mcg once daily) for 24–26 weeks produced greater benefits in lung function, daily symptoms, breathlessness, health-related quality of life, and rescue medication use compared with LAMAs.24 In a one-year trial, combination indacaterol/glycopyrronium (110/50 mcg once daily) prevented COPD exacerbations more effectively than salmeterol/fluticasone (50/500 mcg twice daily) in individuals who have a high risk of exacerbations.25 Additionally, indacaterol/glycopyrronium (110/50 mcg once daily) treatment delayed the time to clinically important deterioration (defined as ≥100 mL decrease in FEV1 or ≥4 unit increase in the St. George’s Respiratory Questionnaire or a moderate to severe COPD exacerbation) compared with salmeterol/fluticasone (50/500 mcg twice daily) therapy in individuals with moderate to very severe COPD.26 A 12-week trial comparing indacaterol/tiotropium and umeclidinium/vilanterol in individuals with COPD showed similar improvements in spirometry, dyspnea, St. George’s Respiratory Questionnaire, and safety profile.27 Combination indacaterol/glycopyrronium treatment is well tolerated with a safety profile and adverse effects similar to each of its components.28

Most recently, indacaterol/glycopyrronium combination therapy has been evaluated in the de-escalation of triple therapy for COPD. The SUNSET trial showed that individuals with COPD and infrequent exacerbations treated with tiotropium (18 mcg once daily) and salmeterol/fluticasone propionate (50/500 mcg twice daily) who were switched to indacaterol/glycopyrronium (110/50 mcg once daily) experienced small reductions in lung function but no change in COPD exacerbations.29 However, the greater exacerbation risk in individuals with ≥300 eosinophils suggested that these individuals would obtain greater benefit from triple therapy.

Olodaterol

Olodaterol was first reported by medicinal chemists at Boehringer Ingelheim in 2010 and approved by the FDA in July 2014. Initially, olodaterol was noted to reverse acetylcholine-induced bronchoconstriction in canines and guinea pigs. This effect persisted for over 24 h, significantly longer than concomitantly tested formoterol.30 In addition to a prolonged duration of effect, olodaterol has a fast onset of action and high β2-adrenoreceptor selectivity.31 Initial placebo-controlled, single dose–response studies in individuals with moderate to very severe COPD showed a dose-dependent response in FEV1 to 2–20 mcg olodaterol.31 Compared with placebo, olodaterol significantly augmented FEV1 at 12 h (121 mL to 213 mL based on dose from 2 to 20 mcg) and 24 h (74 mL to 141 mL based on dose from 2 to 20 mcg).32 In this early study, lung function peaked 2–3 h after all doses and then decreased from 12 to 24 h.32 Subsequent 12-week studies of once daily 5 or 10 mcg olodaterol in individuals with moderate to very severe COPD showed that both doses of olodoterol significantly improved the FEV1 area under the curve from 0 to 3 hours (FEV1 AUC0–3) and trough FEV1 response compared with placebo with a comparable range and incidence of adverse events.33 Further studies showed that once-daily 5 or 10 mcg olodaterol improved FEV1 AUC0–3 and trough FEV1 response after 24 weeks compared with placebo in individuals with moderate to very severe COPD and these improvements were comparable to the effect of twice daily formoterol.34 Although there was no difference in transitional dyspnea index for either olodoterol or formoterol compared with placebo, the St. George’s Respiratory Questionnaire35 total score was significantly improved after olodoterol but not formoterol compared with placebo.34 Subsequent Phase III clinical trials of olodaterol in individuals with COPD demonstrated significant improvements in lung function, breathlessness, and quality of life.36 Studies have generally deemed olodaterol safe based on lack of observed adverse events compared with placebo.32,33 Cough, nasopharyngitis, and headache are the most frequent side effects.

Olodaterol has been combined with tiotropium to develop a long-acting fixed dose combination ULABA/LAMA medication for COPD management.37,38 Tiotropium/olodaterol (5/5 mcg once daily) produced greater increases in lung function, health-related quality of life indices, St. George’s Respiratory Questionnaire, and breathlessness than either drug alone.39

Vilanterol

Medicinal chemists at GSK developed vilanterol, another ULABA. Vilanterol was initially described in a murine model to have a long and potent duration of action along with high β-receptor selectivity.40 Vilanterol’s affinity for the β2-receptor is comparable to salmeterol but greater than olodoterol, formoterol, or indacaterol.41 In human airway tissue, vilanterol has a faster onset and longer duration of action than salmeterol.41 To date, vilanterol is only marketed in combination with other COPD/asthma medications. Studies have been performed on vilanterol monotherapy showing increased FEV1 compared with placebo without an increase in adverse events including electrocardiographic, glucose, or potassium changes.42 Vilanterol, 25–100 mcg, increased FEV1 as quickly as 5 min after dosing and maintained the increases for up to 24 h in individuals with COPD. A dose-ranging study of vilanterol from 3 to 50 mcg in patients with moderate to severe COPD showed that higher doses of vilanterol, 25 and 50 mcg, produced clinically relevant increases in trough FEV1 (>130 mL) after 28 days compared with placebo.43 The safety and tolerability profile of vilanterol was similar to placebo.

Vilanterol has been combined with corticosteroids (fluticasone) and with LAMA (umeclidinium) in dual and triple combinations. Vilanterol/umeclidinium improves lung function, St George’s Respiratory Questionnaire scores, and requirement for rescue inhaler use in individuals with COPD.44–47 Additionally, vilanterol/umeclidinium treatment produced greater improvement in lung function compared with salmeterol/fluticasone.48

A randomized, open-label cross-over trial comparing umeclidinium/vilanterol and tiotropium/olodoterol in individuals with COPD, umeclidinium/vilanterol was non-inferior to tiotropium/olodoterol in the primary endpoint, change from baseline in trough FEV1 at week eight.49 However, umeclidinium/vilanterol produced greater improvements in other measures of lung function as well as reductions in rescue medication use and the COPD Activity Test scores compared with tiotropium/olodoterol.

In a 12-week trial comparing 25 mcg vilanterol and 100/25 mcg fluticasone furoate/vilanterol treatment for 8 weeks in individuals with COPD, the change from baseline trough FEV1 was greater for those receiving combination therapy.50 Although rescue medication use was similar in the two groups, there was a 42% risk reduction in time to first moderate to severe COPD exacerbation in the combination treatment group. Adverse events were similar with either therapy.

Dual combination treatment with fluticasone furoate/vilanterol compared with placebo increases lung function in individuals with COPD.51,52 The annual rate of moderate and severe COPD exacerbations, time to first moderate or severe exacerbation, and frequency of exacerbations requiring steroids in individuals with moderate-to-severe COPD treated with fluticasone furoate/vilanterol are reduced compared with those treated with vilanterol alone.53 The SUMMIT trial randomized over 16,000 participants with COPD to placebo, fluticasone furoate or vilanterol or fluticasone furoate/vilanterol treatment and showed that combination treatment did not affect all-cause mortality or cardiovascular outcomes, but combination and fluticasone furoate alone treatment decreased the rate of FEV1 decline.54

The FULFILL study compared fluticasone furoate/umeclidinium/vilanterol triple combination therapy with budesonide/formoterol dual therapy and showed that triple therapy improved lung function, reported pulmonary symptoms, and quality of life indices.55,56 A large study of over 10,000 participants with COPD compared combined triple therapy, fluticasone furoate/umeclidinium/vilanterol (100 mcg/62.5 mcg/25 mcg) with fluticasone furoate/vilanterol (100 μg/25 μg) or umeclidinium/vilanterol (62.5 mcg/25 mcg) for 52 weeks and showed triple therapy reduced the rate of moderate or severe COPD exacerbations compared with either dual therapy and the rate of COPD hospitalizations compared with umeclidinium/vilanterol dual therapy.55

Equipoise remains in guidelines in regard to the utilization of ULABA agents for bronchodilation in COPD compared with long-acting muscarinic (LAMA) agents. LAMA are preferred as the first choice for bronchodilation in COPD patients.1 However, the tenets of patient-directed care and continual reassessment of symptoms and drug delivery suggest that the opportunity for utilization of ULABA monotherapy in COPD certainly exists and may be appropriate in select patients. The differentiating factor is likely drug delivery. Indacaterol is delivered in a dry powder inhaler device that has been associated with a high degree of user error57 while olodaterol is in a soft mist inhaler that generally improves drug administration and deposition58 but requires necessary motor and coordination skills to actuate and inspire from the device properly. On the balance, all inhaler devices have some degree of potential for patient error and patient-centered device education and continual reassessment are tantamount in determining the best delivery system to use.

Recent Approaches to ULABA Therapy and Experimental Agents

In recent years, ULABAs in combination with LAMAs have changed the paradigm of COPD therapy. This combination is particularly effective due to the synergistic effect between β receptor stimulation and muscarinic receptor antagonism.13 These combinations appear to have considerable clinical benefit and provide bronchodilation without the additional potential risk of pneumonia caused by concomitant inhaled corticosteroid use.25 ULABA/LAMA combination therapy provides bronchodilation and symptom relief with a safety profile similar to either ULABA or LAMA monotherapy,59 and these agents are powerful tools in the treatment of COPD patients whose disease course is marked by persistent chest symptoms. Other studied ULABAs include:

Trantinerol

Trantinterol or SPFF is a unique ULABA that is based upon a 2-amino-2-phenylethanol scaffold rather than the 2-amino-1-phenylethanol backbone used to develop other ULABA drugs such as indacaterol.60 SPFF has high affinity and selectivity for the β2 receptor.61 It relaxes both untreated and acetylcholine or histamine-precontracted isolated guinea pig trachea strips in a dose-dependent manner with a potency similar to isoprenaline. Evaluation of SPFF enantiomers demonstrates that the (-)- enantiomer has greater affinity for the β2 adrenergic receptor than either the (±)- or the (+)- enantiomers and is more potent.62 Subsequent in vivo experiments showed that (-) SPFF inhibited histamine-induced bronchoconstriction in guinea pigs while (+) SPFF did not.63 At the time of this writing, there are no registered clinical trials investigating SPFF.

Abediterol

Abediterol is a novel, long-acting β2 agonist synthesized by medicinal chemists at Almirall.64 Its affinity for the human β2 receptor is greater than salmeterol, formoterol, and indacaterol with high specificity and full agonist function. The onset of action is approximately 7.4 min with a prolonged duration of action. In guinea pig acetylcholine bronchoprovocation testing, abediterol was a more potent bronchoprotectant than formoterol, indacaterol, or salmeterol and had a prolonged protective effect.

In the initial study of abediterol in humans, 48 healthy men inhaled abediterol in a randomized, parallel, single-blind placebo-controlled single-dose escalation protocol.65 Albediterol increased specific airway conductance (sGaw) and reduced airway resistance (Raw) at 24 and 36 h after inhalation. The most common adverse events were palpitations and tremor without clinically significant changes in serum potassium or glucose.

In a dose-ranging randomized, crossover, placebo-controlled study in 62 patients with mild to moderate asthma who were being treated with an ICS, spirometry was performed 36 h after single doses of 0.313, 0.625, 1.25, or 2.5 mcg abediterol.66 Abediterol stimulated a dose-dependent increase in peak FEV1 compared with placebo, comparable to the effect of 400 mg salbutamol. Additionally, the peak and trough FVC and the FEV1 area under the curve for time periods 0–6, 0–12, and 0–24 h were significantly increased compared with placebo. In a similar study of 70 individuals with GOLD stage II/III COPD, single doses of 0.625, 2.5, 5, or 10 mcg Abediterol were compared with 150 mg indacaterol or placebo.67 Spirometry was performed 36 h after medication administration. All doses of abediterol induced significant increases in trough FEV1 compared with placebo and 2.5, 5, and 10 mcg abediterol increased trough FEV1 compared with indacaterol. Adverse events were similar between all the treatment groups.

A randomized, double-blind, crossover, phase IIa trial compared three doses of abediterol (5, 10, and 25 mcg) with salmeterol and placebo added to an inhaled corticosteroid in a stable dose regimen in 25 individuals with mild to moderate persistent asthma.65 Compared with both placebo and salmeterol, all three doses of abediterol stimulated significant increases in trough FEV1 that were sustained for 36 h. Other spirometric measurements including FVC, peak expiratory flow, and FEF25–75 also improved. Dose-dependent mild to moderate adverse effects including tremor, restlessness, and nervousness were noted in those receiving abediterol. Slight decreases in serum potassium and increases in serum glucose and heart rate were noted.

An ascending-dose, crossover study evaluated spirometry after 2.5, 5, and 10 mcg abediterol given once daily for a week compared with placebo in men with stable asthma was performed.68 Both peak and trough FEV1 on day 7 were increased for all doses. Abediterol was associated with a dose-dependent increase in the proportion of participants experiencing tremor and nervousness. As with SPFF, there are no ongoing trials of abediterol at the time of this writing.

Milveterol (TD-3327; GSK 159797)

Milveterol was developed through the creation of dimeric arylethanolamines with varying linkers based upon the albuterol scaffold.69 In the BEAS-2B endogenous cell line, it has a β2 pEC50 of 9.3±0.3 and intrinsic activity 87±9%. Milveterol provides both short- and long-term protection in an in vivo guinea pig bronchoconstriction model.

In a study of 38 patients with mild asthma, a single inhalation of GSK159797 achieved the targeted FEV1 increase over the 24-h study period without cardiovascular toxicity.70 An inhaled dry powder preparation of 10 and 20 mcg GSK159797 significantly elevated FEV1 through 24 hours in a placebo-controlled, dose-ascending crossover trial with 20 participants with mild-to-moderate asthma.71 No results from either of these trials have been posted on ClinicalTrials.gov at the time of this writing.

TD-5471

TD-5471 was developed by modification of the 4-aminophenethylamine linking group of the milveterol scaffold.72 In the guinea pig trachea assay, it has a slow onset of action with pEC50 of 8.7±0.1. TD-5471’s selectivity for the human β2-adrenergic receptor is comparable to formoterol with a β2 pEC50 of 9.4±0.4, intrinsic activity of 83±9%, and functional selectivity β21 of 56 and β23 of 100. TD-5471 demonstrated both short- and long-term bronchoprotection in a guinea pig model of in vivo intravenous acetylcholine-induced bronchoconstriction. As with the above, there are no ongoing trials of TD-5471

TD-4306

Further evaluation and modification of milveterol and TD-5471 through the addition of amine moieties and scaffold modification led to the development of the dibasic β2 agonist, TD-4306.73 TD-4306 has a β2 pED50 of 10.1, and 70% intrinsic activity in the BEAS endogenous cell line assay. In the in vivo guinea pig bronchoprovocation model, TD-4306 provided significantly greater, dose-dependent bronchoprotection than salmeterol. TD-4306 has reduced enteral bioavailability in both rats and dogs. Again, there are no ongoing trials of this agent.

PF-610355

PF-610355 was developed by medicinal chemists at Pfizer who were attempting to synthesize novel, once daily inhaled β2 agonists.74 PF-610355 has a β2 EC50 of 0.26 nM and is approximately 4-fold more potent than salmeterol with a prolonged duration of action in the in vitro guinea pig trachea contraction model.74 In an in vivo canine intravenous acetylcholine bronchoprovocation model, PF-610355 was an equipotent bronchodilator compared with formoterol and more potent than salmeterol. It has low systemic bioavailability with poor absorption through both the intestine and the lungs and is metabolized predominantly through CYP3A4.

A single dose of 450 mcg PF-610355 had a more durable effect on specific airway conductance (sGAW) than either placebo or salmeterol (16.4 h and 9.8 h) longer duration, respectively, in healthy male volunteers.74,75 In a two-week trial, PF-610355 was well tolerated.74,76 An analysis of 10 clinical studies enrolling 579 healthy volunteers and individuals with asthma and COPD using pharmacokinetic/pharmacodynamic modeling suggested that 19% of individuals with COPD treated with 280 mcg of PF-610355 would increase heart rate by 20 or more beats/minute compared with 8% of those receiving placebo.77 Further development of this agent has been discontinued.

AZD 3199

Medicinal chemists at AstraZeneca synthesized a family of dibasic des-hydroxy β2 receptor agonists and selected AZD3199 for further evaluation based upon enhanced duration of action and efficacy.78 AZD3199 has greater than 1500-fold binding selectivity for β2 receptors compared with β1 and β3 receptors, a pEC50 of 7.9±0.12, and intrinsic activity in isolated guinea pig tissue comparable to indacaterol and formoterol with a rapid onset of action and prolonged duration of effect.

Single ascending dose studies using nebulizer delivery and multidose studies using dry powder delivery in healthy participants with either mild-to-moderate persistent asthma or moderate-to-severe COPD showed AZD3199 was rapidly absorbed and had a prolonged half-life of up to 142 h.79 It was well tolerated with mild dose-dependent reductions in serum potassium levels and increases in heart rate. In a double-blind, placebo-controlled, randomized, cross-over, single-dose study in mild-to-moderate asthma, the bronchodilating effects of inhaled AZD3199 delivered by dry-powder inhaler augmented peak FEV1 and maintained bronchodilation at 24 h with 480 and 1920 mcg doses when compared with placebo.80 Throat irritation, tachycardia, and lower serum potassium levels were noted at the highest dose. In a 4-week randomized, double-blind placebo-controlled study of individuals with moderate-to-severe COPD, the efficacy and safety of AZD3199 was compared with formoterol and placebo.81 Peak and trough FEV1 and peak FVC were increased, in comparable fashion to formoterol, compared to placebo without dose response. AZD3199 reduced patient-reported symptoms including breathlessness and total symptom burden as well as Clinical COPD Questionnaire and Saint George’s Respiratory Questionnaire scores. Adverse events were mild and dose-related. There are no ongoing trials of AZD3199 at the time of this writing.

Carmoterol, TA-2005

Carmoterol/TA-2005 was constructed based upon elements from both formoterol and procaterol with a p-methoxyphenyl group on the amine side chain and an 8-hydroxyl group on the carbostyril aromatic ring.71,82 In several models of smooth muscle constriction, carmoterol/TA-2005 produced robust bronchodilation and smooth muscle relaxation with a prolonged duration of action.83,84 Radioligand experiments showed carmoterol/TA-2005 binds the β2 adrenergic receptor with very high affinity and specificity.85 The high-affinity binding of carmoterol/TA-2005 appears to be due in large part to Tyr308 within the transmembrane 7 region of the β2 adrenergic receptor.86 Its onset of action in vitro is similar to formoterol and its duration of muscle relaxation activity is longer than salmeterol or formoterol.87

Phase II studies in individuals with COPD showed that carmoterol/TA-2005 was safe and well-tolerated with no apparent cardiovascular adverse events.88 In a randomized, double-blind parallel group trial enrolling 124 participants with persistent asthma, carmoterol/TA-2005 was as effective as formoterol and significantly more effective than placebo in improving trough FEV1 at the end of the eight-day treatment period.89 Carmoterol/TA-2005 had a safety and tolerability profile similar to formoterol.90 In 2010, clinical trials of Carmoterol/TA-2005 were stopped by Chiesi Famarceutici because it was not considered to have a competitive profile.91

GSK597901; GSK159802; GSK678007

Other ultralong acting β2 agonist bronchodilators include GSK597901; GSK159802; GSK678007.82 There is little information available for GSK597901 or GSK678007. One trial of GSK159802 is registered on Clinicaltrials.gov (NCT00364273). This study assessed the safety and tolerability of single inhaled doses of GSK159802 compared with salmeterol and placebo with no results posted at the time of this writing.

Drug Backbone Structure, β-Arrestins and Bivalent Agents

There is also a recent focus on restructuring the “backbone” of inhaled medications to increase receptor affinity and drug efficacy. This innovation has led to the creation of different ‘classes’ of medication but with the shared goal of achieving bronchodilation through airway smooth muscle relaxation. Additionally, newer β-arrestin biased β2 adrenoceptor agonists are being developed. Finally, bivalent molecules that both possess both muscarinic receptor antagonist and β2 agonist activities are being tested for COPD management.

Drug Backbone Restructuring

Enantiomers and drug scaffolding are a potential target for future LABA medications. Recently, the Medicinal Chemistry group at Shenyan Pharmaceutical University has modified existing ultralong acting β2 agonists to create novel compounds with the potential for clinical applications. They utilized the indacaterol scaffold to create new β2 agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety.92 Two of these novel molecules, 9g and (R)-18c, are potent and selective β2 agonists with a rapid onset of action similar to isoprenaline and a duration of action equivalent to salmeterol in cell and isolated guinea pig trachea assays and were selected for further development. They have also combined the head and tail groups of indacaterol with the core of trantinterol to produce a compound, 5a, and a series of analogs with modifications of the tail group.60 One of these compounds, (S)-5j (8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one), had higher binding selectivity for the β2 than β1 adrenergic receptor, robust stimulation of cAMP through the β2 receptor, and a maximal effect in the isolated guinea pig tracheal relaxation assay similar to isoprenaline.

Modifications of the 3- and 5-positions of the phenyl head group of the trantinterol scaffold have also produced a novel compound, 2f (2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile) that stimulates cAMP production through the β2 adrenoreceptor with an EC50 of 0.25 nM and exhibits β2 receptor selectivity.93 This compound induced smooth muscle relaxation in the isolated guinea pig trachea model that was attenuated by ICI-118551, an antagonist of β2-adrenergic receptor binding. The (S)-isomer was more active than the (R)-isomer.

Modification of the tail group of the olodoterol scaffold produced (R)-18c that is a potent β2 agonist with an EC50 of 24 pM for the in vitro production of cAMP.94 In the guinea pig tracheal assay, the smooth muscle cell relaxant effect was similar to olodoterol with a rapid onset of action and prolonged duration of effect. Clinical studies of these novel β2 agonists will be needed to assess their safety, tolerability, and efficacy.

β-Arrestin-Based β2 Adrenoceptor Agonists

The β2 adrenergic receptor is a G protein-coupled receptor with complex signaling mechanisms that can be transduced by heterotrimeric G proteins and β-arrestins.95 Originally, the β-arrestin adaptor proteins were found to have an inhibitory role in G protein-coupled receptor signaling.96,97 Subsequent studies revealed β-arrestins could initiate endocytosis and kinase activation stimulating intracellular signaling pathways independent of G protein activation by G protein-coupled receptors.97 Thus, biased ligands can target either G protein or β-arrestin signaling with diverse intracellular and biological effects. β-arrestin biased β2 adrenoceptor agonists have the potential to be a new drug class for the treatment of COPD.

Woo and colleagues93 synthesized β-arrestin compounds with a 5-(1-amino-2- hydroxyethyl)-8-hydroxyquinolin-2(1H)-1 core structure that stimulates cellular cAMP production in vitro and induces bronchodilation in a guinea pig trachea relaxation assay, with bronchodilatory effects less robust than isoproterenol. These β-arrestin biased β2 adrenoceptor agonists have a potential role as new therapeutics in the management of COPD.

Combined Muscarinic and Beta Activity

In vitro studies demonstrate that muscarinic receptor antagonists synergistically increase bronchodilation by β2 receptor agonists.98,99 This synergism may be mediated by increases in cAMP concentrations in smooth muscle and bronchial epithelial cells, a decrease in epithelial cell release of acetylcholine, and linkages between G proteins, large-conductance calcium activated potassium channels, and voltage-dependent calcium channels.99 Hence, a unique approach to combination drug therapy for COPD is the creation of molecules with both muscarinic receptor antagonist and β2 agonist activities.100 Batefenterol (GSK961081) is a bivalent inhaled bronchodilator with both properties.101 This molecule binds with high affinity to both muscarinic and β2 adrenergic receptors with specificity for β2 compared with β1 or β3. Batefenterol stimulates cAMP production in vitro and induces smooth muscle cell relaxation in the isolated guinea pig trachea assay. In an in vivo guinea pig model of bronchoconstriction, batefenterol provided dose-dependent bronchoprotection for up to 1 week.

A pharmacokinetic and pharmacodynamic study of 100, 400, and 800 mcg batefenterol once daily and 100, 200, and 400 mcg batefenterol twice daily in 47 patients with COPD measuring day 29 trough FEV1 as the primary endpoint showed no significant difference between once daily and twice daily dosing.102 The optimal dose appeared to be batefenterol 400 mcg. Blood levels of batenfenterol were well described with a two-compartment model and no clear relationships between batenfenterol levels and measured cardiac effects were observed.

In a randomized, double-blind, double dummy, crossover trial comparing 14 days of 400 mcg or 1200 mcg batefenterol once daily, 18 mcg tiotropium once daily and 50 mcg salmeterol twice daily, or placebo in 50 participants with COPD, showed that both doses of batefenterol stimulated a significant increase in FEV1 that was similar to that induced by tiotropium/salmeterol but with a more rapid onset.103 Adverse effects were similar in the treatment groups but tremor, dysgeusia, and dry mouth were only reported after batefenterol inhalation.

In a phase IIb dose-response study, individuals with COPD received 37.5, 75, 150, 300, or 600 mcg batefenterol, or 62.5 mcg umeclidinium and 25 mcg vilanterol, or placebo once daily for 42 days.104 All batefenterol doses stimulated increases in FEV1 measured as weighted mean FEV1 over 0–6 h and trough FEV1 at the end of the study. Batefenterol at doses of 150 mcg or greater had spirometric improvement comparable to umeclidinium/vilanterol. The most common adverse events in those participants receiving batefenterol were cough, nasopharyngitis, and dysgeusia.

A study to determine the bronchodilatory effects of batefenterol compared once daily 100, 400, or 800 mcg batefenterol, twice daily 100, 200, or 400 mcg batefenterol, or placebo in patients with COPD demonstrated significant improvement in trough FEV1 on day 29 compared with placebo in all treatment groups.105 The optimal dose appeared to be 400 mcg daily either as a single dose or 200 mcg twice daily. Glucose, potassium, heart rate, and blood pressure were not affected and no corrected QT elongation dose-response effect was observed.

In healthy volunteers receiving propranolol to induce β2 blockade, 1200 mcg of batefenterol induced bronchodilation measured by specific airway conductance at 1 and 4 h but not 7 or more hours after dosing whereas 400 mcg batefenterol stimulated bronchodilation for only the first hour after dosing.106 These results suggest that the bronchodilatory effect of the antimuscarinic agent dissipates faster than the β-agonist effect.

To assess the effect of adding short-acting β-agonists or muscarinic antagonists to batefenterol, 44 patients with moderate COPD received single inhalations of 400 or 1200 mcg batefenterol followed by multiple doses of salbutamol, ipratropium, or placebo for 24 h.107 Both salbutamol and ipratropium had additional bronchodilating effects measured by an increase in FEV1 at 12 and 24 h after batefenterol administration, an effect not seen at 1 h after dosing. Mild increases in heart rate were noted after salbutamol with both batefenterol doses and four participants experienced declines in serum potassium levels after receiving 1200 mcg batefenterol and either salbutamol or placebo.

As of November 1, 2020, there were no ongoing or new trials of batefenterol registered at ClinicalTrials.gov (clinicaltrials.gov accessed November 1, 2020).

Conclusion

COPD affects over 250 million people worldwide108 and 30 million people in the US.109 As a leading cause of morbidity and mortality, COPD generates a significant and increasing medical, economic, and social burden.110,111 COPD is increasingly being recognized as a heterogeneous disorder with a multitude of unique and overlapping phenotypes and endotypes that can be differentiated by clinical, radiographic, physiologic, cellular, or biochemical features.112–114 Historically, clinical presentation was used to divide COPD into “blue bloaters” (chronic bronchitis) or “pink puffers” (those with emphysema). The number of prior COPD exacerbations can be used to create categories of frequent exacerbators and infrequent exacerbators.115–117 The severity of airflow limitation is used to separate individuals with no, mild, moderate, severe, and very severe obstruction based upon spirometric measurement of the FEV1 and FEV1:FVC ratio. Serum or sputum eosinophil counts may be used to classify and hierarchize patients with COPD based upon their response to inhaled corticosteroids.118 Plasma fibrinogen concentration is an FDA qualified biomarker for all-cause COPD mortality and COPD exacerbations.119 One of the major goals of determining these COPD traits is to develop individualized precision medicine treatment strategies that will provide both prognostic and therapeutic guidance for the management of each person with COPD.9

These traits can be used to prognosticate the clinical course of individuals with COPD. Prior exacerbations predict those who are at increased risk of future exacerbations.117 Elevated plasma fibrinogen levels correlate with increased COPD exacerbation frequency and with mortality.120 A systemic review of over 400 prognostic models in individuals with COPD showed that the most commonly used predictors were age, FEV1, body mass index, and smoking history.121 However, a detailed analysis of these models revealed methodological vulnerabilities and a lack of external validation. Most recently, machine learning algorithms have been used to predict the prognosis of patients hospitalized with COPD exacerbations utilizing 28 variables including vital signs, medical history, comorbidities, and inflammatory markers.122 The C5.0 decision tree classifier analysis was 80.3% accurate with a 0.6991-to-0.8827 95% confidence interval in prognosticating deterioration or death in patients hospitalized with COPD exacerbations.

Other markers can be used to predict response to therapy and may be used to develop individualized therapeutic strategies based upon treatable traits. Elevated blood eosinophil counts predict the clinical response to inhaled corticosteroid treatment in individuals with COPD.118 This relationship appears to start at a level of 100 eosinophils/µl and the clinical response becomes more robust as the eosinophil count increases.123,124 Although only a small proportion of individuals with COPD have alpha-1-antitrypsin deficiency, recognition of the genetic mutations that cause reduced functional alpha-1-antitrypsin within the lung and increased risk of emphysema leads to specific therapy with alpha-1-antitrypsin replacement.125,126

The current mainstays of COPD maintenance therapy consist of three classes of inhaled medications: β-agonists, muscarinic antagonists, and corticosteroids. Bronchodilators started as short-acting medications such as albuterol and ipratropium with durations of effect lasting from 2 to 6 h. Next, long-acting medications with effects lasting up to 12 h were discovered and, most recently, ultralong acting drugs that only require daily dosing have been developed and clinically tested. Although these medications have different durations of effect, within each class, they act through the same receptors and similar intracellular mechanisms. The benefit of less frequent dosing is believed to improve patient adherence and, consequently, clinical outcomes.127

Many of these medications were originally approved for clinical use as monotherapy, were then used and clinically tested with simultaneous use through separate devices, and subsequently joined in combined dual and triple single modality treatments. Vilanterol is the first to be approved only in combination. Although there are many other ULABA’s in various stages of development, clinical testing of these medications is either proceeding slowly or on hold. Instead, existing approved medications are being combined in various permutations to develop new dual or triple therapies that are being tested for clinical use and efficacy. Increasingly these clinical trials are using clinical traits to define study populations and to begin to develop trait-specific therapies.

At this time, we are not aware of any treatable traits that portend clinical response to β-agonists or muscarinic antagonists. As mono- or dual-therapy these medications are the basis of maintenance COPD medication management and may be combined together with ICS as triple therapy. Until there are fundamental breakthroughs in the pathogenesis of COPD and new developments in lung airway biology leading to the development of novel therapeutic drug classes, β-agonists and muscarinic antagonists will remain the foundational medications for maintenance COPD management.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2020.

2. Singh D, Agusti A, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53:1900164. doi:10.1183/13993003.00164-2019

3. Celli BR, Wedzicha JA, Drazen JM. Update on clinical aspects of Chronic Obstructive Pulmonary Disease. N Engl J Med. 2019;381:1257–1266. doi:10.1056/NEJMra1900500

4. Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol. 2006;117:18–24; quiz 5. doi:10.1016/j.jaci.2005.11.012

5. Ejiofor S, Turner AM. Pharmacotherapies for COPD. Clin Med Insights Circ Respir Pulm Med. 2013;7:17–34. doi:10.4137/CCRPM.S7211

6. Billington CK, Penn RB, Hall IP. β(2) Agonists. Handb Exp Pharmacol. 2017;237:23–40.

7. Beeh KM, Beier J. The short, the long and the “ultra-long”: why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Adv Ther. 2010;27:150–159. doi:10.1007/s12325-010-0017-6

8. Malerba M, Radaeli A, Montuschi P, Babu KS, Morjaria JB. Investigational beta-2 adrenergic agonists for the treatment of chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2017;26:319–329. doi:10.1080/13543784.2017.1287172

9. Sidhaye VK, Nishida K, Martinez FJ. Precision medicine in COPD: where are we and where do we need to go? Eur Respir Rev. 2018;27:180022. doi:10.1183/16000617.0022-2018

10. Corlateanu A, Mendez Y, Wang Y, Garnica RJA, Botnaru V, Siafakas N. Chronic obstructive pulmonary disease and phenotypes: a state-of-the-art. Pulmonology. 2020;26:95–100. doi:10.1016/j.pulmoe.2019.10.006

11. Rogliani P, Calzetta L, Coppola A, et al. Optimizing drug delivery in COPD: the role of inhaler devices. Respir Med. 2017;124:6–14. doi:10.1016/j.rmed.2017.01.006

12. Mahon J, Fitzgerald A, Glanville J, et al. Misuse and/or treatment delivery failure of inhalers among patients with asthma or COPD: a review and recommendations for the conduct of future research. Respir Med. 2017;129:98–116. doi:10.1016/j.rmed.2017.05.004

13. Burkes RM, Donohue JF. An update on the global initiative for Chronic Obstructive Lung Disease 2017 guidelines with a focus on classification and management of stable COPD. Respir Care. 2018;63:749–758. doi:10.4187/respcare.06174

14. Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;Cd010177.

15. Zafar MA, Droege C, Foertsch M, Panos RJ. Update on ultra-long-acting β agonists in chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2014;23:1687–1701. doi:10.1517/13543784.2014.942730

16. Beier J, Chanez P, Martinot JB, et al. Safety, tolerability and efficacy of indacaterol, a novel once-daily beta(2)-agonist, in patients with COPD: a 28-day randomised, placebo controlled clinical trial. Pulm Pharmacol Ther. 2007;20:740–749. doi:10.1016/j.pupt.2006.09.001

17. Murphy L, Rennard S, Donohue J, et al. Turning a molecule into a medicine: the development of indacaterol as a novel once-daily bronchodilator treatment for patients with COPD. Drugs. 2014;74:1635–1657. doi:10.1007/s40265-014-0284-7

18. Han J, Dai L, Zhong N. Indacaterol on dyspnea in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized placebo-controlled trials. BMC Pulm Med. 2013;13:26. doi:10.1186/1471-2466-13-26

19. Geake JB, Dabscheck EJ, Wood-Baker R, Cates CJ. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;1:Cd010139.

20. Gotfried MH, Kerwin EM, Lawrence D, Lassen C, Kramer B. Efficacy of indacaterol 75 μg once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. Copd. 2012;9:629–636. doi:10.3109/15412555.2012.729623

21. Donohue JF, Betts KA, Du EX, et al. Comparative efficacy of long-acting β2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017;12:367–381. doi:10.2147/COPD.S119908

22. Scott DA, Woods B, Thompson JC, et al. Mortality and drug therapy in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Pulm Med. 2015;15:145. doi:10.1186/s12890-015-0138-4

23. Metaxas EI, Balis E. The safety of indacaterol for the treatment of COPD. Expert Opin Drug Saf. 2018;17:637–642. doi:10.1080/14740338.2018.1472233

24. Muro S, Yoshisue H, Kostikas K, Olsson P, Gupta P, Wedzicha JA. Indacaterol/glycopyrronium versus tiotropium or glycopyrronium in long-acting bronchodilator-naïve COPD patients: a pooled analysis. Respirology (Carlton, Vic). 2020;25:393–400. doi:10.1111/resp.13651

25. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374:2222–2234. doi:10.1056/NEJMoa1516385

26. Anzueto AR, Kostikas K, Mezzi K, et al. Indacaterol/glycopyrronium versus salmeterol/fluticasone in the prevention of clinically important deterioration in COPD: results from the FLAME study. Respir Res. 2018;19:121. doi:10.1186/s12931-018-0830-z

27. Kalberg C, O’Dell D, Galkin D, Newlands A, Fahy WA. Dual bronchodilator therapy with umeclidinium/vilanterol versus tiotropium plus indacaterol in Chronic Obstructive Pulmonary Disease: a randomized controlled trial. Drugs R D. 2016;16:217–227. doi:10.1007/s40268-016-0131-2

28. Frampton JE. QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease. Drugs. 2014;74:465–488.

29. Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with Chronic Obstructive Pulmonary Disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198:329–339. doi:10.1164/rccm.201803-0405OC

30. Bouyssou T, Hoenke C, Rudolf K, et al. Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett. 2010;20:1410–1414. doi:10.1016/j.bmcl.2009.12.087

31. Bouyssou T, Casarosa P, Naline E, et al. Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010;334:53–62.

32. van Noord JA, Smeets JJ, Drenth BM, et al. 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther. 2011;24:666–672. doi:10.1016/j.pupt.2011.07.006

33. Ferguson GT, Feldman GJ, Hofbauer P, et al. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:629–645. doi:10.2147/COPD.S61717

34. Koch A, Pizzichini E, Hamilton A, et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:697–714. doi:10.2147/COPD.S62502

35. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s respiratory questionnaire. Am Rev Respir Dis. 1992;145:1321–1327. doi:10.1164/ajrccm/145.6.1321

36. Ramadan WH, Kabbara WK, Abilmona RM. Olodaterol for the treatment of chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2016;73:1135–1143. doi:10.2146/ajhp150364

37. Blair HA. Tiotropium/olodaterol: a review in COPD. Drugs. 2019;79:997–1008. doi:10.1007/s40265-019-01133-w

38. Derom E, Brusselle GG, Joos GF. The once-daily fixed-dose combination of olodaterol and tiotropium in the management of COPD: current evidence and future prospects. Ther Adv Respir Dis. 2019;13:1753466619843426. doi:10.1177/1753466619843426

39. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4). Eur Respir J. 2015;45:969–979. doi:10.1183/09031936.00136014

40. Procopiou PA, Barrett VJ, Bevan NJ, et al. Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. J Med Chem. 2010;53:4522–4530. doi:10.1021/jm100326d

41. Slack RJ, Barrett VJ, Morrison VS, et al. In vitro pharmacological characterization of vilanterol, a novel long-acting β2-adrenoceptor agonist with 24-hour duration of action. J Pharmacol Exp Ther. 2013;344:218–230. doi:10.1124/jpet.112.198481

42. Kempsford R, Norris V, Siederer S. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD. Pulm Pharmacol Ther. 2013;26:256–264. doi:10.1016/j.pupt.2012.12.001

43. Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142:119–127. doi:10.1378/chest.11-2231

44. Feldman GJ, Edin A. The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013;7:311–319. doi:10.1177/1753465813499789

45. Malerba M, Morjaria JB, Radaeli A. Differential pharmacology and clinical utility of emerging combination treatments in the management of COPD–role of umeclidinium/vilanterol. Int J Chron Obstruct Pulmon Dis. 2014;9:687–695. doi:10.2147/COPD.S47792

46. Albertson TE, Harper R, Murin S, Sandrock C. Patient considerations in the treatment of COPD: focus on the new combination inhaler umeclidinium/vilanterol. Patient Prefer Adherence. 2015;9:235–242. doi:10.2147/PPA.S71535

47. Siler TM, Donald AC, O’Dell D, Church A, Fahy WA. A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62. 5/25μg on health-related quality of life in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:971–979. doi:10.2147/COPD.S102962

48. Donohue JF, Singh D, Munzu C, Kilbride S, Church A. Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: results from two randomised controlled trials. Respir Med. 2016;112:65–74. doi:10.1016/j.rmed.2016.01.001

49. Feldman GJ, Sousa AR, Lipson DA, et al. Comparative efficacy of once-daily umeclidinium/vilanterol and tiotropium/olodaterol therapy in symptomatic Chronic Obstructive Pulmonary Disease: a randomized study. Adv Ther. 2017;34:2518–2533. doi:10.1007/s12325-017-0626-4

50. Siler TM, Nagai A, Scott-Wilson CA, Midwinter DA, Crim C. A randomised, phase III trial of once-daily fluticasone furoate/vilanterol 100/25 μg versus once-daily vilanterol 25 μg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD. Respir Med. 2017;123:8–17. doi:10.1016/j.rmed.2016.12.001

51. Boscia JA, Pudi KK, Zvarich MT, Sanford L, Siederer SK, Crim C. Effect of once-daily fluticasone furoate/vilanterol on 24-hour pulmonary function in patients with chronic obstructive pulmonary disease: a randomized, three-way, incomplete block, crossover study. Clin Ther. 2012;34:1655–66.e5. doi:10.1016/j.clinthera.2012.06.005

52. Lötvall J, Bakke PS, Bjermer L, et al. Efficacy and safety of 4 weeks’ treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial. BMJ Open. 2012;2:e000370. doi:10.1136/bmjopen-2011-000370

53. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1:210–223. doi:10.1016/S2213-2600(13)70040-7

54. Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387:1817–1826. doi:10.1016/S0140-6736(16)30069-1

55. Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378:1671–1680. doi:10.1056/NEJMoa1713901

56. Tabberer M, Lomas DA, Birk R, et al. Once-daily triple therapy in patients with COPD: patient-reported symptoms and quality of life. Adv Ther. 2018;35:56–71. doi:10.1007/s12325-017-0650-4

57. Pascual S, Feimer J, De Soyza A, et al. Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study. NPJ Prim Care Respir Med. 2015;25:15018. doi:10.1038/npjpcrm.2015.18

58. Dalby R, Spallek M, Voshaar T. A review of the development of respimat soft mist inhaler. Int J Pharm. 2004;283:1–9. doi:10.1016/j.ijpharm.2004.06.018

59. Skolnik NS, Nguyen TS, Shrestha A, Ray R, Corbridge TC, Brunton SA. Current evidence for COPD management with dual long-acting muscarinic antagonist/long-acting β(2)-agonist bronchodilators. Postgrad Med. 2020;132:198–205. doi:10.1080/00325481.2019.1702834

60. Ge X, Woo AY, Xing G, et al. Synthesis and biological evaluation of β(2)-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold. Eur J Med Chem. 2018;152:424–435. doi:10.1016/j.ejmech.2018.04.041

61. Gan LL, Wang MW, Cheng MS, Pan L. Trachea relaxing effects and beta2-selectivity of SPFF, a newly developed bronchodilating agent, in guinea pigs and rabbits. Biol Pharm Bull. 2003;26:323–328. doi:10.1248/bpb.26.323

62. Hao Z, Zhang Y, Pan L, et al. Comparison of enantiomers of SPFF, a novel beta2-Adrenoceptor agonist, in bronchodilating effect in guinea pigs. Biol Pharm Bull. 2008;31:866–872. doi:10.1248/bpb.31.866

63. Pan H, Li Q, Pan L, et al. Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma. Biomedical Rep. 2014;2:539–544. doi:10.3892/br.2014.279

64. Aparici M, Gómez-Angelats M, Vilella D, et al. Pharmacological characterization of abediterol, a novel inhaled β(2)-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models. J Pharmacol Exp Ther. 2012;342:497–509. doi:10.1124/jpet.112.193284

65. Beier J, Fuhr R, Massana E, et al. Abediterol (LAS100977), a novel long-acting β2-agonist: efficacy, safety and tolerability in persistent asthma. Respir Med. 2014;108:1424–1429. doi:10.1016/j.rmed.2014.08.005

66. Singh DPR, Ribera A, Seoane B, Messana E, Astbury C. Efficacy and Safety of Abediterol (LAS100977) in Stable Asthma: Phase II, Randomized, Crossover Study. ERS Annual Congress; 2013.

67. Beier J, Pujol H, Seoane B, et al. Abediterol, a novel long-acting β2-agonist: bronchodilation, safety, tolerability and pharmacokinetic results from a single-dose, dose-ranging, active-comparator study in patients with COPD. BMC Pulm Med. 2016;16:102. doi:10.1186/s12890-016-0266-5

68. Beier J, Fuhr R, Seoane B, et al. Efficacy, safety, and tolerability of once-daily abediterol in patients with stable, persistent asthma: a Phase II, randomized, 7-day, crossover study. Pharmacol Res Perspect. 2017;5:e00356. doi:10.1002/prp2.356

69. Jacobsen JR, Choi SK, Combs J, et al. A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD. Bioorg Med Chem Lett. 2012;22:1213–1218. doi:10.1016/j.bmcl.2011.11.072

70. Cazzola M, Matera MG, Lötvall J. Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease. Expert Opin Investig Drugs. 2005;14:775–783. doi:10.1517/13543784.14.7.775

71. Matera MG, Cazzola M. ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? Drugs. 2007;67:503–515. doi:10.2165/00003495-200767040-00002

72. Jacobsen JR, Aggen JB, Church TJ, et al. Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines. Bioorg Med Chem Lett. 2014;24:2625–2630. doi:10.1016/j.bmcl.2014.04.069

73. McKinnell RM, Klein U, Linsell MS, et al. Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD. Bioorg Med Chem Lett. 2014;24:2871–2876. doi:10.1016/j.bmcl.2014.04.095

74. Glossop PA, Lane CA, Price DA, et al. Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup. J Med Chem. 2010;53:6640–6652. doi:10.1021/jm1005989

75. Macintyre FJI, Surujbally B. A randomised, double-blind study to determine the duration of action of lung pharmacodynamics by plethysmography (sGaw) of a β2 adrenoreceptor agonist, PF-00610355 [abstract]. Eur Respir J. 2009.

76. GL MF L, Surujbally B, Chong CL, Davis J. Safety and toleration of PF-00610355, a novel inhaled long acting β2 adrenoreceptor agonist [abstract]. Eur Respir J. 2009.

77. Diderichsen PM, Cox E, Martin SW, Cleton A, Ribbing J. Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2013;76:752–762. doi:10.1111/bcp.12080

78. Stocks MJ, Alcaraz L, Bailey A, et al. Discovery of AZD3199, an inhaled ultralong acting β2 receptor agonist with rapid onset of action. ACS Med Chem Lett. 2014;5:416–421. doi:10.1021/ml4005232

79. Bjermer L, Kuna P, Jorup C, Bengtsson T, Rosenborg J. Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA). Drug Des Devel Ther. 2015;9:753–762. doi:10.2147/DDDT.S66049

80. Bjermer L, Rosenborg J, Bengtsson T, Lötvall J. Comparison of the bronchodilator and systemic effects of AZD3199, an inhaled ultra-long-acting β₂-adrenoceptor agonist, with formoterol in patients with asthma. Ther Adv Respir Dis. 2013;7:264–271. doi:10.1177/1753465813497527

81. Kuna P, Ivanov Y, Trofimov VI, et al. Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized, double-blind study. Respir Res. 2013;14:64. doi:10.1186/1465-9921-14-64

82. Cazzola M, Matera MG. Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol. 2008;155:291–299. doi:10.1038/bjp.2008.284

83. Kikkawa H, Kanno K, Ikezawa K. TA-2005, a novel, long-acting, and selective beta 2-adrenoceptor agonist: characterization of its in vivo bronchodilating action in guinea pigs and cats in comparison with other beta 2-agonists. Biol Pharm Bull. 1994;17:1047–1052. doi:10.1248/bpb.17.1047

84. Voss HP, Donnell D, Bast A. Atypical molecular pharmacology of a new long-acting beta 2-adrenoceptor agonist, TA 2005. Eur J Pharmacol. 1992;227:403–409. doi:10.1016/0922-4106(92)90158-R

85. Kikkawa H, Naito K, Ikezawa K. Tracheal relaxing effects and beta 2-selectivity of TA-2005, a newly developed bronchodilating agent, in isolated guinea pig tissues. Jpn J Pharmacol. 1991;57:175–185. doi:10.1254/jjp.57.175

86. Kikkawa H, Isogaya M, Nagao T, Kurose H. The role of the seventh transmembrane region in high affinity binding of a beta 2-selective agonist TA-2005. Mol Pharmacol. 1998;53:128–134. doi:10.1124/mol.53.1.128

87. Voss HP, Shukrula S, Wu TS, Donnell D, Bast A. A functional beta-2 adrenoceptor-mediated chronotropic response in isolated guinea pig heart tissue: selectivity of the potent beta-2 adrenoceptor agonist TA 2005. J Pharmacol Exp Ther. 1994;271:386–389.

88. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res. 2010;11:149. doi:10.1186/1465-9921-11-149

89. Kottakis INA, Raptis H, Savu A, Linberg SE, Woodcock AA. Efficacy of the novel very long-acting β2-agonist carmoterol following 7 days once daily dosing: comparison with twice daily formoterol in patient with persistent asthma. Eur Respir J. 2006.

90. Nandeuil AKI, Raptis H, Roslan H, Ivanov Y, Woodcock A. Safety and tolerability of the novel very long acting β2- agonist carmoterol given as a 2 mg qd dose; 8 days comparison with formoterol and placebo in patients with persistent asthma. Eur Respir J. 2006.

91. Chiesi. Annual report 2010. Chiesi Farmaceutici SpA Source document no longer available. 2010

92. Xing G, Pan L, Yi C, et al. Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β(2)-adrenoceptor agonists. Bioorg Med Chem. 2019;27:2306–2314. doi:10.1016/j.bmc.2018.10.043

93. Woo AY, Ge XY, Pan L, et al. Discovery of β-arrestin-biased β(2)-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives. Acta Pharmacol Sin. 2019;40:1095–1105. doi:10.1038/s41401-018-0200-x

94. Yi C, Xing G, Wang S, et al. Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β(2)-adrenoceptor agonists. Bioorg Med Chem. 2020;28:115178.

95. Eichel K, von Zastrow M. Subcellular organization of GPCR signaling. Trends Pharmacol Sci. 2018;39:200–208. doi:10.1016/j.tips.2017.11.009

96. Tian X, Kang DS, Benovic JL. β-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol. 2014;219:173–186.

97. Jean-Charles PY, Kaur S, Shenoy SK. G protein-coupled receptor signaling through β-arrestin-dependent mechanisms. J Cardiovasc Pharmacol. 2017;70:142–158. doi:10.1097/FJC.0000000000000482

98. Kume H. [Role of bronchodilators in therapy for COPD-mechanisms of LABA and LAMA on airway smooth muscle]. Nihon Rinsho. 2016;74:813–819. Japanese.

99. Cazzola M, Calzetta L, Puxeddu E, et al. Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells. Respir Res. 2016;17:70.

100. Hughes AD, Chin KH, Dunham SL, et al. Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules. Bioorg Med Chem Lett. 2011;21:1354–1358. doi:10.1016/j.bmcl.2011.01.043

101. Hegde SS, Hughes AD, Chen Y, et al. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties. J Pharmacol Exp Ther. 2014;351:190–199. doi:10.1124/jpet.114.216861

102. Ambery CL, Wielders P, Ludwig-Sengpiel A, Chan R, Riley JH. Population pharmacokinetics and pharmacodynamics of GSK961081 (batefenterol), a muscarinic antagonist and β2-agonist, in moderate-to-severe COPD patients: substudy of a randomized trial. Drugs R D. 2015;15:281–291. doi:10.1007/s40268-015-0104-x

103. Bateman ED, Kornmann O, Ambery C, Norris V. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther. 2013;26:581–587. doi:10.1016/j.pupt.2013.03.015

104. Crim C, Watkins ML, Bateman ED, et al. Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2019;14:615–629. doi:10.2147/COPD.S190603

105. Wielders PL, Ludwig-Sengpiel A, Locantore N, Baggen S, Chan R, Riley JH. A new class of bronchodilator improves lung function in COPD: a trial with GSK961081. Eur Respir J. 2013;42:972–981. doi:10.1183/09031936.00165712

106. Norris V, Ambery C. Use of propranolol blockade to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers: results from two randomized trials. Drugs R D. 2014;14:241–251. doi:10.1007/s40268-014-0060-x

107. Norris V, Ambery C. Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. Pulm Pharmacol Ther. 2013;26:574–580. doi:10.1016/j.pupt.2013.03.009

108. Iheanacho I, Zhang S, King D, Rizzo M, Ismaila AS. Economic burden of Chronic Obstructive Pulmonary Disease (COPD): a systematic literature review. Int J Chron Obstruct Pulmon Dis. 2020;15:439–460. doi:10.2147/COPD.S234942

109. Riley CM, Sciurba FC. Diagnosis and outpatient management of Chronic Obstructive Pulmonary Disease: a review. JAMA. 2019;321:786–797. doi:10.1001/jama.2019.0131

110. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128. doi:10.1016/S0140-6736(12)61728-0

111. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–2196. doi:10.1016/S0140-6736(12)61729-2

112. Siafakas N, Corlateanu A, Fouka E. Phenotyping before starting treatment in COPD? Copd. 2017;14:367–374. doi:10.1080/15412555.2017.1303041

113. Gonηalves I, Guimarγes MJ, van Zeller M, Menezes F, Moita J, Simγo P. Clinical and molecular markers in COPD. Pulmonology. 2018;24:250–259. doi:10.1016/j.pulmoe.2018.02.005

114. Miravitlles M, Soler-Cataluρa JJ, Calle M, Soriano JB. Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice. Eur Respir J. 2013;41:1252–1256. doi:10.1183/09031936.00118912

115. Le Rouzic O, Roche N, Cortot AB, et al. Defining the “frequent exacerbator” phenotype in COPD: a hypothesis-free approach. Chest. 2018;153:1106–1115. doi:10.1016/j.chest.2017.10.009

116. Blasi F, Neri L, Centanni S, Falcone F, Di Maria G. Clinical characterization and treatment patterns for the frequent exacerbator phenotype in Chronic Obstructive Pulmonary Disease with severe or very severe airflow limitation. Copd. 2017;14:15–22. doi:10.1080/15412555.2016.1232380

117. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128–1138. doi:10.1056/NEJMoa0909883

118. Singh D, Watz H, Beeh KM, et al. COPD sputum eosinophils: relationship to blood eosinophils and the effect of inhaled PDE4 inhibition. Eur Respir J. 2020;56:2000237. doi:10.1183/13993003.00237-2020

119. Miller BE, Tal-Singer R, Rennard SI, et al. Plasma fibrinogen qualification as a drug development tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease biomarker qualification consortium. Am J Respir Crit Care Med. 2016;193:607–613.

120. Mannino DM. Biomarkers for chronic obstructive pulmonary disease diagnosis and progression: insights, disappointments and promise. Curr Opin Pulm Med. 2018.

121. Bellou V, Belbasis L, Konstantinidis AK, Tzoulaki I, Evangelou E. Prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease: systematic review and critical appraisal. BMJ (Clinical Research Ed). 2019;367:l5358.

122. Peng J, Chen C, Zhou M, Xie X, Zhou Y, Luo CH. A machine-learning approach to forecast aggravation risk in patients with acute exacerbation of Chronic Obstructive Pulmonary Disease with clinical indicators. Sci Rep. 2020;10:3118. doi:10.1038/s41598-020-60042-1

123. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2015;192:523–525. doi:10.1164/rccm.201502-0235LE

124. Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6:117–126. doi:10.1016/S2213-2600(18)30006-7

125. Karatas E, Bouchecareilh M. Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathways. Int J Mol Sci. 2020;21:1493. doi:10.3390/ijms21041493

126. Chorostowska-Wynimko J, Barrecheguren M, Ferrarotti I, Greulich T, Sandhaus RA, Campos M. New patient-centric approaches to the management of alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2020;15:345–355. doi:10.2147/COPD.S234646

127. Toy EL, Beaulieu NU, McHale JM, et al. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105:435–441. doi:10.1016/j.rmed.2010.09.006

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