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Home , Abediterol, Glycopyrronium bromide, Ipratropium bromide, Tulobuterol, Umeclidinium bromide

CHAPTER Newer Therapies in COPD

50 Prem Parkash Gupta

INTRODUCTION therapies are available for the patients with difficulties in Chronic Obstructive Pulmonary Disease (COPD), a smoking cessation like withdrawal symptoms. In some common preventable and treatable disease, is characterized countries, influenza and pneumococcal vaccinations are by persistent airflow limitation that is usually progressive also recommended as a preventive therapy as a part of and associated with an enhanced chronic inflammatory National Guidelines. response in the airways and the lung to noxious particles PHARMACOTHERAPIES ESTABLISHED IN VARIOUS or gases. Exacerbations and comorbidities contribute significantly to the overall severity in individual patients. GUIDELINES COPD affects nearly 8% of the world’s population Primary intention of any pharmacological therapy in concerning 160 million people. COPD is a leading cause COPD is to reduce symptoms, decrease the frequency of morbidity and mortality worldwide and results in an and severity of exacerbations, and improve health related economic and social burden that is both substantial and quality of life status and exercise tolerance. COPD increasing. The prevalence of COPD is directly related to medicines available presently have not been conclusively the prevalence of tobacco smoking (being the strongest shown to modify the long-term decline in lung function risk factor ever known), although, outdoor, occupational that is the hallmark of this disease. The recommended and indoor air pollution are also major COPD risk factors. as per Global Initiative for Chronic The burden of COPD is likely to increase in the coming (GOLD) Guidelines (2016) are decades due to continued exposure to COPD risk factors mentioned in tabular form in Table 2. and due to increased life expectancy. A varying degree Inhaled therapy is uniformly accepted of inhalational injury & genetic susceptibility lead to across numerous Guidelines as a first-line therapy for phenotypic heterogeneity - a hallmark of COPD. symptomatic COPD, in contrast to where the THERAPEUTICS IN COPD anti-inflammatory properties of inhaled warrant them as the first-line therapy. Inhaled The management of COPD encompasses in COPD have been shown to improve preventative measures, pharmacological treatment, dyspnea, exercise performance, and overall health status. nonpharmacological management, and surgical options They are also found to be useful in reducing acute COPD in appropriate patients (Table 1). Smoking cessation is exacerbations. The improvement in exercise performance the only intervention established to influence the natural carries potential benefit of an active life often debilitated in history of COPD. Various forms of nicotine replacement severe COPD patients. Exacerbations are uncomfortable and distressing to people with COPD, and often reduce Table 1: Management of COPD health related quality of life. A reduction of exacerbations Management subtype Modality is also having significant impact on health status, health care expenditure, exercise performance, and survival. Preventative Smoking cessation The accumulated data across various studies suggests Avoidance of toxic exposures the beneficial effect of bronchodilator therapy in term of Improvement in airways disease progression in COPD possibly due to a significant pollution reduction in exacerbations thereby portending a mortality Pharmacological Established drugs benefit. Inhaled corticosteroids are recommended in recommended by guidelines severe persistent COPD (forced expiratory volume in 1 second [FEV1] < 50% of predicted). They are usually Newer drugs combined with a LABA as additional benefits include Nonpharmacological Supplemental oxygen an improvement in pulmonary function and reduction Pulmonary rehabilitation in frequency of exacerbation; it is hypothesized that a reduction in airway inflammation and bronchial wall Surgical Lung volume reduction edema account for pulmonary function improvement. surgery, Endoscopic lung volume Group wise treatment in COPD as recommended by reduction GOLD Guidelines is shown in Table 3. The selection of a particular drug amongst its class is largely guided by Lung transplantation. CHAPTER 50 223 Vilanterol trifenatate has β-2 adrenoreceptors similar a to significantly , preferential faster onset of action and but a dose-dependent with affinity a to Umeclidinium to be suitable both been found has bromide Umeclidinium for maintenance use as monotherapy and in combination a period of 24- over in COPD. Sustained bronchodilatation pulmonary improves hour permits once a day therapy. It FEV1), breathlessness, and mean function (weighted by the has been approved health status. Umeclidinium with a dose of April 2014 as a monotherapy US FDA since to be powder a dry as formulated It is daily. 62.5 μg once via an . delivered Monotherapy Long-Acting Beta2-Agonist New Indacaterol has a stronger include longer advantages receptors and its proven affinity for β-2 action of faster onset and bronchodilatation of duration with improved compared to salmeterol. Indacaterol has been shown to cardiovascular safety enduration time and to health status and exercise improve profile when reduce COPD exacerbations. The addition of indacaterol to tiotropium synergistically potentiates bronchodilator effect of later. It appearsin been approved potential. Presently, indacaterol has to have low arrhythmogenic 2011. in more than 50 countries for the maintenance treatment of US in and 2009 in EU the in approved was It COPD. in India as monotherapy The drug is currently available as a combination with Glycopyrronium. as well of this disease and for prevention of its progression its progression of for prevention and disease of this have been identified. under different Many trial phases and yetof enlists some Table-4 and recommendations. acceptance achieve to of desired new molecules molecules. these promising are Long-Acting Long-Acting MuscarinicNew (LAMA) Antagonists Aclidinium in United States approved has been bromide Aclidinium 2012 for maintenance therapy and Europe since of COPD. significantly to aclidinium observed have trials clinical The function (FEV1), dyspnea, and health pulmonary improve a via status. It as dry powder and delivered is formulated in patients tolerated well The drug was inhaler. multidose might which hydrolysis, rapid plasma with COPD due to systemic exposure and a lower account for reduced effects. of adverse reported incidence Glycopyrronium kinetic selectivity has a relative M2 receptors that facilitates airway for the M3 versus bronchodilator proven It has relaxation. muscle smooth effects, and, in comparison with tiotropium, has shown a faster onset of higher FEV1. action Glycopyrronium significantly reduces and the achieves exercise improves also COPD exacerbations and of risk a significantly in the approved was endurance time. Glycopyrronium dry-powder inhaler. via a EU in 2012 and is delivered

Fenoterol Levalbuterol (albuterol) Indacaterol Salmeterol Glycopyrronium bromide Tiotropium Umeclidinium Short-acting beta2-agonists beta2-agonists Short-acting Long-acting beta2-agonists Short-acting Long-acting anticholinergics (SR) Beclomethasone Prednisolone Methyl Table 2: GOLD recommended COPD Medications COPD recommended 2: GOLD Table Beta2-agonists Anticholinergics Inhaled corticosteroids Combination long-acting beta2-agonists & corticosteroids in one inhaler Systemic corticosteroids Phosphodiesterase-4 inhibitors Combination short-acting beta2-agonists & Combination short-acting beta2-agonists Anticholinergic in one inhaler & Combination long-acting beta2-agonist anticholinergic in one inhaler Methylxanthines NEWER THERAPIES FOR COPD FOR THERAPIES NEWER the cost, availability in the local market and acceptance market and in the local availability the cost, drug drug reactions/ by the patient in term of adverse interactions. Our understanding of pathophysiology of COPD has COPD of pathophysiology of Our understanding to new heights during last couple of decades, reached and as a result new potential targets for the management 224 Table 3: Group wise treatment in COPD as recommended by GOLD Guidelines COPD Patient Group A Group B Group C Group D Groups → Recommended first Short-acting Long-acting Inhaled Inhaled choice of treatment anticholinergic as anticholinergic + corticosteroid + long- needed or long-acting beta2- acting beta2-agonist agonist or Long-acting beta2- and/or Short-acting beta2- agonist or Long-acting agonist as needed Long-acting anticholinergic anticholinergic Alternative treatment Long-acting Long-acting Long-acting Inhaled anticholinergic anticholinergic and anticholinergic and corticosteroid + long- or long-acting beta2- long-acting beta2- acting beta2-agonist agonist agonist and long-acting Long-acting beta2-

PULMONOLOGY anticholinergic agonist or or or Long-acting anticholinergic Inhaled Short-acting beta2- and corticosteroid agonist and short- + long-acting acting anticholinergic phosphodiesterase-4 inhibitor beta2-agonist and phosphodiesterase-4 or inhibitor Long-acting beta2- or agonist Long-acting and anticholinergic and phosphodiesterase-4 long-acting beta2- inhibitor agonist or Long-acting anticholinergic and phosphodiesterase-4 inhibitor Other options Theophylline Short-acting beta2- Short-acting beta2- Carbocysteine agonist agonist N-acetylcysteine and/or and/or Short-acting beta2- Short-acting Short-acting agonist anticholinergic anticholinergic and/or Theophylline Theophylline Short-acting anticholinergic, Theophylline

and 24-hour lasting bronchodilatation in patients with of the Th-17 immune response in the development of COPD. Combination therapy with both fluticasone COPD. Olodaterol is a relatively safe drug, approved as and umeclidinium has been shown to improve lung maintenance treatment in COPD and currently permitted function and reduce exacerbations when compared to as a monotherapy in over 30 countries. monotherapy. In US, vilanterol is approved only as a fixed-combination therapy for the maintenance treatment of COPD. Early clinical trials indicate that abediterol to be a potent bronchodilator with rapid onset and long lasting action. A Olodaterol higher selectivity to β-2 adrenoreceptors subtype permits Olodaterol is reported to have a dose-dependent better cardiovascular safety and tolerability profile. bronchodilator action lasting up to 24 hours. Olodaterol and formoterol improved FEV1 when compared to NEW COMBINATION THERAPY placebo; additionally, olodaterol also improved COPD New LAMA + LABA Combination Therapy reported symptoms. Studies indicate olodaterol to During the last decade, various combinations of new have a potential role to counter the detrimental effect LAMA and new LABA have been studied; many of them CHAPTER 50 225 Drugs & Fluticasone Vilanterol & Indacterol & Formetrol & Fluticasone Formetrol + Tiotropium + Salmetrol fluticasone + Glycopyrronoum Formoterol + Budesonide Roflumilast Simvastatin N-acetylcysteine Group New LABA+ICS New LABA+ICS Combination Triple drug LABA+LAMA+ ICS Combination Oral Medications Inhaled Phosphodiesterase Inhibitors Inhaled Phosphodiesterase the and RPL554 as inhibitors, such PDE4 and PDE3 Dual asthma in trial phase under inhibitor CHF6001, are PDE4 shown to be more potent and COPD. CHF6001 was than roflumilast. In fourRPL554 was exploratory found to be studies,an effective inhaled andwell-tolerated drug. as anti-inflammatory bronchodilator as well Triple LABA-LAMA-ICS therapy Triple to be associated been observed Triple therapy has with ICS/ compared with a 40% reduction in mortality lung function and LABA combination and improve health related quality of of the use recommends update monotherapy. GOLD 2013 life compared to tiotropium group D. Currently, triple therapy in patients with COPD inhaled therapy containing LAMA + there are several + ICS combinations undergoing clinical trials, LABA + budesonide, including glycopyrronium + formoterol + tiotropium and fluticasone, + vilanterol + umeclidinium formoterol + ciclesonide. Inhibitors Phosphodiesterase Inhibitors Phosphodiesterase Oral Roflumilast- been Oral phosphodiesterase (PDE) inhibitors have shown to suppress the activation of inflammatory cells, and relax modulate the activity of pulmonary nerves, observed been has Roflumilast (Figure-1). muscle smooth clinical trials, FEV1 comparable to ICSs in to improve but not found to be consistently life. of quality and exacerbation of frequency in efficaciousreduction in term of recommended is inhibitor PDE4 selective a as Roflumilast COPD in US and European Union for treatment in severe profile safety The exacerbations. frequent with associated of roflumilast still limits its use only in advanced COPD as an add-on therapy. terms of both efficacy and tolerability. Formoterolfluticasone and has been approved in Union for GOLD groups C and D. Japan and European

Drugs Aclidinium Aclidinium Glycopyrronium Umeclidinium Indacterol Vilanterol Olodaterol Abediterol Umeclidinium & Vilanterol Glycopyrronium & Indacterol Tiotropium & Olodetrol Aclidinium & Formoterol Glycopyrrolate & Formoterol Fig. 1: Role of phosphodiesterase (PDE) inhibitors in COPD (PDE) inhibitors of phosphodiesterase 1: Role Fig. Table 4: New COPD Therapies COPD 4: New Table Group New LAMA monotherapy monotherapy New LAMA New LABA monotherapy New LAMA+ LABA Combination were found to be promising and approved in various in various approved and to be promising found were combination has countries. Umeclidinium and vilanterol US and European Union for GOLD in been approved groups C and D. The combinations of glycopyrronium and as that of aclidinium and indacaterol as well formoterol have been permitted in European Union for GOLD groups C and D. New LAMA + ICS Combination Therapy LAMA + ICS Combination New been reported and ICS have The combinations of LABA to have synergistic effects. ICS potentiates LABA effects reduction of cell surface expressed the by preventing β-receptors - a hallmark of airway inflammation. On the anti-inflammatory steroid-sparing, has LABA hand, other meta- properties. The Cochrane and antiproliferative to have combination ICS/LABA suggests analysis significant improvement in both and ICS therapy alone. LABA, to LAMA, compared the SGRQ and FEV1 The combination of vilanterol and fluticasone has been permitted in US and European Union for GOLD groups C and D. Formoterol and ciclesonide combination was found to be noninferior to fluticasone & salmeterol in 226 TARGETED DRUG THERAPY IN COPD Humanized monoclonal antibodies targeted to alpha subunit CXCR2 Antagonists of the interleukin (IL)-5 receptor (IL-5Rα) Antagonists of the human CXCR2 receptors target The interlukin (IL) -5 receptor is composed of an α and neutrophil trafficking in COPD inflammatory pathway. a βc chain, α subunit has affinity for IL-5 only whereas MK-7123, a CXCR2 antagonist, is being investigated βc subunit has affinity for IL-5, IL-3 and Granulocyte- in Phase II clinical trials and has shown significant macrophage Colony-stimulating Factor (GM-CSF). improvement in FEV1 compared to placebo in patients Humanized monoclonal antibodies targeted to alpha with COPD. subunit of the interleukin (IL)-5 receptor (IL-5Rα) selectively blocks IL-5 (Table 7). This action is particularly P38 Mitogen-Activated Protein Kinase (P38 MAPK) Inhibitors beneficial in management of asthmatic inflammation P38 mitogen-activated protein kinase pathway involves as well as COPD exacerbations. Soluble IL-5Rα is also a signaling cascade controlling cellular responses to found to be increased during virus-induced COPD cytokines and stress. Table-5 represents the various exacerbations. molecules under study. The molecule PH-797804 studied had shown improvements in dyspnea symptom index Antihuman IL-17R Antibodies and FEV1. Losmapimod (GW856553X) the other potent Interlukin (IL) -17A has been found to induce neutrophilic PULMONOLOGY oral p38α/β MAPK inhibitor, is in a phase II inflammation by releasing CXCL1, CXCL8 and GM-CSF for the treatment of COPD. from airway epithelial cells and smooth-muscle cells. IL- 17A can induce IL-6 expression in bronchial epithelial The efficacy and safety of two inhaled p38 MAPK cells and fibroblasts. IL-17A is involved in human airway inhibitors, RV-568 and PF-03715455 are under various smooth-muscle contraction. Th17 cells also mediate phases of clinical trials. Inhaled delivery of p38 MAPK -resistant airway inflammation and airway inhibitors may enhance p38 inhibition in the lung while hyperresponsiveness. Antihuman IL-17R antibodies reducing unwanted systemic effects. including Ixekizumab, Brodalumab and Ustekinumab Selective Matrix Metalloproteinases (MMP) Inhibitors are under trial for possible clinical efficacy in asthma and As we know COPD is an inflammatory disorder in which COPD. protease and antiprotease imbalance plays an important Phosphoinositide 3-kinases (PI3K) Inhibitors role, antagonizing matrix metalloproteinases (MMP) with The phosphoinositide 3-kinases (PI3K) are a family of selective MMP inhibitors provided an option to revert proteins that are involved in the control of intracellular back to this fine balance. The search for ideal drug in this signaling pathways. Phosphoinositide 3-kinases group goes on; some of the studied molecules are listed inhibitors prevent recruitment of inflammatory cells in Table-6. including t-lymphocytes and neutrophils, prevent release of proinflammatory mediators, and also may restore Table 5: P38 Mitogen-Activated Protein Kinase (P38 MAPK) steroid effectiveness. One molecule with promising Inhibitors phosphoinositide 3-kinases inhibitor property is Drug Group Present status GSK2269557, which is being further evaluated. PH-797804 Oral p38 MAPK Phase II trials of CONCLUSIONS inhibitor this agent have During last decade, a large number of molecules have recently been been investigated for possible potential to be used in discontinued. treatment of COPD; increasing numbers of therapeutic GW856553X/ Oral p38α/β Phase II human agents may appear confusing but brings new optimism Osmapimod MAPK inhibitor clinical trial for COPD management. With current knowledge, it is perhaps advisable to recommend: Acumapimod Orally p38 Active MAPK inhibitor development 1. SABA & SAMA will continue to be necessary for the relief of intermittent symptoms and for use as rescue RV-568 Inhaled p38 Evaluated in . MAPK inhibitors clinical trials PF-03715455 Inhaled p38 Evaluated in 2. LABA and LAMA are suitable as maintenance (daily) MAPK inhibitors clinical trials treatment in patients with persistent symptoms.

Table 6: Selective Matrix Metalloproteinases (MMP) Inhibitors under study Drug/ Molecule Group Action Status AZ11557272 Dual MMP9–MMP12 inhibitor Prevent emphysema, Clinical development has small airway fibrosis, and recently been stopped inflammation in guinea pigs AZD1236 Orally Dual MMP9–MMP12 Failed biomarker endpoints, Further development aborted inhibitor initial promising results CHAPTER 50 227 Expert Opin Investig Investig Expert Opin 2010; 11:149. Eur Respir J 2011; 37:273-9. 2013; 14:49. 2014; 9:397-412. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy et al. Global strategy AG, for Agustí SS, J, Hurd Vestbo of chronic and prevention management, the diagnosis, summary. executive GOLD disease: pulmonary obstructive Med 2013; 187:347-65. Am J Respir Crit Care Eisner MD, Anthonisen N, Coultas American D, Thoracic Society public et policy statement: Novel al. An official global risk factors and the obstructive burden of chronic 182:693- 2010; Med Am J Respir Crit Care pulmonary disease. 718. DP, Fabbri Long-acting beta-agonists in the LM. Tashkin management of chronic obstructive Respir Res current and future agents. pulmonary disease: Once-daily et al. Centanni S, R, O, Dahl Kornmann indacaterol versus twice-daily salmeterol placebo-controlled comparison. for COPD: a Poole P. Combined Nannini LJ, Cates CJ, Lasserson TJ, long-acting beta-agonist in one inhaler and corticosteroid disease. pulmonary obstructive placebo for chronic versus No.: Art. 4: 2007; Reviews Systematic of Database Cochrane CD003794. in antagonists Joos GF. Potential for long-acting muscarinic pulmonary disease. obstructive chronic Drugs 2010; 19:257-64. Cazzola M, Page CP, Rogliani P, Matera MG. therapy 2013; in lung disease. Am J Respir Crit Care Med β2-agonist 187:690-96. bronchodilator Combination GT. DP, Ferguson Tashkin therapy of chronic obstructive in the management pulmonary disease. Respir Res in currently inhibitors PDE M. Cazzola C, Page MG, Matera trials for the treatment of asthma. Expert Opin early clinical Drugs 2014; 23:1267-75. Investig A, Chung KF. Cytokine Adcock IM, Di Stefano Caramori G, Int J Chron Obstruct inhibition in the treatment of COPD. Pulmon Dis Khorasani N, Baker J, Johnson M, Chung KF, Bhavsar of corticosteroid insensitivity by p38 MAPK PK. Reversal inhibition in peripheral cells from blood mononuclear COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:283-91. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. of exacerbations, to prevent the rapid decline in lung in lung decline the rapid to prevent of exacerbations, insensitivity of corticosteroid reversal to achieve function, the while reducing progression the fibrotic to control and process. emphysematous Action Reduce COPD Reduce COPD exacerbations and improve in symptoms patient with higher blood eosinophils in Improvement lung functions, and disease- specific health status Approved by Approved the U.S. FDA in asthma severe EU in December 2015 Status Phase III development Phase III development After cost of therapy reduces to sensible level, Ultra- After cost of therapy reduces to sensible level, once to appear tempting due Ultra-LABA and LAMA reactions as and lesser adverse daily convenience claimed by their developers. Asthma-COPD with COPD Group D or with Patients may be ideal for triple-inhaler Syndrome Overlap therapy (LABA+LAMA+ICS). Frequent exacerbators COPD patients, respiratory tract bacterial colonization, or those lower those with with coexistent bronchiectasis may beneficial achieve efficacy with selective inhibitorPDE4 term antibiotic prophylaxis. and/or long- Drug Table 7: Humanized monoclonal antibodies targeted to alpha alpha to targeted antibodies monoclonal 7: Humanized Table (IL-5Rα) (IL)-5 receptor interleukin of the subunit Benralizumab Benralizumab Mepolizumab FUTURE ANTICIPATIONS ANTICIPATIONS FUTURE Patients with uncontrolled disease despite taking with uncontrolled disease despite both Patients specialist would likely be referred for and LABA LAMA in hopes to at a dedicated COPD centre evaluation identify a specificsuitable COPD for specific phenotype and thatremain shall the objectives pharmacotherapy. Of course, tailored might targeted therapeutic be and reduce the number to prevent to reduce symptoms, 3. 4. 5.