Review: Clinical Trial Outcomes For reprint orders, please contact [email protected] 4 Review: Clinical Trial Outcomes Arformoterol: rationale for use in chronic obstructive pulmonary disease Clin. Invest. Long-acting β-agonists (LABAs) are the standard of care for chronic obstructive Jordan Terasaki1,2, Shawn PE pulmonary disease (COPD) patients with advanced disease, those with mild to Nishi1,2, Bill T Ameredes1,2 & moderate disease and frequent exacerbations or those with significant dyspnea. Gulshan Sharma*,1,2 1 Currently available LABAs include salmeterol, formoterol, indacaterol, vilanterol and Division of Pulmonary Critical Care & Sleep Medicine, University of Texas olodaterol. The bronchodilatory effect of LABAs is mediated via the binding and Medical Branch, Galveston TX, 301 ligation of the β2–adrenergic receptor and the lipophilic nature of the LABA compound University Blvd Galveston TX 77555, USA accounts for their long duration of action. LABAs are available as hand held devices, 2Department of Internal Medicine, either as a single agent or combined with a corticosteroid. Proper inhaler technique is University of Texas Medical Branch, necessary for adequate drug delivery but is often difficult to achieve in older patients Galveston TX, 301 University Blvd Galveston TX 77555, USA with significant impairment in cognition, dexterity or ability to generate adequate *Author for correspondence: inspiratory flow rates. Arformoterol, which is an (R,R) enantiomer of formoterol, is Tel.: +1 409 772 2436 available as a nebulized solution and is clinically equivalent to formoterol or salmeterol. [email protected] Arformoterol as a nebulized solution provides an alternative to device-based LABAs in select patients. Keywords: arformoterol • COPD • dyspnea • formoterol • long-acting β-agonist • metered dose inhaler • nebulizer • quality of life • salmeterol • spirometry Background and arformoterol, an active enantiomer com- Chronic obstructive pulmonary disease ponent of formoterol, available as a nebulized (COPD) is characterized by incompletely solution (Figure 1). The LABAs have received reversible airflow obstruction and progres- a black box warning related to increased sive loss of lung function over time. The risk of death in asthma patients when used natural history is interspersed by exacer- without corticosteroids. However, similar 5 bations. Affecting >64 million individu- adverse event (AE) warning as a single agent als and the fourth leading cause of death in COPD patients is lacking [7]. COPD treat- worldwide, COPD is predicted to become ment guidelines support LABA monotherapy the third leading cause of death by 2030 use in moderate to severe COPD [8]. LABAs 2014 [1,2]. The prevalence of COPD increases improve symptoms and, when administered with age, with up to 15% of adults >65 by nebulizer, have higher patient satisfaction years diagnosed with COPD [3]. Obstruc- than other options [9–11] . However, LABA tive lung diseases contribute substantially to medications are expensive and can add sig- the financial burden of healthcare systems nificant cost burden to both the patient and with US $49.9 billion estimated in the USA the healthcare system (Table 1). Appropriate during 2010; 20.9% was directly related to choice of medication and route of adminis- emergency department and acute hospital tration must be evaluated prior to prescribing care [4–6]. medications. In this review, we discuss the Currently, US FDA-approved Long-acting rationale of using nebulized arformoterol in β-agonists (LABAs) include salmeterol, for- the context of other LABAs for select patients moterol, indacaterol, vilanterol, olodaterol with COPD. part of 10.4155/CLI.14.32 © 2014 Future Science Ltd Clin. Invest. (2014) 4(5), 429–439 ISSN 2041-6792 429 Review: Clinical Trial Outcomes Terasaki, Nishi, Ameredes & Sharma O OH O OH H HN N HO O O N H OH OH Salmeterol Olodaterol Cl H OH OH H H N N O O CH3 Cl HO HO HN CH 3 OH O Indacaterol Vilanterol OH H N CH3 HO OCH3 HN H Arformoterol Figure 1. Chemical structures of different long-acting β-agonists. Chemical structure & mechanism of action of complex (Figure 2), adenyl cyclase, and PKA medi- LABAs ated intracellular signaling within cytosol [22]. For Arformoterol, salmeterol, vilanterol, olodaterol and example, ligation of the β2-adrenergic receptor indacaterol are phenylethanolamine derived compounds results in the relaxation of airway smooth muscle with side groups that vary in structure and in their inter- mediated by upregulation of adenyl cyclase activity, action with the hydrophobic active site of the receptor and increased intracellular cAMP, and subsequent complex [12,13]. The important clinical differences seen decreased smooth muscle myosin light chain kinase between LABAs are the receptor selectivity, the time activity, resulting in the desired therapeutic broncho- to onset of action and the half-life of the medication dilatory effect. However, a number of studies have (Table 2) . Salmeterol, a partial β2-adrenergic agonist, has indicated that β2-adrenergic agonists may also have a uniquely long lipophilic side chain that anchors the anti-inflammatory properties, for example, inhibi- molecule in the membrane exosite, allowing prolonged tion of TNF and vascular leak, in vitro [23–25]. This interaction with the cell receptor [14,15]. Formoterol is anti-inflammatory property of β2-adrenergic ago- moderately lipophilic with an increased ligand available nists in airway smooth muscle has been reviewed outside the lipid layer, similar to albuterol, which allows previously [26] and, similar to the case of broncho- for the rapid onset of action seen with both medications dilation mentioned above, appears to be associated [14] . Indacaterol rapidly disseminates into the lipid layer with β2-adrenergic receptor ligation driven increases with a twofold higher affinity for lipid rafts along with a in intracellular cAMP, which downregulate nuclear high intrinsic efficacy, which may contribute to the rapid transcription and thereby decrease the production of onset and long duration of action [12,16,17]. Vilanterol, a proinflammatory cytokines. This downregulation of LABA structurally similar to salmeterol, has a high β2- proinflammatory cytokines by LABAs may favorably adrenergic receptor affinity, allowing for a more rapid impact treatment in specific COPD subtypes acutely, action than salmeterol and with similar potency as for- and for extended durations, particularly during exac- moterol, at least as demonstrated in vitro [18,19]. Lastly, erbations. olodaterol forms a stable complex with the β2-adrenergic receptor that has a dissociation half-life of greater than (R,R) & (S,S) formoterol enantiomers 18 h, which likely accounts for the ultra-long duration of The differential effects of β2-adrenergic receptor ago- action of this medication [20,21] . nists on the airway smooth muscle, the immune system β2-adrenergic agonists exert pleiotropic effects and the inflammatory cascade is thought to be poten- via the β2-adrenergic associated submembrane Gs tially due, in part, to the differences associated with 430 Clin. Invest. (2014) 4(5) future science group Arformoterol & chronic obstructive pulmonary disease Review: Clinical Trial Outcomes Table 1. Cost of select β-agonist therapies as a single agent or as combination therapies. Medication Amount dispensed Medication cost (US$) Short-acting β-agonists Albuterol nebulizer 25 vials 4–19 Levalbuterol nebulizer 24 vials 62–109 Albuterol/ipratropium nebulizer 30 vials 13–24 Albuterol MDI† 1 inhaler 49–70 Levalbuterol MDI 1 inhaler 58–63 Albuterol/ipratropium SMI 1 inhaler 282–295 Long-acting β-agonists Arformoterol nebulizer 30 vials 278–290 Formoterol nebulizer 30 vials 275–302 Salmeterol DPI 1 inhaler 219–230 Formoterol DPI 1 inhaler 217–227 Indacaterol DPI 1 inhaler 198–208 Long-acting β-agonists/inhaled corticosteroids Salmeterol/fluticasone DPI 1 inhaler 304–317 Vilanterol/fluticasone DPI 1 inhaler 287–300 Formoterol/budesonide MDI 1 inhaler 272–285 Only US FDA approved formulations reviewed for pricing due to data availability of equivalent dosing of medications. Prices are a range of ten different nationwide pharmacies as of 25/2/2014 [11]. Albuterol inhaler formulations evaluated were ProAir, Ventolin, and Proventil. DPI: Dry powder inhaler; MDI: Metered dose inhaler; SMI: Soft mist inhaler. specific enantiomers, and has been previously demon- β2-adrenergic receptor, as compared with the (S,S) strated with enantiomers of albuterol [27,28]. Similar enantiomer, resulting in a 640-fold greater potency in to racemic albuterol, which has two enantiomers, the airway smooth muscle relaxation [30,31] . The two dif- racemic formoterol formulation consists of two enan- ferent enantiomers of formoterol also have been shown tiomeric forms, (R,R) and (S,S), each having two chi- to have opposing effects on inflammatory media- ral carbon centers around which the substituents are tors: the (R,R) isomer suppresses GM-CSF in human arranged by mass number priority in either a clockwise airway smooth muscle cells, while the (S,S) isomer rotatory order (R,R), or a counter-clockwise rotatory increases GM-CSF levels [32]. Thus, it is important to order (S,S) [29]. Of note, the R-enantiomer has a sub- note that this potential effect of the racemic mixture is stituent order similar to that of endogenous epineph- obviated with administration of the single enantiomer, rine made by the adrenal gland; the opposing isomer of (R,R)-formoterol, as arformoterol. epinephrine