Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by National Taiwan University on 01/09/15 For personal use only.
Drug Profile
Fluticasone furoate and vilanterol inhalation powder for the treatment of chronic obstructive pulmonary disease Expert Rev. Respir. Med. Early online, 1–8 (2014)
Maria Gabriella Matera*1, Annalisa Capuano2 and Mario Cazzola3 1 Department of Experimental Medicine, Section of Pharmacology ‘L. Donatelli’, Centre of Excellence for Cardiovascular Diseases, Second University of Naples, Naples, Italy 2 Department of Experimental Medicine, Section of Pharmacology ‘L. Donatelli’, Centre of Excellence for Cardiovascular Diseases and Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Second University of Naples, Naples, Italy 3 Department of System Medicine, Unit of Respiratory Clinical Pharmacology, University of Rome Tor Vergata, Roma, Italy *Author for correspondence: [email protected]
Fluticasone furoate/vilanterol (FF/VI) is a novel inhaled corticosteroid/long-acting b2-agonist (ICS/LABA) fixed dose combination that, by simplifying the dosing schedule, allows, for the first time in a member of the ICS/LABA class, a shift from twice-daily to once-daily treatment. FF/VI is delivered via a novel, single-step activation, multi-dose dry powder inhaler for oral inhalation, ElliptaTM . Regrettably, there are no head-to-head trials that have shown superiority in the safety or efficacy of FF versus other ICSs, but evidence shows that VI has a quicker onset of effect versus salmeterol. However, the clinical utility of this effect in a maintenance medication is still questionable. Furthermore, benefits of FF/VI over twice-daily ICS/LABA comparator have not been shown yet and, in addition, its adverse event profile is generally consistent with the known class effects of an ICS/LABA fixed dose combination. In particular, there is an increase in the risk of pneumonia among patients treated with FF/VI relative to VI, mainly among those who benefit most from FF/VI. Nevertheless, the interesting pharmacological profiles of both FF and VI, the possibility that FF/VI can be administered once-daily, and the attractive characteristics of ElliptaTM are important features that could help FF/VI to be a successful combination in the treatment of chronic obstructive pulmonary disease. KEYWORDS: COPD • Ellipta • fixed-dose combination • fluticasone furoate • vilanterol
The efficacy of combination therapy with an inhaled long-acting b2-agonist (LABA) plus a low dose of an inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) has been well documented [1]. ICSs reduce the risk of exacerbations by 10–20% beyond that achieved by inhaled LABAs [2–4], although, apparently, the beneficial effect of the combination therapy over LABA alone is observed on the frequency of moderate exacerbations (requiring systemic corticosteroids or antibiotic use) but not on that of severe COPD exacerbations (defined as those requiring hospitalization) [5]. Therapy with ICS/LABA is also associated with significant increases over LABA alone in lung function [6–8], health-related quality of life, symptoms score and a decrease in rescue medication use [6]. Although it was informahealthcare.com
10.1586/17476348.2015.986468
suggested that ICS/LABA combination might reduce cardiovascular disease and all-cause mortality in COPD patients [9,10], Rodrigo et al. [5] showed that this is not true. It is not surprising, therefore, that COPD guidelines recommend combining ICSs with a LABA only for patients with severe impairment and high risk of exacerbations [11–14]. ICS/LABA combination could be considered also in the mixed COPD phenotype characterized by airflow limitation that is not completely reversible and accompanied by symptoms or signs of an increased reversibility of the obstruction (the so-called asthma COPD overlap syndrome) and in patients with moderate COPD who persist with exacerbations despite treatment with one or two long-acting bronchodilators [14].
2014 Informa UK Ltd
ISSN 1747-6348
1
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by National Taiwan University on 01/09/15 For personal use only.
Drug Profile
Matera, Capuano & Cazzola
The current opinion is that the observed benefit from combining these two classes of drugs might be due to a synergistic interaction, with the resulting synergetic effect being better than the sum of responses achieved from each drug alone [15]. The mechanism of this interaction has not yet been fully understood [16]. There is evidence documenting that corticosteroids increase the transcription of the b2-adrenoceptor (AR) gene and enhance the coupling of b2-AR to G-protein (Gs). In this manner, they increase the expression of cell surface receptors, enhance b2-agonist effects and reverse the uncoupling of b2-AR that may occur in response to inflammatory mediators, such as interleukin-1b, through a stimulatory effect on a G-protein-coupled receptor kinase [16]. Instead, LABAs increase the translocation of glucocorticoid receptors from cytoplasm to the nucleus after activation by corticosteroids and thus augment the anti-inflammatory effects of corticosteroids [16]. As combination therapy with an ICS and a LABA is considered an important approach for treating patients suffering from severe COPD with frequent exacerbations, there is a strong interest in developing a once-daily ICS/LABA fixed-dose combination (FDC) therapy, in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy [17]. This is a crucial issue in the treatment of COPD because patients suffering from COPD with higher adherence experience fewer hospitalizations and lower healthcare costs than those with lower adherence behavior [18]. There are several once-daily LABAs and once-daily ICSs under preclinical or early clinical development [1,17,19–23]. In this review, we will be focused on the development of fluticasone furoate/vilanterol (FF/VI) FDC. Development of FF/VI FDC
GlaxoSmithKline (London, UK) and Theravance (South San Francisco, CA, USA) have developed an inhaled FDC of the LABA VI and the ICS FF, as a once-daily treatment for COPD. The US FDA has approved FF/VI dry powder inhaler (DPI) for the long-term, once-daily, maintenance treatment of airflow limitation in COPD patients, including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with a history of exacerbations [24], whereas the Committee for Medicinal Products for Human Use (CHMP) of the EMA has recommended the granting of a marketing authorization for VI/FF DPI for the symptomatic treatment of adults with COPD with a FEV1 20%) and beclomethasone and budesonide (both up to 15%) [26]. Moreover, pharmacokinetic/pharmacodynamic models predict that a FF AUC24 of 1000 pg·h/ml, which is several times higher than the average FF AUC24 value observed at clinical doses of FF (£200 mg), would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17%, respectively [30]. Although FF has modestly higher (
Drug Profile
Fluticasone furoate and vilanterol inhalation powder for the treatment of chronic obstructive pulmonary disease Expert Rev. Respir. Med. Early online, 1–8 (2014)
Maria Gabriella Matera*1, Annalisa Capuano2 and Mario Cazzola3 1 Department of Experimental Medicine, Section of Pharmacology ‘L. Donatelli’, Centre of Excellence for Cardiovascular Diseases, Second University of Naples, Naples, Italy 2 Department of Experimental Medicine, Section of Pharmacology ‘L. Donatelli’, Centre of Excellence for Cardiovascular Diseases and Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Second University of Naples, Naples, Italy 3 Department of System Medicine, Unit of Respiratory Clinical Pharmacology, University of Rome Tor Vergata, Roma, Italy *Author for correspondence: [email protected]
Fluticasone furoate/vilanterol (FF/VI) is a novel inhaled corticosteroid/long-acting b2-agonist (ICS/LABA) fixed dose combination that, by simplifying the dosing schedule, allows, for the first time in a member of the ICS/LABA class, a shift from twice-daily to once-daily treatment. FF/VI is delivered via a novel, single-step activation, multi-dose dry powder inhaler for oral inhalation, ElliptaTM . Regrettably, there are no head-to-head trials that have shown superiority in the safety or efficacy of FF versus other ICSs, but evidence shows that VI has a quicker onset of effect versus salmeterol. However, the clinical utility of this effect in a maintenance medication is still questionable. Furthermore, benefits of FF/VI over twice-daily ICS/LABA comparator have not been shown yet and, in addition, its adverse event profile is generally consistent with the known class effects of an ICS/LABA fixed dose combination. In particular, there is an increase in the risk of pneumonia among patients treated with FF/VI relative to VI, mainly among those who benefit most from FF/VI. Nevertheless, the interesting pharmacological profiles of both FF and VI, the possibility that FF/VI can be administered once-daily, and the attractive characteristics of ElliptaTM are important features that could help FF/VI to be a successful combination in the treatment of chronic obstructive pulmonary disease. KEYWORDS: COPD • Ellipta • fixed-dose combination • fluticasone furoate • vilanterol
The efficacy of combination therapy with an inhaled long-acting b2-agonist (LABA) plus a low dose of an inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) has been well documented [1]. ICSs reduce the risk of exacerbations by 10–20% beyond that achieved by inhaled LABAs [2–4], although, apparently, the beneficial effect of the combination therapy over LABA alone is observed on the frequency of moderate exacerbations (requiring systemic corticosteroids or antibiotic use) but not on that of severe COPD exacerbations (defined as those requiring hospitalization) [5]. Therapy with ICS/LABA is also associated with significant increases over LABA alone in lung function [6–8], health-related quality of life, symptoms score and a decrease in rescue medication use [6]. Although it was informahealthcare.com
10.1586/17476348.2015.986468
suggested that ICS/LABA combination might reduce cardiovascular disease and all-cause mortality in COPD patients [9,10], Rodrigo et al. [5] showed that this is not true. It is not surprising, therefore, that COPD guidelines recommend combining ICSs with a LABA only for patients with severe impairment and high risk of exacerbations [11–14]. ICS/LABA combination could be considered also in the mixed COPD phenotype characterized by airflow limitation that is not completely reversible and accompanied by symptoms or signs of an increased reversibility of the obstruction (the so-called asthma COPD overlap syndrome) and in patients with moderate COPD who persist with exacerbations despite treatment with one or two long-acting bronchodilators [14].
2014 Informa UK Ltd
ISSN 1747-6348
1
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by National Taiwan University on 01/09/15 For personal use only.
Drug Profile
Matera, Capuano & Cazzola
The current opinion is that the observed benefit from combining these two classes of drugs might be due to a synergistic interaction, with the resulting synergetic effect being better than the sum of responses achieved from each drug alone [15]. The mechanism of this interaction has not yet been fully understood [16]. There is evidence documenting that corticosteroids increase the transcription of the b2-adrenoceptor (AR) gene and enhance the coupling of b2-AR to G-protein (Gs). In this manner, they increase the expression of cell surface receptors, enhance b2-agonist effects and reverse the uncoupling of b2-AR that may occur in response to inflammatory mediators, such as interleukin-1b, through a stimulatory effect on a G-protein-coupled receptor kinase [16]. Instead, LABAs increase the translocation of glucocorticoid receptors from cytoplasm to the nucleus after activation by corticosteroids and thus augment the anti-inflammatory effects of corticosteroids [16]. As combination therapy with an ICS and a LABA is considered an important approach for treating patients suffering from severe COPD with frequent exacerbations, there is a strong interest in developing a once-daily ICS/LABA fixed-dose combination (FDC) therapy, in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy [17]. This is a crucial issue in the treatment of COPD because patients suffering from COPD with higher adherence experience fewer hospitalizations and lower healthcare costs than those with lower adherence behavior [18]. There are several once-daily LABAs and once-daily ICSs under preclinical or early clinical development [1,17,19–23]. In this review, we will be focused on the development of fluticasone furoate/vilanterol (FF/VI) FDC. Development of FF/VI FDC
GlaxoSmithKline (London, UK) and Theravance (South San Francisco, CA, USA) have developed an inhaled FDC of the LABA VI and the ICS FF, as a once-daily treatment for COPD. The US FDA has approved FF/VI dry powder inhaler (DPI) for the long-term, once-daily, maintenance treatment of airflow limitation in COPD patients, including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with a history of exacerbations [24], whereas the Committee for Medicinal Products for Human Use (CHMP) of the EMA has recommended the granting of a marketing authorization for VI/FF DPI for the symptomatic treatment of adults with COPD with a FEV1 20%) and beclomethasone and budesonide (both up to 15%) [26]. Moreover, pharmacokinetic/pharmacodynamic models predict that a FF AUC24 of 1000 pg·h/ml, which is several times higher than the average FF AUC24 value observed at clinical doses of FF (£200 mg), would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17%, respectively [30]. Although FF has modestly higher (
