Drug Evaluation 5 Drug Evaluation 2015/07/28 A twice-daily, fixed-dose combination of aclidinium bromide and formoterol fumarate for the treatment of COPD Clin. Invest. (Lond.) Inhaled long-acting β2-agonists or long-acting muscarinic antagonists monotherapies Jutta Beier are recommended as the first choice of treatment for patients with symptomatic insaf Respiratory Research Institute, chronic obstructive pulmonary disease. The different but complementary modes of Biebricher Allee 34, 65187 Wiesbaden, Germany action of these treatments make them suited for use in a fixed-dose combination. Tel.: +49 611 985 4410 Aclidinium bromide 400 μg (a long-acting muscarinic antagonist) twice daily improves Fax: +49 611 985 4348 patient lung function and health status and reduces breathlessness compared with [email protected] placebo, and is well tolerated. Combining these effects with the rapid onset of action of formoterol fumarate 12 μg in a twice-daily treatment may provide 24-h relief from chronic obstructive pulmonary disease symptoms. This review discusses the aclidinium/ formoterol 400/12 μg combination clinical trial data to date. Keywords: aclidinium bromide • bronchodilation • combination • COPD • formoterol fumarate • symptoms Combining long-acting bronchodilators inhaler could add further benefit by simplify- with complementary mechanisms of action ing treatment regimens, which may improve to treat patients with chronic obstructive patient adherence and thereby ultimately pulmonary disease (COPD) has the poten- reduce healthcare costs [8–10]. Indeed, three tial to improve lung function and symptom fixed-dose combinations of a LABA and management compared with monotherapy LAMA, one administered twice daily, and treatment [1] . There are currently two classes two administered once daily, have already of long-acting bronchodilators: long-acting been approved for use in patients with β2-agonists (LABAs) and long-acting mus- COPD (twice-daily aclidinium/formoterol ® ®a carinic antagonists (LAMAs). LABAs are [Duaklir Genuair™/Pressair ] [11], once- 8 ® thought to primarily act on prejunctional β2- daily indacaterol/glycopyrronium [Ultibro ® adrenoreceptors to induce G protein-coupled Breezhaler ] [12] and once-daily umecli- ® ® change in intracellular messenger systems dinium/vilanterol [Anoro Ellipta ] [13,14]), and to directly trigger airway smooth muscle and treatment with a LABA/LAMA com- 2015 relaxation and bronchodilation [2,3]. LAMAs bination is now recommended as an alter- block the muscarinic receptors targeted by native choice for patients with moderate to acetylcholine, thereby reducing acetylcholine severe COPD [1] . Factors that will impact on binding and amplifying the bronchodilation the decision to use an alternative treatment induced by the LABA [3]. may include disease severity, frequency of Studies combining LABAs and LAMAs exacerbations and treatment costs. using a free combination with separate inhalers have demonstrated improved bron- Aclidinium bromide chodilation and reduced rescue medication In two randomized studies, monotherapy use in patients with COPD compared with treatment with the LAMA, aclidinium bro- monotherapy [4–7]. A dual bronchodilator mide 400 μg twice daily, provided clinically combination therapy administered using one meaningful improvements in key COPD end part of 10.4155/CLI.15.34 © 2015 Future Science Ltd Clin. Invest. (Lond.) (Epub ahead of print) ISSN 2041-6792 Drug Evaluation Beier points, such as lung function (forced expiratory volume rate combination for investiGative use in the treat- in 1 s [FEV1]), versus tiotropium and placebo, while MENT of moderate-to-severe COPD (AUGMENT; being well tolerated. [15,16] Other studies have shown NCT01437397) (Figure 1B) [27]. These were 24-week, significant improvements in lung function end points randomized, double-blind, parallel-group studies that versus placebo [17–20] . Treatment with aclidinium has recruited 1729 (ACLIFORM) and 1692 (AUGMENT) also been found to improve health status, exercise patients. Inclusion and exclusion criteria were identical endurance and night-time symptoms in patients with in both studies and they shared the same coprimary COPD [20–22]. Aclidinium bromide 400 μg twice daily end points of change from baseline to week 24 in 1-h was approved for maintenance treatment of COPD morning postdose FEV1 versus aclidinium and change in the USA in July 2012 and in the EU in September from baseline to week 24 in morning predose (trough) 2012 [23,24]. FEV1 versus formoterol [27,28]. A 28-week extension to AUGMENT, examining long-term efficacy and safety, Formoterol fumarate included 921 patients from the core study [32]. Formoterol fumarate is a well-established LABA The two core studies comprised 3398 patients in that has been used to treat COPD for a number of total and the patient demographics were comparable years [2,25]. It has been shown to improve lung func- with the general COPD population; most were male tion, COPD symptoms, health-related quality of life Caucasians in their early 60s with COPD of moderate and exacerbations while having an acceptable safety severity [27,28]. profile [2,25]. Moreover, it has a rapid onset of action (1–3 min) with a sustained effect of approximately 12 Lung function h that makes it particularly attractive for use in combi- In both studies, 1-h morning postdose FEV1 changes were nation therapy [26,27]. significantly greater with the aclidinium/formoterol 400/12 μg combination at all time points versus acli- Aclidinium/formoterol 400/12 μg dinium and placebo (Figure 2A & B). Similarly, trough combination FEV1 changes were significantly greater with acli- Following the completion of two successful Phase III dinium/formoterol 400/12 μg versus formoterol and trials [27,28], dual bronchodilation with aclidinium placebo at all time points (Figure 2C & D). In addition, bromide 400 μg/formoterol fumarate 12 μg has the aclidinium/formoterol 400/12 μg combination recently been approved as a maintenance treatment was numerically better than aclidinium for trough (Figure 2C & D) to relieve symptoms in adult patients with COPD [11] . FEV1 , although this did not reach sta- It has a twice-daily dosing regimen and is delivered tistical significance. Improvements versus placebo were via a multidose dry powder inhaler device named maintained for up to 52 weeks in the AUGMENT ®a Genuair™/Pressair [3,29,30]. extension [32]. The purpose of this review is to summarize and discuss the published data from studies of the COPD symptoms aclidinium/formoterol combination with a focus on The aclidinium/formoterol 400/12 μg combina- clinical trial data. tion resulted in clinically and statistically significant improvements in transition dyspnea index (TDI) Pharmacokinetic data focal score versus placebo at week 24 in both ACLI- Studies assessing the pharmacokinetic profile of the FORM and AUGMENT (Figure 3) [27,28]. Witek and aclidinium/formoterol 400/12 μg combination con- Mahler [33] defined the minimum clinically important cluded that the monotherapies were combinable [31], difference for TDI focal score as a ≥1-unit change and terminal elimination half-lives (t½) for aclidinium versus baseline and this was achieved throughout and formoterol have been shown to be approximately 5 AUGMENT for the aclidinium/formoterol combi- and 8 h, respectively [31] . nation [32]. Similarly, in the AUGMENT extension study, aclidinium/formoterol 400/12 μg significantly Clinical trials improved TDI focal score from baseline at all visits Two pivotal Phase III studies have been conducted, com- versus placebo [32]. In the individual studies, while paring the approved aclidinium/formoterol 400/12 μg treatment with aclidinium/formoterol resulted in dose with aclidinium 400 μg monotherapy, formoterol numerically greater improvements in TDI focal scores 12 μg monotherapy and placebo: ACLidinium bro- compared with either monotherapy, improvements mide/FORMoterol fumarate in the treatment of mod- were not statistically significant. This indicates that erate-to-severe COPD (ACLIFORM; NCT01437397) combining aclidinium with formoterol may not be (Figure 1A) [28] and Aclidinium/formoterol fuma- entirely additive. Indeed, it would suggest that there is 10.4155/CLI.15.34 Clin. Invest. (Lond.) (Epub ahead of print) future science group Aclidinium & formoterol combination for COPD treatment Drug Evaluation ACLIFORM SV V1 V2 V3 V4 V5 V6 V7 ≤ 1 month 2–3 weeks Day 1 Day 8 Week 4 Week 12 Week 18Week 24 2 weeks Wash-out Run-in Treatment period – 24 weeks Follow-up ≤ 6 weeks 2–3 weeks Day 1 Day 4 Week 4 Week 12 Week 18 Week 24 2 weeks V0 V1 V2 V3 V4 V5 V6 V7 V8 AUGMENT Figure 1. Study design for the two pivotal Phase III studies of aclidinium/formoterol fixed-dose combination twice daily, ACLIFORM and AUGMENT. SV: Screening visit; V: Visit. some overlap in function and one possible explanation of symptoms. It has been suggested that improving could be the difference in the timing of the effects of 24-h symptoms may improve lung function, quality the component drugs, in other words, the rapid effect of life and exacerbation frequency, while reducing the of formoterol [2,30,34] quickly reduces breathlessness emergence of cardiovascular disease, cognitive effects, and, as the effect of this drug diminishes, the slower depression and mortality [35]. onset but sustained effect of aclidinium maintains the reduced level of breathlessness [19,20]. Health status Both ACLIFORM and AUGMENT showed The St. George’s Respiratory Questionnaire (SGRQ) statistically