`
`Vol.95, (200i) (SUPPLEMENT B), Sl2—Sl6
`
` respiraterweoicwe
`
`Clinical outcome of adding long-acting fi-agonists to
`inhaled corticosteroids
`
`P. J. BARNES
`
`Department of Thoracic Medicine, National Heart and Lung Institute, London, UK
`
`
`
`
`Abstract Current asthma management guidelines state that where a patient is receiving a low to moderate dose of
`iahaled corticosteroids and is still experiencing symptoms the dose ofcorticosteroid should be increased and,
`if neces—
`sary, a long—acting bronchodilator should be added. Many studies have now shown that the addition ofa fiZ-agonist witi
`long—acting properties is more effective atcontrolling asthma symptoms than increasing the dose ofcorticosteroid alone.
`‘he Formoteroi and Corticosteroid EstablishingTherapy (FACET) study was a lanonth study comparing exacerbation
`rates in patients treated with budesonide (IOO lug or 400 ,ug) twice daily alone vs, treatment with budesonide (IOO ,ug or
`WOO Mg) twice da‘ly plus formoterol 9 ,Lig twice daily (delivered dose) (I). The addition offormoterol reduced the rates of
`mild and severe exacerbations compared with budesonide alone, with the lowest rates seen in patients receiving high—
`dose budesonide and formoterol. There was no difference in the profile of exacerbations in any groups,
`indicating for—
`moterol does no. mask any signs of inflammationThe addition offormoterol to budesonide was also shown to result in
`improved lung fu action (as measured by peak expiratory flow rate and forced expiratory volume in l second), night—time
`awakenings and he use ofas—needed medication when compared with an increase in the close of budesonide. In all cases,
`increasing the dose of budesonide and addition offormoterol resulted in the most improvement and a significant increase
`in quality of life. measured by Asthma Quality of Life Questionnaire (AQLQ), was noted. in conclusion, the addition of
`formoterol to established treatment with inhaled corticosteroids provides superior asthma control compared with an
`increase in the dose ofcorticosteroid alone.
`
`
`
`Cc) 200i Harcourt Pu alishers Ltd
`
`doi:l0.lOS3/rmed.200 .| I40
`
`1 gamma formoteroi;corticosteroid; (budesonideanacerbation _
`
`INTRODUCTION
`
`Over the past IOO years, the management of asthma has
`changed considerably. In the early part of the twentieth
`century asthma was recognized as a chronic disorder, but
`treatment was aimed at treating exacerbations, with little
`attention to the ongoing, day-to-day complications. With
`the introduction offlrst adrenaline and then oral corticos-
`teroids, both of which were derived from adrenal extract,
`
`treatment was aimed more at preventing these exacerba-
`tions. Great strides forward were made with the introduc—
`
`tion of inhaled therapy, both with short-acting fig-agonists
`and, more recently, corticosteroids, in treating symptoms
`and providing maintenance therapy. Over time goals have
`changed, and we are now looking towards achievement of
`normal lung function for patients, rather than just prevent-
`ing symptoms and exacerbations.
`
`
`Correspondence should be addressed to: R]. Barnes, Department of
`Thoracic Medicine, National Heart and Lung Institute, Imperial
`College, Dovehouse St, London SW3 6LY, UK, Fax: (+44) 0207 35l 5675;
`E—mail: p.j.barnes@ic.ac.uk
`
`Newer agents are becoming available and it is the use
`of these agents in combination with existing drugs that
`may help to achieve this goal. Such agents include salme—
`terol, a long—acting [iZ-agonist, and formoterol, a fiz-ago-
`nist that has not only a long duration, but also a fast
`onset of action (2).These drugs have a potential applica-
`tion in maintenance therapy and, in the case offormoter-
`ol, also in as-needed therapy. Traditionally,
`if a patient
`was poorly controlled on a low to moderate dose of cor-
`ticosteroid, increasing the dose was the accepted treat-
`ment strategy. However, recent evidence suggests that
`adding a fiz-agonist with a long duration of effect to cur-
`rent therapy produces a greater improvement in asthma
`control compared with increasing the dose of corticos-
`teroid alone—patients have been shown to experience
`fewer symptoms, have improved lung function and re-
`quire less as-needed medication. Also, the rate of both
`mild and severe exacerbations has been shown to de-
`
`crease using this treatment strategy.
`For a time there was some debate about whether it
`
`was appropriate to use [J’z-agonists regularly as mainte—
`nance therapy (3). Several studies have suggested an in-
`
`CIP2161
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR201 7-00807
`
`APOTEX_AZFL 0131994
`
`1
`
`CIP2161
`Argentum Pharmaceuticals v. Cipla Ltd.
`IPR2017-00807
`
`

`

`CLINICALOUTCOME OFADDING LONG—ACTING fi—AGONlSTS TO lNHALED CORTICOSTEROIDS
`
`SIB
`
`crease in mortality and morbidity associated with regu-
`lar use of inhaled fiZ-agonist bronchodilators, particu-
`larly fenoterol (4—6). Larger studies have since shown
`that maintenance therapy with fiz-agonists is not asso—
`ciated with increased risks compared with as-needed
`use. in theTRUSTstudy (The Regular Use of Salbutamol
`Trial), there was no evidence that regular use of inhaled
`salbutamol increased the exacerbation rate of asthma
`
`when compared with as-needed use (7).
`The aim of this paper is to review the position of [3;-
`agonists with long-acting properties and the place they
`have in combination therapy with inhaled corticosteroids.
`
`THE ADDITION OF LONG-ACTING [32-
`AGONISTS TO INHALED STEROIDS
`
`The first study to suggest that the addition of long-acting
`fiz-agonists to inhaled corticosteroids would provide
`better asthma control was performed by Greening et al.
`(8). The guidelines for asthma management at this time
`stated that in patients poorly controlled on a low dose
`of inhaled corticosteroid, the first step should be an in-
`crease in the dose. in this study, patients receiving in-
`haled beclomethasone dipropionate (BDP) 200 ,ug twice
`daily, who were still experiencing symptoms, were ran-
`domized to receive either salmeterol 50ug plus BDP
`200,ug twice daily or a higher dose of BDP, 500 pg twice
`daily, for 6 months. An improvement in lung function,
`measured by mean morning peak expiratory flow (PEF),
`was noted in both groups, but the difference was signifi-
`cantly greater in the salmeterol group at
`all
`time
`
`+ Salmeterol 50 ,ug bd
`+ beclomethasone 200 [1g bd
`—O— Beclomethasone 500 pg bd
`
`ChangeinPEF(1/min)
`
`1
`
`5
`
`13
`9
`Weeks of treatment
`
`17
`
`21
`
`Figure I. Effect on mean morning PEF rate of adding salme—
`terol to beclomethasone 200 pg tvvice daily compared with in—
`creasing beclomethasone dose to 500 tig twice daily (8).
`Changes from baseline (iSE) in mean morning and evening
`PEF rate during
`6 months study treatment. *P<0.05;
`**P<0.0| ; ***P<0.00I. (Reproduced with permission from The
`Lancet.)
`
`points (P<0.05) (Fig. |).When considering the use of as-
`needed relief medication and asthma symptoms (day-
`and night-time), the results in the salmeterol group were
`also significantly improved compared with increasing the
`dose of BDP alone.
`
`Similar results have been seen in a study by Woolcock
`etal. (9) who randomized moderate and severe asthmatic
`patients, poorly controlled on BDP 500 ,ug twice daily to
`receive either salmeterol 50 Hg or lOOug twice daily with
`their current dose of BDP or an increase in BDP to
`
`lOOO ,ug twice daily. Even though these patients were in-
`itially receiving a higher dose of inhaled corticosteroids
`than taken in the Greening study, the addition of either
`dose of salmeterol produced a significant improvement
`in lung function compared with increasing the dose of
`BDP. Both salmeterol groups also had a significantly in-
`creased percentage of symptom-free days and nights and
`reduced use of as—needed relief medication compared
`with BDP. Interestingly, there was no difference between
`the two salmeterol groups and exacerbation rates did
`not differ between all three groups. A meta—analysis of
`nine studies has confirmed that addition of salmeterol
`
`to a low dose of inhaled corticosteroids gives better
`asthma control,
`in terms of reduced symptoms,
`im—
`proved lung function and reduced as-needed [fl-agonist
`use, than doubling the close of inhaled corticosteroids
`(ID).
`A landmark trial in this area is the FACET trial, which
`
`compared the effects of adding formoteroi to budeso-
`nide with budesonide only over a longer period than pre—
`viously studied, a total of l2 months (I). This study
`provided further evidence demonstrating that flz-ago-
`nists with a long-acting profile do not have a detrimental
`effect on the long-term control of asthma. For the first
`time, frequency of exacerbations was chosen as the pri-
`mary outcome in a trial of this type, defined as either: I]
`severe, Le. a requirement for oral glucocorticoids as
`judged by the investigator or following a decrease in the
`peak flow to more than 30% below the baseline value on
`2 consecutive days; or 2] mild,
`i.e. 2 consecutive days
`when morning peak flow decreased more than 20% be-
`low baseline, the use of more than three additional inha-
`lations of terbutaline in a 24 h period or night-time
`awakening due to asthma. As exacerbation rates give a
`clear indication of disease advancement, this study pro-
`vides invaluable data about the underlying inflammatory
`disease. Other endpoints studied were lung function,
`measured by forced expiratory volume in I second
`(FEVI) and PEF, asthma symptoms, night-time awaken-
`ings, and the requirement for as—needed fiz-agonist use.
`Patients with asthma taking a mean daily dose of bude-
`sonide 800,ug were randomly assigned to one of four
`treatments delivered by means of a dry—powder inhaier
`(Turbuhaler‘fi’): I] budesonide IOO ,ug twice daily plus pla-
`cebo; 2] budesonide lOOng twice daily plus formoterol
`Wig twice daily, delivered dose; 3] budesonide 400 ,ug
`
`APOTEX_AZFL 0131995
`
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`
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`

`RESPIRATORY/MEDICINE
`Sl4
`
`E Budesonide 100 ,ug bd (A) - Budesonide 400 gig bd (C)
`
`m Budesonide 100 ,ug bd +
`formoterol 9 pg bd (B)
`1.00
`
`WI/A Budesonide 400 mg bd +
`formoterol 9 ,ug bd (D)
`
`.O \1 m
`
`0.50
`
`exacerbations/patient/year
`Severe
`
`.0 to an
`
`0
`
`Figure 3. Rate of severe exacerbations during lZ—months'
`treatment with formoterol and budesonide in the FACET—study
`(I). increasing the dose of budesonide (A vs.C): P<0.00i ; adding
`iormoterol,
`irrespective of budesonide close (A+C vs. B+D):
`P=0.0I.
`
`
`
`Formoterol 9 pg bd + budesonide 400 lug bd
`- — — - Formoterol 9 pg bd + budesonide 100 ,ug bd
`— — - Budesonide 400 Mg bd
`— - - - Budesonide 100 pg bd
`
`twice daily plus placebo; or 4] budesonide 400 ,ug twice
`daily plus formoterol 9,ug twice daily. During a 4-week,
`run-in period, patients were treated with a high dose of
`inhaled corticosteroid (budesonide 800 ,ug twice daily) to
`ensure they were stable and active treatment was then
`given for a l2-month period. Terbutaline was permitted
`as needed for relief of symptoms.
`When compared with budesonide 200 pg daily and pla-
`cebo, rates of severe and mild exacerbation were re—
`
`duced in all other groups, with the lowest rates seen in
`patients who received the higher dose of budesonide plus
`formoterol (Figs 2 and 3). Patients in this group had a re—
`duction in severe exacerbations of 63% (P<0.00|) and in
`mild exacerbations of 62% (P<0.00|). Although the de-
`crease in the rate of severe exacerbations was not unex-
`
`pected following previous research, the decrease in the
`rates of mild exacerbations observed had not been an-
`
`ticipated.
`It had been suggested that use of formoterol might
`mask any underlying inflammatory process, preventing
`symptoms and therefore disguising the build up to an
`acute attack. This would result in exacerbations with a
`
`Interestingly,
`more rapid onset and greater severity.
`further analysis from FACET showed the time course,
`severity and duration of exacerbations to be similar in
`each study group (II).
`During the run—in period FEV; increased in all groups
`and increased further with the addition of formoterol
`
`(Fig. 4). The greatest increases were again observed in
`the group receiving budesonide 800,ug and formoterol
`l8,ug daily, however, the addition of formoterol to low-
`
`Budesonide 100 ,ug bd (A) - Budesonide 400 pg bd (C)
`m Budesonide 100 ,ug bd +
`7////A Budesonide 400 ,ug bd +
`formoterol 9 ,ug bd (B)
`formoterol 9 pig bd (D)
`40
`
`Numberofmild
`
`exacerbations/patient/year
`
`too
`
`s
`
`Figure 2. Rate ofmild exacerbations during lZ—months'treat—
`ment with formoterol and budesonide in the FACETstudy (i). in—
`creasing the dose of budesonide (A vs. C): P<0.00l; adding
`iormoterol,
`irrespective of budesonide dose (A+C vs. B+D):
`P<0.00l.
`
`FEVl(%ofpredictedvalue)
`0000\D0UIO
`
`
`
`
`
`\1Ln
`
`710 1
`
`2
`
`3
`
`6
`Month
`
`9
`
`12
`
`FEV, during the FACETstudy (l), FEVI is shown as a
`Figure 4.
`mean percentage ofthe predicted value during the run—in period
`and the treatment periodThe bars indicate 2 SE. (Reproduced
`with permission from N Engl J Med.)
`
`dose budesonide treatment had a greater effect than in-
`creasing the dose of budesonide alone. These results
`were maintained throughout the l2-month period of
`the study. Morning peak flow also increased on the addi-
`tion of formoterol. This response was greatest over the
`first 2 days of treatment and then decreased slightly, sug-
`gesting a small degree of tolerance had developed. After
`this time point, the peak flow remained stable for the
`rest of the l2-month period, and was significantly higher
`than either ofthe budesonide-only groupsThe tolerance
`
`APOTEX_AZFL 0131996
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`
`CLINICALOUTCOIVIE OFADDING LONG—ACTING ,B—AGONISTS TO INHALED CORTICOSTEROIDS
`SIS
`
`produced was felt to have little or no clinical significance.
`The requirement for as-needed medication, symptom
`scores and the number of days with symptoms were all
`significantly lowered following the addition of formoter—
`ol compared with budesonide alone.
`The authors concluded that the addition of formoterol
`
`to budesonide resulted in superior asthma control com-
`pared with budesonide only over a long-term period.The
`greatest improvements were observed where the dose
`of budesonide was also increased. All treatments were
`
`well tolerated and no safety issues were identified.
`As quality of life is an important outcome indicator for
`patients,
`the Asthma Quality of Life Questionnaire
`(AQLQ) was completed in 470 patients who completed
`the FACET study and analysed separately (l2). An in-
`crease in AQLQ after the initial
`improvement during
`the run-in phase was observed in patients treated with
`budesonide 400 pg plus formoterol 9 lug twice daily This
`improvement was sustained throughout the l2-month
`study. However,
`the correlation between changes in
`AQLQ and the results observed with respect to asthma
`control were weak.
`
`Similar results as those seen in the FACET study
`have also been seen in a study in mild asthmatic patients.
`The addition of formoterol 4.5 pg twice daily to budeso-
`nide IOOMg twice daily resulted in fewer severe exacer-
`bations
`and
`poorly
`controlled
`days
`compared
`with increasing the dose of budesonide to 200 ,ug twice
`daily (l3).
`
`substantially mediate the anti-inflammatory actions of
`corticosteroids, observed both in vitro (l6) and in vivo (l7).
`In these cost—conscious times it
`is important that
`any treatment is not only efficacious, but also cost—effec-
`tive. A group of independent physicians has estimated
`the average healthcare resources and productivity
`losses following exacerbations in FACET-like patients,
`and this information was evaluated against the clinical
`data from the FACET study (IS). The conclusions were
`that,
`for a marginal net cost
`increase, considerable
`improvements for
`all outcome measurements were
`observed.
`
`What, then, are the implications for patients? Patients
`with mild to moderate asthma, experiencing mild
`exacerbations, frequent night—time awakenings, limited
`daytime activity and high use of as-needed medication
`would generally benefit from the addition of a fiZ-agonist
`with
`long-acting
`properties.
`For
`those
`patients
`with more severe symptoms,
`i.e. frequent and severe
`asthma exacerbations, often requiring hospitalization
`or oral corticosteroid therapy, an increase in the dose
`of their inhaled corticosteroid plus a fiZ-agonist with
`a long duration of effect
`is
`likely to improve their
`condition. Although the effect of adding formoterol to
`all patient subgroups needs to be researched further,
`it appears that this treatment strategy provides a cost-
`effective treatment with rapid control of symptoms
`and is both well tolerated and effective in the long
`term.
`
`CONCLUSIONS
`
`REFERENCES
`
`The evidence presented indicates that patients with
`poorly controlled asthma will benefit from the addition
`of a fiZ-agonist with long-acting properties to their es-
`tablished inhaled corticosteroid treatment. Increases in
`
`lung function and improvement in symptom control have
`been observed and, very importantly, a reduction in
`both mild and severe exacerbations has been shown with
`formoterol.
`The mechanism for this effect is not understood. A
`
`possible explanation is that the dose-response curve for
`corticosteroids is relatively flat and, therefore, most of
`the anti-inflammatory effect can be obtained from lower
`doses of the drug (l4).Thus, increasing the corticoster-
`oid dose would have little effect compared with adding a
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