Targeting small airways on asthma

treatment

高雄長庚兒童過敏免疫風溼科
王玲 主任
2012-9-8

1
 Contents
I. Small airway and physiology

II. Small airway disease and clinical correlates

III. GINA guideline recommendations in asthma treatment

IV. Ideal properties of an ICS for asthma Tx

V. Clinical efficacy, safety and tolerability of ciclesonide

I. Small airway anatomy and physiology

3
The bronchial trees in the lungs are made up of
conducting and respiratory zones

Conducting zone
First 16-17 branches
Transport air into smaller airways

Respiratory zone
Lower 6-7 branches
Sites of gaseous exchange

4
 The majority of bronchial tree generations are
made up of small airways (<2mm diameter)
18

16 Large airways Small airways

14
Diameter (mm)

12

10

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Airway Generation

The small airways include: terminal bronchioles, respiratory bronchioles, alveolar ducts and alveolar
sacs

1. Figure adapted from: Weibel ER. Morphometry of the Human Lung, Academic Press, 1963. 5
 The small airways (<2 mm diameter) account
for ~98.9% of total lung volume1
104
Cross-sectional area (cm2)

Large airways Small airways

103 Volume: 50mL Volume: 4500mL

102

10

0 2 4 6 8 10 12 14 16 18 20 23
Airway generation

The small airways are often considered to be a ‘quiet zone’, because they contribute little to the
total airway resistance of the bronchial tree

Virchow JC. Pneumologie 2009;63 Suppl 2:S96-101.

Figure adapted from: Weibel ER. Morphometry of the Human Lung, Academic Press, 1963.
6
 Factors affecting airflow and ventilation
Airway resistance

Increased airway resistance

Lung compliance

Normal lung compliance Poor lung compliance

Alveolar surface tension

Alveolus with surfactant Alveolus lacking surfactant

1. Wagner EM, et al. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584-8.
7
 The small airways only contribute to ~10% of
total airway resistance

• The cross-sectional area of the small airways is high, although their

contribution to the total airway resistance of the bronchial tree is
small

Current methods such as bronchoscopy, measures of

lung function and induced sputum typically assess
abnormalities in the large airways

• Hence, the small airways are known as the ‘silent zone’ of the lung

Contoli M, et al. Allergy 2010;65:141-151.

8
 Methods are available to assess small airway
function

Lung function tests (FEF25–75 and RV)

Impulse oscillometry

High resolution computed tomography

(HRCT)

Nitrogen washout

Alveolar exhaled nitric oxide (eNO)

FVC: forced vital capacity; FEF25–75: forced expiratory flow between 25–75% of FVC; RV: residual volume; CC: closing capacity; CV: closing
volume; HRCT: high-resolution computed tomography; eNO: exhaled nitric oxide
1. Contoli M, et al. Allergy 2010;65:141-151; 2. Kaminsky DA, et al. J Appl Physiol 2004;97:1849-58.
9
 1. Specific lung function parameters can be
used to assess the small airways

Pulmonary function Small airway function

Normal Air trapping

FVC FVC

RV
RV

RV and FEF25–75 reflect peripheral abnormalities

Spirometry (FEV1 or PEF) mainly detects volume
and airflow changes in the large airways A reduction in FVC also reflects an increase in
small airway obstruction

FVC: forced vital capacity; FEF25–75: forced expiratory flow between 25–75% of FVC; RV: residual volume

1. Contoli M, et al. Allergy 2010;65:141-151.

10
 2. 脈衝振動法 (Impulse oscillometry) can
detect subtle changes in peripheral resistance

By using short pulses of air pressure, respiratory

impedance, which accurately reflects the various
components of breathing, can be measured

Low oscillation frequencies (5Hz) reflect resistance

in the small airways and high oscillation
frequencies reflect resistance in the large airways

1. Contoli M, et al. Allergy 2010;65:141-151.

2. Kaminsky DA, et al. J Appl Physiol 2004;97:1849-58.
11
 3. High-resolution CT can provide anatomical
detail of the bronchial tree

Inspiration Expiration
Air trapping

HRCT can provide spatial resolution of airway diameters ~1–2mm

The technique allows for indirect assessment of small airway inflammation in particular with regards
to air trapping on expiration

HRCT: high-resolution computed tomography

Contoli M, et al. Allergy 2010;65:141-151.

12
 4. Nitrogen washout can distinguish ventilation
inconsistencies between large and small airways

Nitrogen concentration (%N/L)

30
IV

20 III

10
II
I
0
TLC
Lung volume CV RV

CC

In the single-breath test, increased closing volume (CV) or closing capacity (CC), and an
increase in the phase III slope of the washout curve reflect air trapping

RV: residual volume; CC: closing capacity; CV: closing volume; TLC: total lung capacity

1. Contoli M, et al. Allergy 2010;65:141-151.

2. In ‘t Veen JC, et al. Am J Respir Crit Care Med 2000;161:1902-1906.
13
 5. Alveolar eNO is a biomarker of small airway
inflammation

Alveolar eNO is an easy to perform,

noninvasive test which can estimate the
degree of peripheral airway inflammation

Alveolar eNO is measured at multiple

expiratory flows and is increased in
patients with asthma of different severity

Adapted from: GINA Global Strategy for Asthma Management and Prevention 2011 (update)

eNO: exhaled nitric oxide

1. van Veen IH, et al. Eur Respir J 2006;27:951-956. 14

II. Small airway disease and clinical
correlates

15
 Asthma inflammation is evident in the small
airways
200

Eosinophils (EG2)/mm2
Small
airways
100 Large
airways
*

n=16
0
>2 <2
Internal airway diameter (mm)

An increased eosinophil count has been observed in the small airways of asthma patients

*p<0.05 vs. small airways

Adapted from: Hamid Q, et al. J Allergy Clin Immunol 1997;100:44-51.

16
 Chronic inflammation causes pathological
changes in both large and small airways
Inflammatory filtrate
Increase in smooth muscle mass

Peripheral airway of a patient with

severe asthma

Airway remodelling is not limited to

the bronchi and bronchioles -
chronic inflammation also thickens
the walls of the small airways

Subepithelial fibrosis
Lumen occlusion (mucous plug)

Reproduced from: Contoli M, et al. Allergy 2010;65:141-151 with permission from John Wiley and Sons.
17
 Peripheral resistance is significantly increased in mild
asthma with normal lung function (L) & in nocturnal asthma
(R)

Peripheral resistance (cm H2O/mL/min)

Mild asthma
0.08
Average peripheral resistance

* *
0.07
0.069
(cm H2O/mL/min)

0.06
0.05
7 fold
0.04 increase
0.03
0.02
*
0.01
n=15
0 0.009 n=18
Healthy Patients with Non-nocturnal Nocturnal
subjects mild asthma asthma asthma

*p=0.013 vs. healthy subjects

1. Adapted from: Wagner EM, et al. Am Rev Respir Dis 1990;141:584-8.

2. Hyde DM, et al. J Allergy Clin Immunol 2009;124:S72-7.
18
 The recruitment of small airways determines the
severity of exercise-induced bronchoconstriction1
0.3 Exercise-induced asthma
Peripheral resistance

0.2 Cool, dry air

(cm H2O/L/sec)

stimulation increases
*
peripheral lung
0.19
resistance in patients
0.1
with mild asthma2

0 NS
0.09
0.07
0.05
n=14
-0.1
Pre-challenge Post-challenge Pre-challenge Post-challenge

Healthy subjects Patients with asthma

Cool, dry air is a stimulus which can be used to mimic exercise-induced asthma

*p<0.01 vs. healthy subjects

NS: not significant

1. Anderson SD, et al. Curr Opin Allergy Clin Immunol 2006;6:37-42; 2. Adapted from: Kaminsky DA, et al. Am J Respir Crit Care Med 1995;152:1784-90
19
 Summary
• The small airways account for the majority of bronchial tree
generations and the vast proportion of total lung volume
• Inflammation in the small airways is an important feature of asthma
and is associated with pathological changes in this lung
compartment

• Currently used methods such as spirometry (FEV1 or PEF) and

bronchoscopy typically assess the large airways
• Biological, functional and imaging techniques are available and can
be used to assess the small airways

• Small airway disease is associated with severe asthma, and

increased peripheral resistance has been observed in mild asthma
• Inflammation in the small airways may also play an important role in
nocturnal, exercise-induced and allergic asthma

1. Weibel ER. Morphometry of the Human Lung, Academic Press, 1963; 2. Contoli M, et al. Allergy 2010;65:141-151;
3. Hamid Q, et al. J Allergy Clin Immunol 1997;100:44-51; 4. Kraft M, et al. Am J Respir Crit Care Med 2001;163:1551-6;
5. In ‘t Veen JC, et al. Am J Respir Crit Care Med 2000;161:1902-1906; 6. Zeidler MR, et al. J Allergy Clin Immunol 2006;118:1075-1081; 20
7. Wagner EM, et al. Am Rev Respir Dis 1990;141:584-8; 8. Kaminsky DA, et al. Am J Respir Crit Care Med 1995;152:1784-90.
III. GINA Guideline recommendations in
asthma treatment

21
GINA Guideline for Asthma Management

Since 1993

1995 NHLBI/WHO
Workshop report

2002 GINA guideline

2003.10 revised
2004.10 revised
2005.10 revised
2006. 12 revised
2009. 3 <5 Y/O children
2010.12 revised
2011.12 revised
 GINA guidelines recommend ICS treatment as
the foundation of asthma management
In treatment-naïve patients with persistent asthma,
treatment should be started at Step 2 or if very symptomatic at Step 3

Reduce 3. Treatment steps Increase

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education. Environmental control.
(If step-up treatment is being considered for poor symptom control, first check inhaler technique, check adherence and confirm symptoms are due to asthma)

As needed rapid-acting β2-agonist As needed rapid-acting β2-agonist

To Step 3 treatment, To Step 4 treatment, add

Select one Select one
select one or more either

Medium or high-dose ICS

Low-dose ICS plus long- Oral glucocorticosteroid
Low-dose ICS* plus long-acting
acting β2-agonist (lowest dose)
β2-agonist

Controller options*** Medium or high-dose ICS Leukotriene modifier

Leukotriene modifier** Anti-IgE treatment
Low-dose ICS plus Sustained release
leukotriene modifier theophylline

Low-dose ICS plus

sustained release
theophylline

Adapted from: GINA Global Strategy for Asthma Management and Prevention 2011 (update ). www.ginasthma.org
23
 Assessment of current clinical control is a
cornerstone of asthma management
1. Assessment of current clinical control (preferably over 4 weeks)
Characteristic Partly controlled
Controlled
(Any measure Uncontrolled
(All of the following)
present)

Daytime symptoms None Three or more 2. Management approach

More than twice per features of partly
(twice or less per
week controlled asthma*† Level of control Treatment action
week)
Controlled Maintain and find
Limitation of lowest controlling step
activities None Any
Partly controlled Consider stepping up
to gain control
Nocturnal
symptoms/ Uncontrolled Step up until
None Any
awakening controlled
Exacerbation Treat as exacerbation
Need for reliever/ None
rescue treatment More than twice per
(twice or less per
week
week)

Lung function (PEF

or FEV1) ‡ <80% predicted or
Normal personal best (if
known)

*Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate; † By definition, an exacerbation in any week makes that an
uncontrolled week; ‡ Without administration of bronchodilator, lung function is not a reliable test for children 5 years and younger
24
Adapted from: GINA Global Strategy for Asthma Management and Prevention 2011 (update). www.ginasthma.org
Step-up therapy in childhood asthma with ICS

Step 2Step3

J Allergy Clin Immunol 2011;128:915

 Treating to Maintain Asthma Control
Stepping up treatment in response to loss of control
Doubling the dose of ICS is not effective in the management of
impending asthma exacerbations. (Evidence A)
 雙倍劑量 I ＣＳ效果不好 Thorax 2004;59:550.

Short-term increased doses of ICSs (4 X baseline) might be effective in

reducing exacerbations. Am J Respir Crit Care Med 2009;180:598.

High-dose of ICS is equivalent to a short course of oral corticosteroid.

(Evidence A) Eur Respir J 2006:28:182

Adapted from: GINA Global Strategy for Asthma Management and Prevention 2011 (update).
 1. Removed the asthma indication of Single-agent LABA
by FDA in 2008
Seretide
oxis

Balancing the Benefits and Risks of Inhaled LABA —

The Asthma indication of combination products (seretide, symbicort) for
adults, adolescents, children 4 ~11 y/o.
 2017-SL-11-09

2. Anti-IgE antibodies omalizumab (Xolair)

-approved by the FDA in 2003

Taiwan Indication

• 適應症 - 2010 年 4 月 13 日取得衛生署核准函

Xolair( 樂無喘 ) 為 add on therapy 附加療法
1. 用於改善已接受 high dose ICS+LABA 治療下仍有頻繁的日間症
狀或夜間覺醒且具有多次重度氣喘惡化記錄的 severe persisted
asthma 成人、青少年及兒童 (6 歲及以上 ) 的氣喘控制。
2. 這些氣喘患者必須有經由皮膚測試或體外試驗顯示對長期空氣
中過敏原呈陽性且肺功能降低 (FEV1 < 80%) 。樂無喘僅適用於
證實為 IgE 媒介型的氣喘病人。
3. Ciclesonide (Alvesco®)
• 160μg/puff, 60 puffs /pack
• NT 568 /pack approved by the FDA in 2006 ( 衛生署 in 2012)

• 適應症 : 4 歲以上小孩 , 青少年及成人持續性氣喘

• 使用劑量 :
成人 : 每天一次 , 每次 2 puffs
小孩 : 每天一次 , 每次 1 puff

• Pharmacology :
1. Conversion to an active metabolite
2. High pulmonary deposition and retention
3. High protein binding
4. Low bioavailability
 Estimated equipotent daily doses of ICSs for
adults†

Low Daily Dose Medium Daily High Daily

Drug
(µg) Dose (µg) Dose (µg)‡
Beclomethasone dipropionate - CFC 200-500 >500-1000 >1000-2000

Beclomethasone dipropionate - HFA 100-250 >250-500 >500-1000

Budesonide* 200-400 >400-800 >800-1600

Ciclesonide* 80-160 >160-320 >320-1280

Flunisolide 500-1000 >1000-2000 >2000

Fluticasone propionate 100-250 >250-500 >500-1000

Mometasone furoate* 200 ≥400 ≥800

Triamcinolone acetonide 400-1000 >1000-2000 >2000

*Approved for once-daily dosing in mild patients ; †Comparison based upon efficacy data
‡Patients considered for high daily doses except for short periods should be referred to a specialist for assessment to consider alternative combinations
of controllers. Maximum recommended doses are arbitrary but with prolonged use are associated with increased risk of systemic side effects.

30
Adapted from: GINA Global Strategy for Asthma Management and Prevention 2011 (update ). www.ginasthma.org
IV. Ideal properties of an ICS for asthma
treatment

Presented by Takeda Pharmaceuticals International GmbH

31
 Ideal properties of an ICS

For the treatment of asthma, an ICS should:

1 .Have high pulmonary deposition and small airway distribution
( 有效 )
2 Possess prolonged lung activity for once-daily dosing ( 方便 )
3. Have high protein binding and receptor affinity ( 副作用小 )
4. Improve pulmonary function and asthma control ( 有效 )
5. Minimize local and systemic side effects ( 副作用小 )

ICS: inhaled corticosteroid

Zitt M. Allergy and Asthma Proc 2005;26:173-182.

32
 1. Lung deposition and small airway distribution are
dependent on drug particle size

Monodisperse β-agonist aerosols

Poor lung penetration Good lung penetration

Particle size: 6µm 3µm 1.5µm

Total lung deposition: 46% 51% 56.3%
Small airway distribution: 24.6% 34.3% 43.9%
Adapted from Usmani et al., 2005

Small particles achieve good lung

deposition and small airway distribution1-3

Usmani OS, et al. Am J Respir Crit Care Med 2005;172:1497-504.

Leach CL, et al. Chest 2002;122:510-516.
Newman S, et al. Respir Med 2006;100:375-384. 33
 Large particles are more likely to be deposited in
the oropharynx than smaller particles

Large particles may

become deposited in the
oropharynx1

Small particles are swept

down into lungs with
laminar airflow2

1. Martin RJ. J Allergy Clin Immunol 2002;109:S447-S460.

2. Newman S, et al. Respir Med 2006;100:375-384. 34
 DPIs have variable particle size distributions which
is dependent on inhalation technique (PIF)
PIF reached within 0.5 seconds PIF reached within 1 second using
using budesonide Turbuhaler budesonide Turbuhaler

Flow during the initial

Respirable range Respirable range part of inspiration is
important in
20 20
determining the
Volume (%)

particle size
distribution generated
by a DPI
10 10

Rapid inhalation is
needed to produce a
high proportion of
0 0 particles within the
1.0 10.0 100.0 1.0 10.0 100.0 respirable range

Particle diameter (µm)

DPI: dry powder inhaler; PIF: peak inspiratory flow; MMAD: mass median aerodynamic diameter

Adapted from: Everard ML, et al. Respir Med 1997;91:624-28.

35
 Airway distribution with pMDIs is independent
of inspiratory flow but not of drug formulation
Suspension pMDI Solution pMDI

懸浮液 溶液

Suspension pMDIs produce high Solution pMDIs produce low

spray velocities, which may spray velocities, which may
result in greater deposition in the result in lower oropharyngeal
mouth and throat deposition1

pMDI: pressurized metered-dose inhaler

1. Richter K, et al, J Clin Pharmacol 2005;45:145-152

36
 Particle Size of ICS Products
• They can penetrate into small airways
that have an internal diameter of less 2μm
2 puff bid
Products Alvesco Pulmicort Duasma Flixotide Flixotide
Turbuhaler Accuahaler Evohaler
Brand ALTANA AZ BI GSK GSK

Active Ciclesonide Budisonide Fluticasone

Ingredient
Device HFA-MDI DPI CFC-MDI DPI HFA-MDI
solution powder suspension powder suspension

Shaken
before use - - + - +

Particle
Size(um) 1.1-2.1 5 3.4-4.0 5 3.4-4.0

Immunol Allergy Clin N Am. 25(2005);469-488

 Lung Deposition of Inhaled Corticosteroids

Dose to the lung

Ciclesonide 52%
HFA-MDI solution
HF
AM
Fluticasone DPI 12% DI
52%
Fluticasone
16%
HFA-MDI suspension
Budesonide MDI 22 - 28%
Budesonide DPI 28 %

Deposition characteristics of 99mTc-labeled CIC (ex-actuator) ;Leach CL, et al. Chest. 2002;122:510-516.; Borgström L, et
al. Eur Respir J. 1994;7:69-73. Pickering H, et al. Clin Ther. 2000;22:1483-1493.; Hirst PH, et al. Respir Med. 2001;95:720-
727. Thorsson L, et al. J Clin Pharmacol. 2001;52:529-538.; Thorsson L, et al. Eur Respir J. 1994;7:1839-1844.
2. Prolonged Activity in the Lungs
Importance of lipophilicity

High lipophilicity Low lipophilicity

親脂性越高 ,
藥物於肺部分佈情形越廣
藥效越長

High volume of distribution Low volume of distribution

Long duration of action Short duration of action
CIC > des-CIC > FP > BUD
Lipworth BJ, et al. Drug Saf. 2000;23:11-33; Miller-Larsson A, et al. Am J Respir Crit Care Med.
2003;167(suppl):A773; Crim C, et al. Clin Ther. 2001;23:1339-1354.
 Ciclesonide Activation

• 支氣管內皮細胞中進行快速的代謝作用

ciclesonide (CIC) to desisobutyryl-ciclesonide (des-CIC)

– 24 小時內 100% 轉變 (CIC) to (des-CIC)
– des-CIC 作用集中於支氣管內皮細胞比 CIC 高出 100 倍
– des-CIC 於實驗証實 , 約 25.8% 的 des-CIC 於肺的支氣管
內皮細胞中與 FA 結合 ( 酯化反應 Esterfication) 隱藏於支氣
管內皮細胞中 , 形成緩釋做用 , 造成一天一次的效果

• Prolonged Activity in the Lungs ( 親脂性高 +des-CIC 酯化反

應)

Mutch E, et al. Eur Respir J. 2003;22(suppl 45):267s-268s. Abstract P1749. Nave R, et al. Am J Respir Crit
Care Med. 2003;167:A771. Abstract A1510. Nave R, et al. Am J Respir Crit Care Med. 2004;169:A91.
Data on file, ALTANA Pharma.
 3. Ciclesonide is highly plasma protein-bound,
reducing the risk of systemic side effects1
25

Fraction unbound (%)

20

15
13%
12%
10%
10

5
Plasma protein binding
ensures that only 1% of 1% 1% 1%
ciclesonide and des-CIC is 0
unbound in the systemic CIC1 des-CIC1 MOM2 FP3 BUD4 BDP5
circulation

Only unbound systemic drug fractions can exert unwanted systemic pharmacological
effects
Alvesco 是蛋白結合率極高 . 到達全身的量非常低
CIC: ciclesonide; des-CIC: desisobutyryl ciclesonide; MOM: mometasone furoate; FP: fluticasone; BUD: budesonide; BDP: beclomethasone dipropionate
1. Nave R, et al. Clin Pharmacokinet 2004;43:479-486; 2. Affrime MB, et al. J Clin Pharmacol 2000;40:1227-1236;
3. Rohatagi S, et al. J Clin Pharmacol 1996;36:938-941; 4. Ryrfeldt A, et al. Eur J Respir Dis 1982;122(suppl):86-95; 41
5. Martin LE, et al. Postgrad Med J 1975;51:11-20.
4. Ideal ICS should have high receptor affinity
Brand Alvesco Pulmicort Duasma Flixotide Flixotide
MDI DPI MDI Accuhaler Evohaler
(DPI) (MDI)
Active
Ciclesonide Budesonide Fluticason propionate
Ingredient
Dose
160μg/puff 200μg/puff 250μg/puff
Oral deposition 48%
72% 72% 88% 84%
(CIC)
Protein binding
99% 88% 90%
GR affinity CIC:12
935 1800
Des-CIC: 1200
Activity drug
Des-CIC Budesonide Fudicason propionate
Pro-durg
+ - -
 5. Ciclesonide has a low oral bioavailability1

ICS Oral bioavailability (%)

Ciclesonide1 <1

Fluticasone propionate2 <1

Beclomethasone dipropionate3 41
Budesonide4 11

Mometasone furoate5 <1

Low oral bioavailability is an important safety feature of inhaled corticosteroids

Ciclesonide has low oral bioavailability due to high first pass metabolism and does not appreciably
contribute to the systemic availability of the drug

ICS: inhaled corticosteroid

. Nave R, et al. Clin Pharmacokinet 2004;43:479-486; 2. Rohatagi S, et al. J Clin Pharmacol 1996;36:938-941;
. Daley-Yates PT, et al. Br J Clin Pharmacol 2001;51:400-409; 4. Ryrfeldt A, et al. Eur J Respir Dis 1982;122(suppl):86-95;
. Affrime MB, et al. J Clin Pharmacol 2000;40:1227-1236. 43
 The fate of inhaled ICS

Inhaled fraction Complete absorption

from the lungs
Mouth and
pharynx Lungs

Swallowed Fraction
Systemic
Orally bioavailable circulation
fraction

Gut absorption
GI tract Liver High
Plasma
protein
binding
High first-pass
metabolism
Systemic
High clearance side effects

44
V. Clinical efficacy, safety and tolerability
of ciclesonide

45
 In clinical trials
• Clinical Efficacy
– Alvesco vs BUD
– Alvesco vs FP

• Safety
– Long-term use of Alvesco: growth
– Alvesco vs BUD
– Alvesco vs FP

• Tolerability
– Placebo-like tolerability
 Ciclesonide once-daily improves FEV1 (L) and reduces
asthma symptoms (R) as effectively as FP

0.6
Change in FEV1 vs. baseline

* ** 0.5
0.5
0.46
after 24 weeks (L)

0.4

0.3

0.2

0.1
n=479
0
Ciclesonide FP HFA
80µg OD 100µg BID

Low dose ciclesonide once-daily is as effective as fluticasone propionate 100µg twice-daily in

improving FEV1 over 24 weeks

Data are presented as means; *p<0.0001 vs. baseline; **p<0.0001 vs. baseline
FEV1: forced expiratory volume in one second; OD: once-daily; BID: twice-daily
Adapted from: Dahl R, et al. Respir Med 2010;104:1121-1130. Boulet LP, et al. Respir Med 2007;101:1677-1686 with permission from Elsevier. 47
 Once-daily ciclesonide achieves a greater reduction
in eNO than twice-daily fluticasone propionate
2 weeks 4 weeks 8 weeks 12 weeks
0
eNO reduction from baseline (%)

-10

-20

-30

-40 * FP 200µg BID

* * *
-50 * CIC 80µg OD
* *
-60 CIC 160µg OD
*
-70
n=35

Ciclesonide has high anti-inflammatory activity with once-daily dosing

eNO: exhaled nitric oxide; OD: once-daily; BID: twice-daily; FP: fluticasone propionate; CIC: ciclesonide
*p<0.05 vs. fluticasone propionate

Adapted from: Zietkowski Z, et al. Respir Med 2006;100:1651-1656. 48

 Comparison of ciclesonide and fluticasone
propionate on small airway function

Baseline period Treatment period

8 weeks 8 weeks

Ciclesonide 200μg OD

Fluticasone 100μg BID

Fluticasone 100μg BID

Randomized, open-label, parallel group study with a treatment period of 8 weeks to compare the
effectiveness of a small particle ICS (ciclesonide) and a large particle ICS (fluticasone DPI) on
small airway function

Fluticasone propionate *DPI: particle size 5.4µm diameter; ciclesonide HFA: particle size of 1.1µm diameter
OD: once-daily; BID: twice-daily; ICS: inhaled corticosteroid; DPI: dry powder inhaler

Hoshino M. Allergol Int 2010;59:59-66. 49

 Ciclesonide significantly improves small
airway resistance and ACT score than FP

Change in ACT score vs. baseline

Small airway resistance (kPa/L/s)

0.01 2.5
NS *
2
0 1.5
Fluticasone propionate
100µg BID 1
-0.01
0.5
NS
-0.02 0
-0.02 Ciclesonide
* -0.5 200µg OD
Ciclesonide Fluticasone propionate
100µg BID
200µg OD n=30 -1
-0.03 n=30

Small airway resistance (R5–R20) was assessed using impulse oscillometry

*p<0.05 vs. baseline; NS: not significant; OD: once-daily; BID: twice-daily
All patients were pretreated with fluticasone propionate 100μg twice-daily during an 8 week run-in period

Adapted from: Hoshino M. Allergol Int 2010;59:59-66.

50
Efficacy and safety data in children

51
 Once-daily ciclesonide significantly improves
symptom-, rescue medication-, nocturnal awakening-
free days and FEV1 in children than FP

Mean change in FEV1 from baseline (L)

0.3
CIC 80µg CIC 160µg FP 88µg BID
10 0.25
OD OD
0
80 0.2

60 0.15
Days
(%)

40 0.1

20 0.05

0 0
Symptom- Rescue Nocturnal
free medication- awakening- FP 88µg BID CIC 80µg OD CIC 160µg OD
days free days free days

n=744 Age 6–11 years

Reproduced from: Pedersen S et al. Pulm Pharmacol Ther 2009;22:214–220

OD: once-daily; BID: twice-daily; CIC: ciclesonide; FP: fluticasone propionate

52
Ciclesonide in wheezy preschool children with a positive
asthma predictive index or atopy-efficiency
BACKGROUND:
• Few large-scale studies have examined ICS treatment in preschool
children with recurrent wheeze. We assessed the effects of
ciclesonide in preschool children with recurrent wheeze.
METHODS:
• We included children 2-6 yrs with recurrent wheeze and a positive API
or aeroallergen sensitization to, excluding patients with episodic viral
wheezing. After a 2-4-week baseline period, patients with ongoing
symptoms or rescue medication use were randomised to once-daily
ciclesonide 40, 80, 160 μg or placebo for 24 weeks.
CONCLUSIONS: In preschool children with recurrent wheeze and a
positive API, ciclesonide modestly reduces wheeze exacerbation
rates and improves lung function. A large placebo response and
unexpected selection of patients with mild disease may have affected
outcomes, highlighting the heterogeneity of preschool wheezing
disorders

Respir Med. 2011 Nov;105(11):1588-95.

 Once-daily ciclesonide does not significantly
reduce urine free cortisol levels in children
FP 88µg BID CIC 80µg OD CIC 160µg OD
0
Change in urinary-free cortisol from

-0.06
-0.2
baseline (nmol/mmol)

-0.4

-0.6 -0.67

-0.8

-1.0
-1.21
-1.2
* n=744
-1.4
Age 6–11 years
Adapted from: Pedersen S et al. Pulm Pharmacol Ther 2009;22:214–220

*P=0.0103 vs. baseline

FP: fluticasone propionate; CIC: ciclesonide; OD: once-daily; BID: twice-daily
54
 Once-daily ciclesonide has significantly less
influence on growth than budesonide

1.2 *
Change from baseline in body height

1.18
1

0.8
(cm)

0.6 0.7

0.4

0.2
n=84
0
CIC 160µg OD BUD HFA 400µg OD
Age 6–11 years
Reproduced from: Von Berg A et al. Pediatr Allergy Immunol 2007;18:391-400

OD: once-daily; CIC: ciclesonide; BUD: budesonide

*p=0.0025 vs. budesonide
55
Assessment of the long-term safety of inhaled ciclesonide
on growth in children with asthma
OBJECTIVE: To assess the effects of the new ICS ciclesonide on
growth in children with asthma.
METHODS: We performed a multicenter, randomized, double-
blind, placebo-controlled study to assess the effects of ICS
ciclesonide on growth in children with mild, persistent asthma.
After a 6-month run-in period, 661 prepubertal children who
were aged 5.0 to 8.5 years were randomly assigned to once-
daily morning treatment for 1 year with ciclesonide 40 or 160
microg or placebo, followed by a 2-month follow-up period. The
primary end point was the linear growth velocity over the
double-blind treatment period. Growth was recorded as the
median of 4 stadiometer measurements. Adverse events and
10-hour overnight and 24-hour urinary free cortisol levels were
also assessed.
CONCLUSIONS: Ciclesonide demonstrated no detectable
effect on childhood growth velocity, even at the highest
dosage, which may ease concerns about systemic adverse
events.

Pediatrics. 2008 Jan;121(1):e1-14.

 The influence of ciclesonide on growth in
children is comparable to placebo
10
9
double-blind treatment period
Mean change in stadiometer
height from baseline during

8
7
6
(cm)

5
4
3
2
1
0
n=661
3 months 6 months 12 months 3 months 6 months 12 months 3 months 6 months 12 months

Placebo CIC 40µg OD CIC 160µg OD Age 5–8.5 years

Baseline values: 6.49cm 6.59cm 6.20cm
Ciclesonide has no significant effect on childhood growth velocity, even at the highest pediatric
dosage over a period of 1 year

OD: once-daily
Adapted from: Skoner DP, et al. Pediatrics 2008;121:e1-e14.
57
 Oropharyngeal deposition with ciclesonide is
low1,2
4500
Low oropharyngeal
4000 deposition helps to avoid
Concentration in mouth-rinsing

local side effects

3500
solution (nmol/L)

3000

2500

2000

1500

1000

500
n=18
0
Time after inhalation: 4 minutes 25 minutes 4 minutes 25 minutes
Ciclesonide + des-CIC Fluticasone propionate

des-CIC: desisobutyryl ciclesonide

1. Figure adapted from: Richter K, et al, J Clin Pharmacol 2005;45:145-152.

2. Newman S, et al, Respir Med 2006;100:375–384.
58
Placebo-like tolerability
 Summary

• Ciclesonide significantly improves FEV1, morning PEF and asthma

control in patients with mild-to-moderate persistent asthma
• Ciclesonide improves small airway function and reduces asthma
inflammation
• In patients pre-treated with fluticasone propionate DPI, ciclesonide
further improves asthma control
• In children, ciclesonide improves lung function and quality of life
• Ciclesonide has no detectable effect on childhood growth velocity,
suggesting that it has a favourable therapeutic index in the pediatric
population
• Even at the highest doses, ciclesonide does not significantly affect
plasma or urinary cortisol levels

FEV1: forced expiratory volume in one second; DPI: dry powder inhaler; PEF: peak expiratory flow

1. Dahl R, et al. Respir Med 2010;104:1121-1130; 2. Boulet LP, et al. Respir Med 2007;101:1677-1686; 3. Adachi M, et al. Respirology 2007;12:573-580;
4. Cohen J, et al. Eur Respir J 2008;31:1213–1220; 5. Hoshino M. Allergol Int 2010;59:59-66; 6. Pedersen S et al. Pulm Pharmacol Ther 2009;22:214–220
7. Derom E, et al. Pulm Pharmacol Ther 2005;18:328-336; 8. Skoner DP, et al. Pediatrics 2008;121:e1-e14 60
 Assessment of the efficacy and safety of ciclesonide (with
or without spacer) in children with asthma
Objective: To evaluate the efficacy and safety of 3 doses of ciclesonide (with
or without spacer) in children with persistent asthma.
Patients and methods: This was a multicentre, double-blind, placebo-
controlled, 12-week study of ciclesonide 40, 80 or 160 mg (once daily pm).
Children (6-11 years) were randomised 1:1 to treatment via a MDI or MDI +
spacer. The primary variable was change from baseline in mean morning
PEF. Secondary variables included: time to first lack of efficacy (LOE),
asthma control, FEV1, and asthma symptom score Safety assessments
included: adverse events (AEs), urinary cortisol excretion and body height.
Results: In total, 1073 children received treatment. At endpoint, mean
morning PEF significantly improved with all doses of ciclesonide vs.
placebo. There was no difference over placebo in time to first LOE, but
ciclesonide was superior to placebo on asthma control, symptom score,
and FEV1. There were no differences between the spacer or non-
spacer.

From Respiratory Medicine (2010) 104, 1618

謝謝聆聽