Management Severe

Persistent Allergic Asthma

(fokus on Anti IgE)

Staf Medical Functional Saiful Anwar Hospital,

Pulmonology and Respiratory Medicine,
Medical Faculty, Brawijaya University Malang
Curriculum Vitae
Nama : Dr. dr. Susanthy Djajalaksana, SpP(K)
Instansi : RSUD Dr. Saiful Anwar Malang
Tempat tanggal lahir : Bandung, 7 Mei 1962
Alamat Rumah : Jl. Danau Limboto A5 C33 Malang
Telp : (0341) 715161
Fax : (0341) 347110
HP : 0811367731
Alamat Kantor : Jl. Jaksa Agung Suprapto No. 2 Malang
Telp : (0341) 362101 pes. 2034
Fax : (0341) 347110
Alamat Email : bimodj@yahoo.com
Riwayat Pendidikan : Spesialis Paru / FKUB Malang
Doktor Ilmu Kedokteran /
Pasca Sarjana FKUB Malang
Riwayat Pekerjaan : 1. PNS di RSSA Malang
2. Sekretaris PDPI Cabang Malang
3. Sekretaris Program Studi Pulmonologi & IK.
Respirasi
4. Ka. IRNA I RSSA
 TOPIC PRESENTATION

► Definition and Phenotype of Asthma

► Asthma Severity & Current management of asthma
► Pathophysiology Allergic Asthma & Omalizumab MoA
► Xolair® (Omalizumab) : Indication & Phase III Clinical Study
► Xolair® (Omalizumab) : Treatment evaluation & Safety
Profile
► Summary

3
 What is asthma?

► Asthma is a heterogeneous disease, usually

characterized by chronic airway
inflammation. It is defined by the history of
respiratory symptoms such as wheeze,
shortness of breath, chest tightness and
cough that vary over time and in intensity,
together with variable expiratory airflow
limitation

GINA Report 2016 Available at: www.ginasthma.org

4
 Phenotype of Asthma (GINA 2016)

► Allergic asthma
► Non-allergic asthma
► Late-onset asthma
► Asthma with fixed airflow limitation
► Asthma with obesity

GINA Report 2016 Available at: www.ginasthma.org

5
 Allergic and non-atopic asthma
► Rackeman (1947) proposed two types of asthma: intrinsic (now called allergic)
and extrinsic (now called non-atopic)1
Asthma2

Allergic asthma Non-atopic asthma

• IgE-mediated • Non–IgE-mediated
• Th2-dependent • T–cell-dependence
• Mast cells, basophils, unclear
eosinophils, • Neutrophils involved
dendritic cells involved • Less responsive to ICS
• Responsive to ICS
IgE-mediated
allergic asthma
ICS = inhaled corticosteroids; IgE = immunoglobulin E; Th2 = T-helper 2 cells.

1. Rackeman FM. Am J Med 1947;3:601–6;

2. O’Byrne PM. Allergic vs non-allergic asthma. Available at: 6
www.worldallergy.org/educational_programs/world_allergy_forum/neworleans2010/obyrne/index.php?dir=prev&slide=1
 Prevalence of allergic versus
non-atopic asthma
► Estimates of the relative rates of allergic and non-atopic asthma
vary, but allergic asthma is more common
– Allergic and non-atopic asthma are not usually distinguished
in epidemiological studies1

► Approximately 70% of people with asthma also have allergies2

► In ECRHS II, 63.4% of respondents had IgE sensitization3

► Adult-onset asthma is more likely to be non-atopic4

ECRHS = European Community Respiratory Health Survey.

ECRHS II was a 9-year follow-up prospective survey of more than 10,000 young adults that began in 1998.

1. Bollag U, et al. Fam Pract 2009;26:96–101; 2. World Health Organization. Global surveillance, prevention and control
of chronic respiratory diseases. Available from: www.who.int; ; 3. Accordini S, et al. Allergy 2008;63:116–24; 4. Leynaert B, 7
et al. Thorax 2012;67:625–31.
Risk of asthma is related to the
level of serum IgE

40
n=2,657
Asthma (odds ratio)*

20

10

5.0

2.5

1.0

0.32 1 3.2 10 32 100 320 1,000 3,200

*Logarithmic scale
Serum IgE (IU/mL)*
Burrows B, et al. N Engl J Med 1989;320:271–7.
8
 Regional prevalence of asthma:
Asia and Oceania

No. of
Total people with Prevalence of
population asthma clinical asthma
Region (millions) (millions) (%)
Central Asia and
224.7 9.7 4.3
Pakistan
Southern Asia 1,210.0 42.2 3.5
China/Taiwan/Mongolia 1,324.1 27.8 2.1
Northeast Asia 196.8 11.4 5.8
Southeast Asia 529.3 17.5 3.3
Oceania 30.7 4.5 14.6

1. 1.Masoli M, et al. Global burden of asthma report, 2004. Available from: www.ginasthma.org/documents/8 9
GINA definition of asthma severity
(2005)
Moderate Severe
Intermittent Mild persistent persistent persistent
More than once
Less than once
Symptoms a week but less Daily Daily
a week
than once a day
May affect May affect activity
Exacerbations Brief Frequent
activity and sleep and sleep
Nocturnal Not more than More than twice More than once
Frequent
symptoms twice a month a month a week
Limitation of
Daily use of inhaled
Other No No physical
SABA
activities
FEV1 or PEF
≥80% ≥80% 60–80% ≤60%
(% predicted)
FEV1 or PEF
<20% 20–30% >30% >30%
variability
FEV1 = forced expiratory volume in 1 second; GINA = Global Initiative for Asthma; PEF = peak expiratory flow;
SABA =short-acting β2-agonist

GINA Report 2005. Available at: www.ginasthma.org 10

Most severe group of patients have TENOR
the highest incidence of hospitalization and
emergency visits
25
21
20 Mild (n=149)
Patients (%)

Moderate (n=2,285)
15 Severe (n=2,285)
11
10
10
6
5 3
1
0
Emergency department Hospitalization
visit

Data from TENOR, a 3-year prospective cohort study of

4,756 patients aged ≥6 years with severe or difficult-to-treat asthma.

Dolan CM, et al. Ann Allergy Asthma Immunol 2004;92:32–9.

11
In exacerbating patients, severity of asthma is
associated with greater severity of exacerbations
● Patients with severe asthma were more likely to require intubation and ICU admission,
and had a higher risk of in-hospital mortality (p=0.001 vs. non-severe)*

Intermittent (n=486) Mild (n=477) Moderate (n=903) Severe (n=727)

18
16
14
Patients (%)

12
10
8
6
4
2
0
Intubation ICU admission In-hospital mortality
*All patients were admitted following an exacerbation.
ICU = intensive care unit.

Rodrigo GJ, et al. Allergol Immunopathol (Madr) 2009;37:225–9.

12
13
The burden of asthma is greater for TENOR

uncontrolled asthma than controlled asthma

Controlled (n=216)
Mean †
*
13.6 Uncontrolled (n=3,700)
14 **
12.0
12
***
10.0
10

6
3.8
4
** ***
2 1.4 1.3 1.1
0.3 0 0
0
Work days School days Physician Hospital ED
lost lost visits nights visits
*p<0.05; **p<0.01; ***p<0.001; †in previous year.
ED = emergency department.

Sullivan SD, et al. Allergy 2007;62:655–60.

14
15
Unmeet Gaining Optimal Asthma ControL
Needs
Study (GOAL)
► In GOAL, rates of asthma control were compared in 3,421
patients receiving fluticasone or salmeterol/fluticasone
– Randomized, double-blind, parallel-group 1-year study
– Patients had uncontrolled asthma at baseline
– Stratified by ICS use in previous 6 months
– Doses were stepped up until total control achieved
(maximum corticosteroid dose 500 μg twice daily)
– Patients who had not achieved total control at the end of
phase II (Weeks 44–52) entered a 4-week, open-label phase:
• oral prednisolone (0.5 mg/kg up to 60 mg/day for 10
days), AND
• salmeterol/fluticasone 50/500 μg twice a day for 4 weeks

ICS = inhaled corticosteroids.

Bateman ED, et al. Am J Respir Crit Care Med 2004;170:836–44.

16
Unmeet Gaining Optimal Asthma ControL Study
Needs
(GOAL)
38% of patients with severe asthma* remain inadequately controlled despite
optimized treatment with salmeterol/fluticasone combination therapy

Well controlled at 1 year

Patients (%)
Inadequately controlled at 1 year

80
69
62
60

40 38
31

20

0
Salmeterol/fluticasone Salmeterol/fluticasone
plus course of oral corticosteroids
*>500–1,000 µg BDP or equivalent at entry
Bateman E, et al. Am J Respir Crit Care Med 2004
17
 Severe Asthma patients with the
greatest unmet need
Patient
Patients with severe persistent asthma who
Type remain symptomatic despite treatment with
high-dose ICS and LABA and one or more of the
following :
– are identified as high risk for asthma-related mortality
– have ≥2 severe exacerbations per year
– require ≥3 courses of OCS per year
– have regular disruptive nocturnal or daytime symptoms
– have severely restricted their lives in an effort to avoid
symptoms and exacerbations

Candidates for anti-IgE therapy

18
 TOPIC PRESENTATION
► Epidemiology & Burden of disease of Asthma
► Asthma Severity & Current management of asthma
► Pathophysiology Allergic Asthma &
Xolair® (Omalizumab) Mechanism of Action
► Xolair® (Omalizumab) : Indication & Phase III Clinical Study
► Xolair® (Omalizumab) : Treatment evaluation & Safety
Profile
► Summary

19
 Xolair® (Omalizumab) as Anti-IgE:
Mechanism in Allergic Asthma
Reduces allergy chemicals release

B lymphocyte Allergic
Inflammation:
Allergic eosinophils and
-switch mediators lymphocytes

Plasma cell

Release
of IgE Clinical
Allergens Exacerbation

Binds free IgE Reduces asthma

attacks
Reduces IgE receptors on
allergy cells
IgE = immunoglobulin E.
20
1. Rabe KF, et al. Allergy 2011;66:1142–51; 2. Galli SJ, Tsai M. Nat Med 2012;18:693‒704.
Xolair® (Omalizumab) is a recombinant,
humanized monoclonal antibody against IgE
► Omalizumab consists of a
human IgG framework onto
which is grafted the
complementarity-
determining region from a
murine anti-IgE antibody

► ‘Humanization’ process
ensures that residues of
murine origin constitute less
than 5% of the omalizumab
molecule
– Minimizing the potential
for an immune response
IgE/G = immunoglobulin E/G.

Boushey HA Jr. J Allergy Clin Immunol 2001;108:S77–83.

21
 TOPIC PRESENTATION
► Definition and phenotype of Asthma
► Asthma Severity & Current management of asthma
► Pathophysiology Allergic Asthma &
Xolair® (Omalizumab) Mechanism of Action
► Xolair® (Omalizumab) : Indication & Phase III Clinical Study
► Xolair® (Omalizumab) : Treatment evaluation & Safety
Profile
► Summary

22
Xolair® Approved Indication in
Asthma
 Omalizumab is indicated as add on therapy to improve asthma
control in adult, adolescent patients (12 years of age and older)
and children (6 to 12 years of age) with :
 Severe persistent allergic asthma
 Positive skin test or in vitro reactivity to a perennial aeroallergen
 Reduced lung function (FEV1 < 80%)
 Frequent daytime symptoms or night-time awakenings
 Multiple documented severe asthma exacerbations despite high
dose inhaled corticosteroid plus long-acting beta2-agonist
 Treatment should only be considered for patients with convincing
IgE mediated asthma

Xolair® Product Information – BPOM latest update by BPOM Jan 2015 23

 Innovate Study : Significant Reduces
Severe Asthma Exacerbations
INNOVATE :
Randomized double-blind clinical study
0.6 50%
Severe asthma exacerbation per patients

p<0.002
0.5 Relative reduction in
0.48 severe asthma
0.4 50% exacerbations*^
REDUCTION
(28 weeks)

0.3
*. Severe asthma exacerbations in this
0.2 study were defined as when a

0.24 patient’s lung function was reduced <

60% of personal best and systemic
0.1 corticosteroids were required. Primary
endpoint in this study was the
reduction in exacerbations.
0 ^. Baseline adjusted
Placebo Group XOLAIR® Group
(n=210) (n=209)

Humbert M et al. Benefits of omalizumab as add-on therapy in patients with

severe persistent asthma who are inadequately controlled despite (GINA step 4 treatment) : 24
INNOVATE. Allergy 2005: 60:309-316
 Xolair® (Omalizumab) has consistent
Efficacy
reduction in asthma exacerbation rates
across studies
Annual exacerbation
rate treatment difference

ETOPA1 SOLAR2 Busse3 Solèr4 Holgate5 ALTO

0

0.18#
0.29†
0.5 0.40** 0.42§

0.70**
1.0

1. Ayres JG, et al. Allergy 2004; 2. Vignola AM, et al. Allergy 2004
1.5 3. Busse W, et al. J Allergy Clin Immunol 2001
1.49** 4. Solèr M, et al. Eur Respir J 2001
**p0.001; †p=0.027; #p=0.077; §p=0.165 5. Holgate ST, et al. Clin Exp Allergy 2004

25
Innovate Study : Significant Improvement
in Lung Function (FEV1)
INNOVATE :
Randomized double-blind clinical study
P=0.043
200
FEV1 (% predicted) was
Improvement from baseline in FEV1 (ml)

180 significantly improved

160 190 with XOLAIR® compared
140 with placebo at study
120 completion
100 p=0.042
80
60 96
40
20
0
Placebo Group XOLAIR® Group
(n=210) (n=209)

Humbert M et al. Benefits of omalizumab as add-on therapy in patients with

severe persistent asthma who are inadequately controlled despite (GINA step 4 26
treatment) : INNOVATE. Allergy 2005: 60:309-316
Innovate Study : Significant Improvement in
Lung Function (Peak Expiratory Flow Rate)

22 L/MIN
Meta-analysis of three randomized clinical study
p= 0.026 XOLAIR® vs placebo

IMPROVEMENT
n=135
22L/min In morning peak expiratory
flow rate after 16 weeks vs
baseline
12L/min (p=0.045)

n=11
10 L/min
12 L/MIN
9
IMPROVEMENT
In morning peak expiratory
flow rate after 16 weeks vs
placebo
(p=0.026)

Holgate S et al. Current Medical Research and Opinion 2001;17:233-40 27

 Xolair® : Reduces the number of asthma –
related Emergency Room Visits
INNOVATE :
Randomized double-blind clinical
44%
Mean exacerbation rate per patient, (number)

study
0.5
P=0.038
0.45 RELATIVE REDUCTION IN
0.4 EMERGENCY ROOM
0.43
0.35 44% VISITS1^
REDUCTION
0.3 In a separate real-word
0.25 questionnaire based
study, adding XOLAIR® to
0.2
standard of care
0.15 0.24 reduced emergency
0.1
room visits by 65%2*
0.05 BSC = Base Standard Care, as defined by NHLBI
0 guidelines; moderate to high dose : ICS+/- LABA,
with systemic Corticosteroid allowed in the most
BSC* group XOLAIR®+ BSC sever patients
(n=106) group (n=206)

1. Humbert M et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled
despite (GINA step 4 treatment) : INNOVATE. Allergy 2005: 60:309-316 28
2. Molimard M et al. Effectiveness of Omalizumab in the first patients treated in real life practice in France. Respiratory Medicine 2008; 102:71-6
Xolair® : Reduces Severe Allergic Asthma-
Related Hospitalizations

67%
EXALT : Open-label study
Mean hospitalisation rate
(32 week treatment period) SIGNIFICANT REDUCTION IN
ASTHMA-RELATED
OAT (n=128)
HOSPITALISATIONS
P=0.037
0.14
Additionally, mean total
number of emergency visits
due to an exacerbation was
significantly reduced by 58%
XOLAIR® + OAT (n=272) with XOLAIR® +OAT vs OAT
(Optimized asthma therapy)
alone over the 32 week
0.05 treatment period (p≤ 0.001)

Bousquet J et al. Persistency of response to omalizumab therapy in severe allergic (IgE mediated)
asthma. Allergy 2011 ; 66: 671-8. 29
 Xolair® : Reduces the daytime and night
time symptoms of severe allergic asthma

Open Label Observational Study

80%
RELATIVE REDUCTION IN
DAYTIME SYMPTOMS
p<0.001

86%
RELATIVE REDUCTION IN
NIGHT-TIME SYMPTOMS
p<0.001

*. Daily asthma symptoms. **. Nocturnal awakenings

Korn S et al. Omalizumab in patients with severe persistent allergic asthma in a real life setting in Germany. Respiratory Medicine 2009;
103:1725-31 30
Xolair® : Significantly stopped or reduced
oral corticosteroid (OCS) use
EXALT : Open-label study
63%
Patients in XOLAIR group were
able to reduce or stop OCS,
compared with 30% of patients
in the optimized asthma
therapy group, at week 32.

In the XOLAIR group, 30%

(n=18) were able to reduce
OCS and 32% (n=19) were able
to stop OCS, at week 32.

OAT = Optimized asthma therapy

Siergiejko Z, et al. Oral corticosteroid sparing with omalizumab in severe allergic (igE-mediated) asthma 31
patients. Current Medical Research & Opinion 2011: 27: 2233-40
Xolair® : consistently improves overall Quality
of Life (QoL) across study
AQLQ score† Omalizumab
1.6 1.39
Control
**
1.4 1.19
***
1.2 1.12 1.02 1.01
0.94 0.93 *** ***
1.0 *** ***

0.8
0.61 0.64 0.61
0.6 0.49 0.46
*
0.4 0.26
0.18
0.2
0
INNOVATE ETOPA SOLAR Busse Solèr Holgate Pooled
study study study study study study
*p<0.05; **p<0.01; ***p<0.001 vs control
†Change from baseline (least squares mean). AQLQ = Asthma Quality of Life Questionnaire

Chipps B, et al. Curr Med Res Opin 2006 32

 TOPIC PRESENTATION
► Epidemiology & Burden of disease of Asthma
► Asthma Severity & Current management of asthma
► Pathophysiology Allergic Asthma &
Xolair® (Omalizumab) Mechanism of Action
► Xolair® (Omalizumab) : Indication & Phase III Clinical Study
► Xolair® (Omalizumab) : Treatment evaluation & Safety
Profile
► Summary

33
Xolair® : Individualized Dosing
► Omalizumab is administered as a subcutaneous injection every 2
or 4 weeks based on patients’ bodyweight and baseline serum
IgE levels

► Dosing requirements can be determined using an individualized

dosing table

► Treatment is intended to be administered by a healthcare

professional

Xolair Local Product Information, latest update by BPOM Jan 2015 34

 Xolair® Dosing Calculator

Xolair® Local Product Information latest update by BPOM Jan 2015 35

Treatment Response

► At 16 weeks after commencing omalizumab

therapy, patients should be assessed by their
physician for treatment effectiveness before further
injections are administered

► The decision to continue omalizumab should be

based on whether or not a marked improvement in
overall asthma control is seen

Xolair® Local Product Information latest update by BPOM Jan 2015 36

Xolair® : Adverse Reaction
Infections and Infestations
Uncommon Pharyngitis
Rare Parasitic Infections
Immune System Disorders
Rare Anaphylactic reaction and other allergic conditions, anti-
therapeutic antibody development
Nervous System Disorders
Common Headache**
Uncommon Dizziness, somnolence, parasthesia, syncope
Vascular Disorders
Uncommon Postural hypotension, flushing
Respiratory, thoracic and mediastinal disorders
Uncommon Coughing, allergic bronchospasm
Rare Larnyoedema

** Very common in 6 < 12 year old children

Frequencies are defined as: Very common (≥1/10), common (>1/100; <1/10), uncommon (>1/1000;
<1/100), rare (<1/1000).

Xolair® Local product information, latest update by BPOM Jan 2015 37

Xolair® : Adverse Reaction
Gastrointestinal disorders
Common Abdominal pain upper*
Uncommon Nausea, diarhoea, dyspeptic signs and
symptoms
Skin and subcutaneous tissue disorders
Common Urticaria, rash, pruritus, photosensitivity
Uncommon Angioedema
General Disorders and administration site conditions
Very common Pyrexia*
Common Injection site reactions such as pain, erythema,
pruritus, swelling
Uncommon Weight increase, fatigue, swelling arms,
influenza-like illness

* In 6 to < 12 year old children

Frequencies are defined as: Very common (≥1/10), common (>1/100; <1/10), uncommon (>1/1000;
<1/100), rare (<1/1000).

Xolair® Local product information, latest update by BPOM Jan 2015 38

Contraindication

► Hypersensitivity to the active substance

or to any of the excipients

Xolair® Local product information, latest update by BPOM Jan 2015 39

 Xolair® : Safety Overview

► Safety profile evaluated in more than 9,300 subject who treated with
Xolair® in clinical trial1
► Adverse events and laboratory profile for omalizumab were similar to
placebo/control
► > 400,000 patients had experience with Xolair® usage, since approved
in US in 2003 and in Europe in 20051
► Xolair® has been approved in > 90 countries worldwide1
► Evaluating Clinical Effectiveness and Long-term Safety in Patients with
Moderate to Severe Asthma (EXCELS) Study show no evidence of an
association between omalizumab use and an increased risk of
malignancy2

1. Xolair® PSUR (Periodic Safety Update Report Version18.

2. Long et al. Incidence of malignancy in patients with moderate to severe asthma treated with or without omalizumab. 40
J Allergy Clin Immunol 2014
 TOPIC PRESENTATION
► Epidemiology & Burden of disease of Asthma
► Asthma Severity & Current management of asthma
► Pathophysiology Allergic Asthma &
Xolair® (Omalizumab) Mechanism of Action
► Xolair® (Omalizumab) : Indication & Phase III Clinical Study
► Xolair® (Omalizumab) : Treatment evaluation & Safety
Profile
► Summary

41
 Summary
► Asthma is among the most prevalent chronic disease,
affecting 300 million people worldwide
► Approximately 70% asthma patients have allergies
► IgE plays a key role in allergic respiratory disease
* The anti-inflammatory effects of omalizumab provide proof of concept of the
importance of IgE in allergic respiratory disease

► There are lots of risk on uncontrolled asthma

► Anti-IgE treatment is add-on therapy to improve
asthma control in adult, adolescent patients (12 years
of age and older) and children (6-12 years of age)
with uncontrolled severe persistent allergic asthma
despite high dose inhaled corticosteroids, plus along
acting β2-agonist
42