IgE plays a central role in asthma

1
• Approximately two-thirds of asthma is estimated to be allergic
• A correlation between ‘total’ IgE levels and the risk of developing asthma
2
in adults has been reported
• A recent publication challenged the view that the prevalence of atopy
3
declines with age
– atopy has increased over the last 30 years
– atopy does not decline with increasing age
– more recent birth cohorts are more likely to express atopy
4
• More than 50% of patients with severe asthma have allergic asthma
– skin-prick positive ≥1 common aeroallergen

1. Novak N, Bieber T. J Allergy Clin Immunol 2003; 2. Burrows B, et al. N Engl J Med 1989
3. Law M, et al. BMJ 2005; 4. ENFUMOSA. Eur Respir J 2003
 Asthma Control ?

Asthma control is defined in the latest

update of GINA guidelines 2007 as :
 No daytime symptoms ,
 No limitations of daily activities ,
 No nocturnal symptoms ,
 No need for reliever treatment ,
 Normal or near normal lung function ; and
 No exacerbation

38% patients remain inadequately controlled despite optimised treatment with ICS and LABA*.

*GOAL Study
 Summary of the allergic inflammatory
cascade in patients with IgE-mediated
asthma
B lymphocyte Allergic
inflammation:
Allergic eosinophils and
ε -switch mediators lymphocytes

Plasma cell

Release Allergens
of IgE Asthma exacerbation

Mast cells
Basophils
 Humanized
monoclonal anti-IgE antibody: Xolair®

IgE

Xolair®

Cε 3
 Effects of Omalizumab on IgE

Omalizumab
IgE
Fcε RI

omalizumab

• Binds circulating IgE

• Reduces mast cell bound IgE
• Decreases IgE receptor
• numbers
 Omalizumab mechanism of action
in IgE-mediated asthma
Reduces
mediator release
B lymphocyte Allergic
inflammation:
Allergic eosinophils and
ε -switch mediators lymphocytes

Plasma cell

Perennial
Release Omalizumab aeroallergens
of IgE Asthma exacerbation
Reduces
Binds to free high-
IgE, reducing affinity
receptors Reduces asthma
cell-bound IgE
Mast cells exacerbations
Basophils and
symptoms
Proposed mechanisms of action of
Omalizumab
 INNOVATE: anti-IgE as a treatment for
inadequately controlled severe allergic
asthma
INNOVATE: INvestigatioN of Omalizumab
in seVere Asthma TrEatment

• A 28-week randomized double-blind, placebo-

controlled study to assess the efficacy and safety of
add-on omalizumab therapy in patients with severe
persistent asthma (GINA 2002)
– inadequately controlled despite high doses of
ICS (>1,000 μg/day BDP) and LABA

Humbert M, et al. Allergy 2005

 Study design

28 weeks

Omalizumab or placebo as Off

add-on to GINA step 4 therapy study
Screening drug
tests
(7 days) Visits 0, 1, 2, 4, 12, 20 and 28 weeks

Run-in phase Follow-up

(8 weeks) (16 weeks)

Randomization
Humbert M, et al. Allergy 2005
 Efficacy variables

• Rate of clinically significant asthma exacerbations

(primary efficacy variable)
– worsening of asthma symptoms requiring treatment with systemic
corticosteroids

• Severe exacerbation rate

– PEF or FEV1 <60% of personal best, requiring treatment with
systemic corticosteroids

• Emergency visit rate

– hospital admissions
– emergency department visits
– unscheduled doctor’s visits
Humbert M, et al. Allergy 2005
INNOVATE targeted greatest unmet need population
Target population according to GINA

Current treatment step

Step 1 Step 2 Step 3 Step 4
No controller <500 µg BDP 200–1,000 µg >1,000 µg BDP
Clinical features BDP + LABA + LABA ± other
Step 1 Intermittent Mild Moderate Severe
Symptoms <1 x week
persistent persistent persistent
Nocturnal symptoms ≤2x month
Lung function normal between episodes

Step 2 Mild Moderate Severe Severe

Symptoms >1 x week
persistent persistent persistent persistent
Nocturnal symptoms <1 x week
Lung function normal between episodes

Step 3 Moderate Severe Severe Severe

Symptoms daily
persistent persistent persistent persistent
Nocturnal symptoms ≥1 x week
FEV1 60–80% predicted

Step 4 Severe Severe Severe Severe

Symptoms daily
persistent persistent persistent persistent
Frequent nocturnal symptoms
FEV1 <60% predicted

Patients included in INNOVATE study

Inadequately controlled population despite very
high asthma medication use

Patient baseline characteristics

Humbert M, et al. Allergy 2005

 Omalizumab significantly reduces clinically
significant exacerbations

Clinically significant exacerbation rate*

1.2 ∆ –26.2%
p=0.042
1.0
0.91
0.8
0.68
0.6

0.4

0.2

0
Omalizumab Placebo
(n=209) (n=210)
*Adjustment due to a pre-study imbalance in
exacerbation rate; –19.2% (p=0.156) reduction unadjusted Humbert M, et al. Allergy 2005
Omalizumab significantly reduces severe
exacerbations and emergency visits

Severe exacerbation rate Total emergency visit rate

∆ –50.0% ∆ –43.9%
0.6 p=0.002 0.6 p=0.038
• Large imbalances in asthma
0.5 0.48 exacerbation rate during both the
0.5
year prior to start of drug
studyand
andthe
0.43 the
0.4 run-in
0.4

0.3 •0.3
Previous exacerbations are the
0.24 single most
0.24important predictive
0.2 factor of future events
0.2

0.1 0.1

0 0
Omalizumab Placebo Omalizumab Placebo
(n=209) (n=210) (n=209) (n=210)
Humbert M, et al. Allergy 2005
 INNOVATE: conclusions

• In patients with severe persistent asthma, omalizumab

therapy as add-on to best available treatment:
– significantly reduced clinically significant exacerbations
• requiring unscheduled systemic corticosteroids
– significantly reduced severe exacerbations
– significantly reduced emergency visits

• Omalizumab add-on therapy also significantly improved

QoL and asthma symptoms and demonstrated a safety
and tolerability profile similar to that of placebo

Humbert M, et al. Allergy 2005

Omalizumab efficacy in severe
allergic asthma (pooled data)
Omalizumab clinical efficacy programme:
controlled trials

• Seven large phase III controlled trials in adults and

adolescents with allergic asthma
– five double-blind placebo-controlled studies
• including INNOVATE
– two open-label standard therapy controlled studies

• Omalizumab given as add-on therapy in all studies

 Summary of omalizumab phase III studies
in adult and adolescent allergic asthma
Number of Treatment
Study patients duration Efficacy endpoint
INNOVATE study1 419 28 weeks Asthma exacerbation rate
ETOPA study2 312 52 weeks Asthma exacerbation rate
SOLAR study3 405 28 weeks Asthma exacerbation incidence
Busse study4 525 52 weeks Asthma exacerbation rate
Solèr study5 546 52 weeks Asthma exacerbation rate
Holgate study6 341 32 weeks Reduction in ICS use
ALTO study 1,899 24 weeks Asthma exacerbation rate

93% of patients met GINA 2002 criteria for severe persistent asthma

1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004; 3. Vignola AM, et al. Allergy 2004
4. Busse W, et al. J Allergy Clin Immunol 2001; 5. Solèr M, et al. Eur Respir J 2001
6. Holgate ST, et al. Clin Exp Allergy 2004
 Efficacy variables

 Primary efficacy variable

– asthma exacerbation rate

 Other efficacy variables

– emergency visit rate
– QoL
– global evaluation of treatment
effectiveness

Bousquet J, et al. Allergy 2005

Patient baseline characteristics

Bousquet J, et al. Allergy 2005

 Omalizumab significantly reduces
asthma exacerbation rate: pooled data

Annualized ∆ –38.3%
exacerbation rate p<0.0001
1.5 1.47

1.0
0.91

0.5

0
Omalizumab Control
(n=2,476) (n=1,797)
Bousquet J, et al. Allergy 2005
 Efficacy of Omalizumab
Summary of phase III studies in allergic asthma

Number of Treatment Annual Percent P-value

patients duration exacerbation rate reduction
Study treatment
difference

INNOVATE study1 419 28 weeks 0.37 19.2% 0.156

ETOPA study2 312 52 weeks 1.49 60.4% <0.001
SOLAR study3 405 28 weeks 0.29 37.5% 0.027
Busse study4 525 52 weeks 0.40 40.3% <0.001
Solèr study5 546 52 weeks 0.70 57.6% <0.001
Holgate study6 341 32 weeks 0.42 26.5% 0.165
ALTO study 1,899 24 weeks 0.18 15.3% 0.077

Pooled 7 - - 0.56 38.3% <0.0001

93% of patients met GINA 2002 criteria for severe persistent asthma
1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004; 3. Vignola AM, et al. Allergy 2004
4. Busse W, et al. J Allergy Clin Immunol 2001; 5. Solèr M, et al. Eur Respir J 2001
6. Holgate ST, et al. Clin Exp Allergy 2004;7. Bousquet J, et al. Allergy 2005
 Omalizumab significantly reduces
emergency visits for asthma: pooled data

Bousquet J, et al. Allergy 2005

 Omalizumab consistently improves
overall QoL

AQLQ score† Omalizumab

1.33
1.4 Control
* 1.19 1.16
1.2 ** ***
0.96 1.07
0.91
1.0 *** 0.91
*** 0.85
0.8
0.6
0.46 0.48
0.35
0.4
**
0.2
0.06
0
INNOVATE ETOPA SOLAR Busse Solèr Holgate
study1 study2 study3 study4,5 study6,7 study8

1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004

*p<0.05; **p<0.01; ***p<0.001 vs control 3. Vignola AM, et al. Allergy 2004; 4. Busse W, et al. JACI 2001
†
Change from baseline (least squares mean) 5. Lanier BQ, et al. AAAI 2003; 6. Solèr M, et al. ERJ 2001
7. Buhl R, et al. ERJ 2002; 8. Holgate ST, et al. Clin Exp Allergy 2004
Physician overall assessment showed greater proportion
of omalizumab patients who were responders

80 Omalizumab
68.5*
Marked improvement or complete

Control 66.2**
60.5** 60.2**
60
control† (% patients)

53.1**

42.8 42.0 44.2

40 33.3 34.7

20

0
INNOVATE1 SOLAR2 Busse3 Solèr4 Holgate5

*p<0.01, **p<0.001; †physician’s overall assessment

1. Humbert M, et al. Allergy 2005; 2. Vignola AM, et al. Allergy 2004
3. Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ 2001
5. Holgate ST, et al. Clin Exp Allergy 2004
 Summary

• Pooled data from seven controlled studies clearly demonstrate that

add-on omalizumab significantly reduces the rate of
– clinically significant asthma exacerbations
– emergency visits

• Omalizumab significantly improves QoL

• Significantly more patients achieved either complete control or

a marked improvement in control of asthma symptoms

• Omalizumab should be considered as add-on treatment for patients

who continue to suffer with inadequately controlled asthma despite
the use of high-dose ICS and LABAs
 Adverse reactions with omalizumab
in clinical trials
Infections and infestations
Rare Parasitic infection
Immune system disorders
Rare Anaphylactic reaction , other serious allergic conditions
Nervous system disorders
Common Headache
Uncommon Dizziness,somnolence,paraesthesia,syncope
Vasular disorders
Uncommon Postural hypotension, flushing
Respiratory , thoracic and mediastinal disorders
Uncommon Pharyngitis , coughing, allergic bronchospasm
Gastrointestinal disorders
Uncommon Nausea, diarrhoea , dyspeptic signs and symptoms
Skin and subcutaneous tissue disorders
Uncommon Urticaria , rash, pruritus , photosensitivity
General disorders and administration site conditions
Common Injection site reactions such as pain , erythema pruritus ,swelling
Uncommon Weight increase , fatigue , swelling arma , influenza like illness

Common(>1/100; <1/10), uncommon (>1/1000 ; <1/100) and rare (<1/1000)

 Safety , warnings and precautions

• Omalizumab is well tolerated

• frequency and severity profile of adverse events (AEs) similar to
that with placebo or best available therapy.

• Allergic reactions :
• In clinical trials , anaphylaxis was reported in 3 out of 3507 (0.1%)
patients .
• Based on Post marketing reports , reported incidence from June’03
to Dec’06 has been 0.2% (124 out of 57,300 patients) .
Approximately 1/4th of these patients had a prior history of
anaphylaxis.

• Malignancies :
• Malignant neoplasms were reported in 20 of 5015 patients (0.5%)
omalizumab treated patients and 5 of 2854 (0.2%) control
patients .
• No cases of malignant neoplasia were considered drug related
when carefully assessed by a panel of independent oncologists ,
blinded to treatment assignments.
 GINA 2007 guidelines* includes
anti-IgE therapy at step 5
Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education
Environmental control
As needed rapid- As needed rapid-acting β2-agonist
acting β2-agonist
Controller options Select one Select one Add one or more Add one or more
Low-dose ICS Low-dose ICS plus Medium- or Oral corticosteroid
LABA (lowest dose)
high-dose ICS
plus LABA

Leukotriene modifier† Medium- or Leukotriene modifier Anti-IgE treatment

high-dose ICS

Low-dose ICS plus Sustained release

leukotriene modifier theophylline

Low-dose ICS plus

sustained release
theophylline

*For children older than 5 years, adolescents and adults

†
Receptor antagonist or synthesis inhibitor GINA Workshop Report 2007
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist
 Identification of patients for
omalizumab
What the omalizumab package leaflet says…
Severe persistent asthma (GINA step 4)


IgE-mediated asthma
perennial allergy (skin test or RAST)

Continuous treatment with high-dose ICS plus LABA

regular symptoms plus history of exacerbations

Age > 6 years

FEV1 <80% of predicted for patients ≥ 12years

IgE level >30 < 1500 IU/mL

Selecting patients for omalizumab therapy

Severe asthma? No
Yes
Patient ≥ 6 years? No
Yes
Symptomatic with ICS plus LABA? No
Yes
Multiple documented severe exacerbations? No
Yes
Frequent daytime and nocturnal symptoms? No
Yes
FEV1 <80% predicted No
Yes

Allergy Test Positive (SPT or RAST) No

Yes

Bodyweight 20–200 kg and total lgE 30–1500IU/mL? No

Yes

Consider treating with omalizumab Patient not suitable for omalizumab

ADMINISTRATION EVERY 4 WEEKS. Xolair doses (milligrams per dose)
administered by subcutaneous injection every 4 weeks

Body weight (kg)

Baseline IgE >20-25 >25-30 >30-40 >40-50 >50-60 >60-70 >70-80 >80-90 >90- >125-
(IU/mL) 125 150

≥ 30–100 75 75 75 150 150 150 150 150 300 300

>100–200 150 150 150 300 300 300 300 300
>200–300 150 150 225 300 300
>300–400 225 225 300

>400–500 225 300 ADMINISTRATION EVERY 2 WEEKS

SEE TABLE 3

>500–600 300 300

>600–700 300

Reference - India Prescribing Information

 ADMINISTRATION EVERY 2 WEEKS. Xolair doses (milligrams per
dose) administered by subcutaneous injection every 2 weeks

Body weight (kg)

Baseline IgE (IU/mL) >20‑ 25 >25‑30 >30‑40 >40‑ 50 >50‑ 60 >60‑ 70 >70‑ 80 >80‑ 90 >90-125 >125-150 >150-200

> 30‑100 ADMINISTRATION EVERY 4 WEEKS 225

SEE ABOVE
> 100‑200 225 300 375

> 200‑300 225 225 225 300 375 525

> 300-400 225 225 225 300 300 450 525

> 400-500 225 225 300 300 375 375 525 600

> 500-600 225 300 300 375 450 450 600

> 600-700 225 225 300 375 450 450 525

> 700-800 225 225 300 375 450 450 525 600

> 800-900 225 225 300 375 450 525 600

> 900-1000 225 300 375 450 525 600

> 1000-1100 225 300 375 450 600 DO NOT ADMINISTER – data is unavailable for dose recommendation

> 1100-1200 300 300 450 525 600

> 1200-1300 300 375 450 525

> 1300-1500 300 375 525 600

Reference - India Prescribing Information

UK responder algorithm
 Omalizumab – Cost Effectiveness

Omalizumab offers both therapeutic and economic value and

represents a major advance for the treatment of patients with
inadequately controlled severe persistent asthma .
R Brown et al , Allergy 2007 :62 :149-153

Omalizumab is clinically beneficial in patients with severe

persistent allergic asthma despite high-dose ICS plus a LABA
particularly in a subgroup of patients who respond to therapy .
• S D Sullivan et al , Allergy 2008 : 63: 670-684