Prof. Dr. U. Wahn

Long term use of omalizumab – Long term use of omalizumab – Is the IgE response modified?Is the IgE response modified?

Ulrich Wahn

Department of Pediatric Pneumology and Immunology

Monoclonal antibody target in Monoclonal antibody target in asthmaasthma

Cately M. et al, Pharmacology & Therapeutics 132 (2011): 333-351

Monoclonal antibody targets in asthmaMonoclonal antibody targets in asthma

Catley M. et al, Pharmacology & Therapeutics 132:333-351, 2011

Cell membrane

CCLLCC11

CC22

22 1

IgE

Allergen binding site

Holgate. QJM 1998

C3 CC44

VVHHVVLL

FcRIout

in

Binding of IgE to Binding of IgE to

high-affinity (Fchigh-affinity (FcRI) receptorRI) receptor

Rationale for anti-IgE therapy

B-cellB-cell

B-cellB-cell

T-cellT-cell

IgM

IgG

Clinicaleffects

IgE

APC Anti-IgE

Mast cellBasophil

Eosinophil? Macrophage?

Anti IgE antibodies

• Omalizumab

• MaG 12

Action of Anti-IgE

• Binding to IgE

• Reduce Mast Cell survival

• Attenuate tissue MC function

• Reduce sputum eosinophils

• Prevent production of proinflammatory mediators

• Down-regulation of Fcε RI on antigen presenting cells

Allergic airway disease

Monospecific Allergy Multiple Allergies

Trees + Grasses + Ragweed

• Anti-IgE?• Combination of anti-IgE and SIT

Trees

Grasses

Ragweed

Active Vaccination

(SIT)

Early sensitisation and allergen exposure to perennial Early sensitisation and allergen exposure to perennial

allergens * and lung function at school ageallergens * and lung function at school age

0

20

40

60

80

100

120

140

160

FEV1 (% pred) MEF75 (% pred) MEF50 (% pred) MEF25 (% pred)

p = 0.020

p = 0.003

FEV1 (% FVC)

p = 0.018

p = 0.003

p = 0.001

p = 0.025

p < 0.001

not sensitised sensitised / low exposure sensitised / high exposure

Mea

n +

/–S

D

* Sensitisation / exposure to mites and/or cats up to the age of 3 yearsMAS-90

Anti-IgE: Controller or disease modifier?

• Label for aIgE

• Mechanism of action

• Possible new indications

• More than a blocker?

• Potential for prevention?

IA05: inclusion criteriaIA05: inclusion criteria

• Male or female, aged 6–<12 years on entry– body weight 20–150 kg

– total serum IgE ≥30 to ≤1,300 IU/mL

• Diagnosis of allergic asthma ≥1year (ATS criteria)

• History of moderate or severe persistent asthma (NHLBI 1997 guidelines)

• Positive skin-prick test or RAST to ≥1 perennial allergen within past 2 years or at screening

• Demonstrable 12% increase in FEV1 within 30 minutes of short-acting β2-agonist (SABA) within the past year

Inadequately controlled population despite Inadequately controlled population despite very high asthma medication use in study IA05very high asthma medication use in study IA05

Overall IA05

Mod ITT (n=576 )

High-dose ICS + LABA

Mod ITT (n=235)

Age (years), mean (SD) 8.6 (1.7) 9.0 (1.7)

Sex % female 32.3 34.5

Duration of asthma, mean (SD) 5.7 (2.6) 6.1(2.8)

IgE (IU/mL), mean (SD) 469.7 (338.0) 440.0 (321.0)

FEV1 [% predicted], mean (SD) 86.4 (18.0) 82.1 (18.1)

FEV1 [% reversibility], mean (SD) 25.1 (16.5) 28.0 (18.5)

ICS daily dose, mean (SD)

(fluticasone equivalent)515.1 (285.4) 744.0 (262.7)

LABA use, % 67.4 100

Daily OCS use, % 1.3 2.6

Anti-leukotriene, % 36.6 57.4

LABA = long-acting β2-agonist; SD = standard deviation

IA05: study design – overviewIA05: study design – overview

Evaluate steroid dose sparing every 2 weeks

Reduction every 8 weeks

–9 –8 0 24 52 68

Steroid adjustment

Steroid stable

Double-blind treatment period

Follow-upRun-in

40

Sc

ree

nin

g

PPrimary efficacy objective: clinically significant rimary efficacy objective: clinically significant asthma exacerbation rateasthma exacerbation rate

• Definition:– worsening of asthma symptoms as judged clinically by the investigator,

requiring doubling of the baseline ICS dose for ≥3 days and/or treatment with rescue systemic (oral or IV) corticosteroids

• Criteria:– PEF or FEV1 <60% of personal best

– PEF or FEV1 60–80% of personal best following β2-agonist administration

– fall in PEF of >20% on ≥2 of any 3 consecutive days compared to personal best

– >50% increase in 24-hour rescue medication use on ≥2 of any 3 consecutive days compared to normal use (≥8 puffs of salbutamol)

– ≥2 night time awakenings due to asthma symptoms requiring rescue medication within previous 7 days

– any other specified clinically important reason

0.71

0.32

Omalizumab(n=384)

Control(n=192)C

linic

ally

sig

nific

ant e

xace

rbat

ion

rate

†

1.0

0.8

0.6

0.4

0.2

0

2nd 28 weeks

–54.2%

p<0.001

Exacerbations are reduced and efficacy is Exacerbations are reduced and efficacy is

maintained over timemaintained over time 1st 24 weeks – primary analysis

0.64

0.45

Omalizumab(n=384)

Control(n=192)

Clin

ical

ly s

igni

fican

t exa

cerb

atio

n ra

te*

1.0

0.8

0.6

0.4

0.2

0

–31%

p=0.007

*24-week treatment period†28-week treatment period

Study IA05: consistent reduction in asthma Study IA05: consistent reduction in asthma exacerbation rates irrespective of LABA use in exacerbation rates irrespective of LABA use in

IA05IA05

LABA usersn=381

0 1 2Decreased risk of exacerbations

Relative risk of exacerbations

LABA non-usersn=195

Increased risk of exacerbations

Consistent reduction in asthma exacerbation rates Consistent reduction in asthma exacerbation rates

across pediatric and adult studiesacross pediatric and adult studies Percent reduction p value

IA05 31% 0.007

IA05: patients on high ICS + LABA 34% 0.047

Study 10  46% <0.001 

Adult studies

INNOVATE study 26%* 0.156

ETOPA study 60%  <0.001  

SOLAR study 38% 0.027

Busse study 40% <0.001

Solèr study 58% <0.001

Holgate study 27% 0.165

ALTO study 15% 0.077

Pooled adult studies1 38% <0.001

1. Bousquet J, et al Allergy 2005* adjusted for an imbalance in history of asthma exacerbations

IA05: secondary and other endpointsIA05: secondary and other endpoints

• Secondary end points (at 24 weeks):

– nocturnal symptoms

– β2 rescue medication use

– quality of life

– clinically significant asthma exacerbation rate (52 weeks)

• Other end points included:

– hospital admissions, ER visits and unscheduled doctor’s office visits

– global patient and physician evaluations

– lung function

– school and caregiver absenteeism

– analysis of primary for the subgroup ‘inadequately controlled, on high-dose ICS and a LABA’

**p<0.01; ***p<0.001†as assessed by physician’s global evaluation of treatment effectiveness

Physician’s overall assessment shows Physician’s overall assessment shows consistently greater proportion of omalizumab consistently greater proportion of omalizumab

patients achieving marked improvementpatients achieving marked improvementMarked improvement or completecontrol† (% patients)

Omalizumab

Control

IA05 Study 10 INNOVATE1 SOLAR2 Busse3 Solèr4 Holgate5

100

80

60

40

20

0

60.5***

42.8

60.2***

42.0

53.1***

33.3

66.2***

34.7

68.5**

44.2

1. Humbert M, et al. Allergy 2005; 2. Vignola AM, et al. Allergy 20043. Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ 2001

5. Holgate ST, et al. Clin Exp Allergy 2004

55.7

79.1***

84.8***

59.2

FEVFEV11 (mL): most effect achieved after (mL): most effect achieved after

12–16 weeks in study IA0512–16 weeks in study IA05

0

50

100

150

200

250

0 12 24 28 40 52

Change from baseline, LSM

*

*p<0.05

Omalizumab

Placebo

Weeks

Seasonal variation in days with Seasonal variation in days with symptoms and frequency of exabationsymptoms and frequency of exabation

Busse W. et al, N Engl J Med 364;11, 2011

Omalizumabwith grasspollen SIT

Placebowith grasspollen SIT

Omalizumabwith birchpollen SIT

Placebo withgrass pollen

SIT

All subjects

No. subjects (n=59) (n=53) (n=55) (n=54) (n=221)

Age, yr *(min – max)

12(6 – 17)

12(6 – 17)

12(6 – 17)

12(6 – 17)

12(6 – 17)

History of SAR *, yr(min – max)

6(3 – 12)

5(3 – 13)

6(3 – 13)

5(3 – 13)

5(3 – 12)

Total IgE, [kU/l] *(min – max)

413(87 – 962)

409(53 – 745)

315(71 – 913)

302(52 – 880)

345(75 – 906)

Specific IgE birch [kU/l] *(min – max)**

10(1 – 125)

5(0 – 125)

6(1 – 73)

9(1 – 125)

7(1 – 125)

Specific IgE grass[kU/l]*(min - max)**

75(3 – 125)

58(1 – 125)

66(2 – 125)

52(2 – 125)

62(2 – 125)

** = spec. IgE values > 100 have been set to 125; <0.35 set to 0

* = median

Anti-IgE in polysensitized allergic childrenAnti-IgE in polysensitized allergic childrenDemography and baseline characteristics

SYMPTOM LOAD (grass pollen season)

0.61

0

0.2

0.4

0.6

0.8

1S

ymp

tom

load

(m

edia

n)

n=53

P=0.001*

P=0.032*

0.26

n=59SIT grass +

OmalizumabSIT grass +

Placebo

0.89

n=54

P<0.001*

0.49

n=55SIT birch +

OmalizumabSIT birch +

Placebo

* = Wilcoxon test (2-sided)

RESCUE MEDICATION SCORE(entire pollen season)

0

0,2

0,3

0,1

P=0.001*

81%

0.16

0.03

P<0.001*

78%

0.06

0.27

*=Wilcoxon test (2-sided)

SIT grass +Placebo

n=53

SIT grass +Omalizumab

n=59

SIT birch +Omalizumab

n=55

SIT birch +Placebo

n=54

Res

cue

med

icat

ion

sco

re (

med

ian

)

In vitro release of leukotrienes during In vitro release of leukotrienes during and after treatment with anti-IgEand after treatment with anti-IgE

Nasal tryptase secretion during anti-IgE Nasal tryptase secretion during anti-IgE treatmenttreatment

Bez C, Clin Exp Allergy 2004; 34 (7):1079-85

300mg administered once monthly for 48 weeks topatients with moderate-to-severe asthma

Day 0 = screening (n=93)

Days (not to scale)

Reduction in serum free IgE following

s.c. administration of omalizumab

Day 1 post-dose

0

300

200

100

0 1 3 7 14 112 168 252 336

Median free IgE (ng/mL)

Ongoing studies including pediatric Ongoing studies including pediatric evaluationsevaluations

• ICATA: Inner-city anti-IgE therapy for asthma (Phase IV)

– multi-center, randomized, double-blind, placebo-controlled, parallel group study: omalizumab vs placebo

– children and adolescents (6–20 years) with moderate-to-severe allergic asthma (n=500)

– ICATA will evaluate: unmet need, burden of illness, efficacy safety, mechanism of action

• US26 (Phase IV)

– descriptive non-interventional study

– children with moderate-to-severe allergic asthma (n=500)

– US26 will describe: unmet need, burden of illness

Basophil Activation Basophil Activation

Histamin

CD63

CD203c

CD203c+ CD63- CD203c+ CD63+

naiv aktiviert

Histamin

Long term use of Anti IgELong term use of Anti IgE

• Reduction of basophil sensitivity persists for years Disease Modification?

Effects of anti-IgE therapy on food Effects of anti-IgE therapy on food allergen specific T cell responses in allergen specific T cell responses in

eosinophil associated gastrointestinal eosinophil associated gastrointestinal disordersdisorders

Barbara Foster, Shabnam Foroughi, Yuzhi Yin and Calman Prussin Clinical and Molecular Allergy 2011, 9:7

„… this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo.“

Anti-IgE strategies currently under Anti-IgE strategies currently under investigationinvestigation

Rabe K.F., et al, Allergy 66:1142-1151, 2011

ConclusionConclusion

• Anti IgE reduces symptoms and exacerbation in children and adults with IgE mediated disease induced by food or aeroallergens

• Few studies suggest that anti IgE might have the potential to modify the course of asthma

• Larger studies are needed to assess the disease modifying effects of anti IgE-treatment