Indication of Anti-IgE

treatment in children

Matthias Kopp

Pediatric Pulmonology and Allergology

University of Lübeck

Annual meeting of the Danish Society of

Paediatric Allergology and Pulmonology

Kolding, 15th of January 2010

severe asthmatic attack after

a ride with a horse-drawn

carriage

history of allergy to horses

one week ago: transfusion of

600 ml blood from a man with

a known allergy to horses

factor in the blood is able to transfer allergic complaints

reagine = immunglobuline IgE

Anecdotic Case Report

Ramirez MA, JAMA 1919

Johansson SG, Lancet 1967

Antigen-presenting

cells

TH2-cells

naive T-cell

sensitis

ation

mastcells basophils

YY

effe

cto

r-phase

F FF

IgE

IL-4

IL-13IL-5

eosinophils

Pathophysiology

effector cells

B-cells

Allergic reaction

Allergen

IgE

IgE-receptor

effector cells

histamine

leukotriene, IL-4, IL-5

Omalizumab

Anti-IgE

IgE and Anti-IgE

allergen

Corne J, J Clin Invest 1997

IgE and Anti-IgE

Kopp MV, JACI 2002

Omalizumab: Leukotrienes

before - after before - after0

1000

2000

3000

4000

5000Grass Allergen

Birch Allergen

Leukotr

iene r

ele

ase [

ng/L

]

therapy therapy

SIT-Grass + Anti IgE

p = 0.0001

p = 0.0002

before - after before - after0

1000

2000

3000

4000

5000Grass Allergen

Birch Allergen

Leuko

trie

ne r

ele

ase [

ng/L

]

therapy therapy

SIT-Grass + Placebo

SIT + Omalizumab SIT + Placebo

IgE

IgE-receptor

effector cells

histamine

leukotriene, IL-4, IL-5

Omalizumab

Anti-IgE

IgE and Anti-IgE

allergen

MacGlashan, J Immunol 1997

Lin H, J Allergy Clin Immunol 2004

Prussin C, J Allergy Clin Immunol 2003

expression of Fc R1 on

basophils before (open bar)

and after therapy (shaded

bar) with omalizumab

Omalizumab reduce the

expression of the high

affinity IgE receptor

(Fc R1) on basophils and

mastcells as well as

dendritic cells significantly

within 14 days

Anti-IgE: Fc R1

Omalizumab is able to

attenuate the eosinophilic

inflammation in patients

with allergic

rhinokonjunctivitis (AR)

during the pollen season

eosinophils before and during

the pollen season in patients

with a birch pollen induced AR

treated with omalizumab

(right) or placebo (left)

Plewako H, J Allergy Clin Immunol 2002

Bez C, Clin Exp Allergy 2004

Anti-IgE : Eosinophils

Omalizumab

Possibilities and Indication

Allergic diseases

allergic rhinitis – allergic asthma – severe

allergic asthma – food allergy – atopic dermatitis

– bee venom allergy – wasp venom allergy –

urticaria – latex allergy – drug allergy – contact

allergy – allergic rhinokonjunctivitis – allergic

rhinitis - allergic asthma – drug allergy – urticaria

- severe allergic asthma – food allergy – atopic

dermatitis – bee venom allergy – wasp venom

allergy – urticaria – latex allergy – drug allergy –

contact allergy – allergic rhinokonjunctivitis

allergic rhinitis – allergic asthma – severe

allergic asthma – food allergy – atopic dermatitis

– bee venom allergy – wasp venom allergy –

urticaria – latex allergy – drug allergy – contact

allergy – allergic rhinokonjunctivitis allergic

rhinitis – allergic asthma – severe allergic

asthma – food allergy – atopic dermatitis – bee

venom allergy – wasp venom allergy – urticaria

Indication of Anti-IgE

Xolair (Omalizumab) is indicated for

1. adults and children (> 6 y) with

2. severe persistent allergic asthma

3. who have a positive skin test or in vitro

reactivity to a perennial aeroallergen

4. > 12 y: FEV1 < 80%

5. IgE > 30 - 700 kU/l (< 12 y: - 12000)

6. whose symptoms are inadequately

controlled despite optimal therapy.

age > 12 13-year old boy

symptoms since his first year of life

optimal therapy budesonide 400 – 800 µg 2 x daily

salmeterol

montelukast

IgE 30 – 700 kU/l

peren. allergen

IgE 468 kU/l

mites (Der p) CAP-class 3; grass

pollen 2; birch pollen 3

special notes 5 x hospitalisation nesecessary

physical fatigue currently

Case Report

• Bronchiolitis obliterans

• good clinical response to

high doses of systemic

steroids

• Omalizumab not indicated

Recomendation:

The diagnosis of severe asthma must

be critically reviewed!

Case Report

COPD,

BO

CF

α1-AT- deficiency

cardiomyoptahy

VCD

31%: other or additional pulmonary disease!Robinson DS, Eur Respir J 2003

Difficult-to-treat asthma

Systematic assesment

1. sensitization to a perennial

aeroallergen ?

2. safety and efficacy of anti-IgE

treatment in young children with

sever asthma ?

3. use of Anti-IgE in case of other

allergic diseases ?

Anti-IgE in children

n age duration symptoms allergen

Casale TB, JAMA 2001 536 12 - 75 3 mo ragweed

Ädelroth E, JACI 2000 251 17 - 66 4 mo. birch

Kuehr J, JACI 2002 225 6 - 17 9 mo birch and grass

Casale TB, JACI 2006 123 18 - 50 20 we ragweed

Okubo K, Allergol Int 2006 100 20 - 64 24 we cedar

Kopp MV, 2008 sub. 140 12 - 46 18 we grass

Perennial allergens

Inhalant steroids (ICS)

+ placebo

4 w 16 w 8 w 4 w

primary outcome: number of asthma exacerbations

28 weeks

Trials: Anti-IgE & asthma

+ omalizumab

stepwise

reduction

of ICS

lowest

tolerated

ICS dose

Clinical Trials in children 6 - 12 years:

p< 0.001

18

38

0

10

20

30

40

50

60

Omalizumab Placebo

asthma exacerbation (%)

Milgrom H, Pediatrics 2001

Adolescents > 12 y

55

39

0

10

20

30

40

50

60

70

Omalizumab Placebo

children without ICS (%)

p< 0.001

0.77

0.29

0.63

0.42

Num

ber

of

clin

ical re

levant exacerb

ations

1.2

1.0

0.8

0.6

0.4

0.2

0Omalizumab

(n=159)

Placebo

(n=76)

1.2

1.0

0.8

0.6

0.4

0.2

0

24 weeks: stable ICS dose 28 weeks: ICS reduction phase

Omalizumab

(n=159)Placebo

(n=76)

–34%

p=0.047

–63%

p<0.001

Asthma exazerbations

Num

ber

of

clin

ical re

levant exacerb

ations

ERS, Vienna 2009 (Poster)

IA05

high dose

ICS + LABA

(n=235)

IA05 total

(n=576)

INNOVATE

(n=419)

Clinical relevant

exacerbations 1,4 1,7 2,7

Number needed to treat

ERS, Vienna 2009 (Poster)

…to prevent asthma exacerbation

Es ist ein Mammut!

Evidence from clinical trials

It is a mammoth!

number of adverse

events

causal relationship:

Urtikaria

anaphylactic reaction

?

Anti-IgE-AK

Komplementaktivierung

Immunkomplexablagerung

local reaction:

mild- moderat

severe adverse

events

Safety (n > 5200 patients)

Limb SL, JACI 2007

Risk of anaphylaxis

• June 2003 – December 2006; 77.300 patients

• 124 cases of anaphylaxis (1:625)

• mean age 43 y (9 – 78); 82% females

• pulmonary involvement 89%; hypotension or syncope 17%

• 39% first-dose; 19% second-dose; 33% > third dose reaction

• time to onset < 30 min 35%; < 60 min 26%; < 120 min 8%;

> 24 h up to 4 days 5%

Delayed onset and protracted progression of

symptoms!

effective

safety

Allergic Rhinitis

Anti-IgE + SIT

ABPAfood-allergyAtopic

DermatitisUrticaria

Indication and Perspectives

Krathen RA , J Am Acad Dermatol 2005

Vigo PG, J Am Acad Dermatol 2006

Some case reports show that Anti-IgE might be effective in AD

Lane JE, J Am Acad Dermatol 2006

effects:

Atopic Dermatitis & Anti-IgE

Lane Krathen Vigo recommendation0

400

800

2500

7500

12500

17500

22500

IgE

[ku

/l]

only case reports!

good satisfying +/- 0

worse

Atopic Dermatitis & Anti-IgE

11 patients

IgE levels:

1.343 – 39.534 IU/ml

Results:

6/11 satisfying –

good

Belloni B, JACI 2007

150 mg omalizumab every second week over 10 weeks

=> effect in selected patients

No data from randomized controlled trials

available

No recommendation for standard use

based on case series.

Atopic Dermatitis & Anti-IgE

Aspergillus fumigatus: fungi

• Allergic bronchopulmonary

aspergillosis: pulmonary

complication in CF patients

• CF: ~ 50% colonized with

Aspergillus fumigatus

• CF: prevalence of ABPA in

Europe ~7.8%

• Therapy: systemic

steroids & antimycotic

drugs

Mastella G, Eur Respir J 2000

Thia LP, Pediatric Respir Rev 2009

inhalation of fungi => TH2-

driven inflammationIgE

mastcells

complement

ABPA

ABPA + Anti-IgE

• are there additive therapeutic effects of omalizumab in CF

patients with ABPA treated with steroids?

• is omalizumab a steroid-saving therapeutic option?

Patient

age

Genotyp ABPA Therapy:

Itraconazol + …

Outcome afetr Xolair 300 mg sc

every other week:

13-y

boy

F508/

A141D

7 y Prednison 4 weeks 1

mg/kg KG

Weaning impossible

0.5 mg/kg every

other day

Prednison-Weaning

Stop of steroids after 9 m

FEV1 77% => 87%

13-y

Boy

F508/

F508

6 y Prednison 20 mg/ Tag

Weaning impossible

1 mg/kg every other

day

Prednison-Weaning

Stop of steroids after 18

months

17-y

boy

F508/

F508

6 y Prednison 20 mg/

every other day

Prednison-Weaning

Stop of steroids after 4 m

FEV1 83% => 102%

Zirbes JM, Pediatric Pulmonology 2008

Summary: effective Steroid-saving

ABPA + Anti-IgE

Case report: Maria, 12 years

• CF, F-508/ F-508; FEV1 pred. 92%

• cough exercise tolerance

• Serratia marescens => i.v. antibiotics, no improvement

• tentative diagnosis: ABPA

- 27% eosinophils; absolut 3180/µl

- IgE increased 133 kU/l => 524 kU/l

- rAsp. f. 4: 3,27 kU/l; IgG-AK

- Sputum: Asp. fumigatus

- SPT positive

- expirium , rhonchi

- shortness of breath

=> ABPA confirmed

• therapy: steroids – Itraconazol - Xolair

• rapid improvement

• symptom free: 10 days after start of Xolair

• normal exercise tolerance after 4 weeks, LuFu

1,00

1,20

1,40

1,60

1,80

2,00

2,20

2,40

2,60

2,80

May October January

FEV1

FVC predicted

predicted

Case report: Maria, 12 years

• only published case reports

• open issues:

- How effective is omalizumab?

- Responder and non responder?

- Steroid-saving effect?

- Therapy without steroids possible?

- Early or late therapy with omalizumab?

ABPA & Omalizumab

Anti-IgE & SIT

Anti-IgE & SIT

1. Are additional clinical benefits of

omalizumab + SIT?

2. Is the number of adverse events of

SIT reduced by pretreatment of

omalizumab?

3. SIT + omalizumab: enhanced long-

lasting effects?

Allergic Rhinitis

• Grass- and birch pollen Kühr 2002

• ragweed Casale 2006

Saisonal asthma

• grasspollen Kopp 2009

Anti-IgE & SIT

35%

P=0.01*

0.30

0.46 45%

P=0.011*

0.38

0.21

0

0,2

0,4

0,1

0,3

0,5

symptom load - score (median)

*=Wilcoxon Test

n=53

SIT grass +

placebo

n=59

SIT grass +

omalizumab

n=55

SIT birch +

omalizumab

n=54

SIT birch +

placebo

Kühr J, JACI 2002

6 - 17 years

sensitization:

birch + grass

SIT

+ placebo

+ placebo

+ Anti-IgE

+ Anti-IgE

Anti-IgE & SIT

start of the

ragweed season

9 weeks

Omalizumab

Visit 0

Rush-SIT

8 weeks

> 3 weeks

Rush-IT: 6 injections in 3 h Build-up Maintenance

0.012–1.2 µg Amb a 1 2-4-6-8 µg 12 µg

12 weeks4 weeks

Anti-IgE & SIT

Placebo

Omalizumab + Placebo

Omalizumab + SIT

Placebo + SIT

n= 11 (29.7%)

n= 12 (33%)

n= 22 (56%) *

n= 7 (18.9%)

all adverse events

n= 1 (2.7%)

n= 2 (5.6%)

n= 10 (25.6%) *

n= 1 (2.7%)

anaphylaxis

Placebo + SIT: 20.5% received epinephrine

Casale, JACI 2006

120 ragweed-sensitized patients (18–50 y) with allergic rhinitis

Anti-IgE prior to SIT

Omalizumab

Placebo

8 w season 18 w pre2 w

w 0 w 2 w 10 w 18

2006

+ Rush-SIT

+ Rush-SIT

2007 2008

SIT

SIT

s 2 s 3

Anti-IgE & SIT: DUAL

- Population: n= 132 (2006) and n= 119 (2007; 92% )

- 12 – 45 years; allergic rhinitis + seasonal asthma

- endpoint: symptom load (symptoms + medication)

0,0

0,1

0,2

0,3

0,4

0,5

SIT + Placebo SIT + Omalizumab

Sym

pto

m s

eve

rity

sc

ore

(m

ed

ian

)

p = 0.01

0.42

0.29

Allergic Rhinitis and Asthma

Kopp MV, Clin Exp Allergy 2009

Asthma Control

Questionnaire

SIT + Omalizumab: asthma control significantly improved

Asthma Quality of

Life Questionnaire

1,0

1,2

1,4

1,6

1,8

2,0

2,2

SIT + Placebo SIT + Omalizumab

LS

mean

s

1.96

1.63

p = 0.03

5,7

5,8

5,9

6,0

6,1

6,2

6,3

6,4

6,5

6,6

SIT + Placebo SIT + OmalizumabL

S m

ean

s

6.07

6.41

p = 0.029

Kopp MV, Clin Exp Allergy 2009

Quality of life improved

Kissing decreases IgE

production

Kimata H, J Psychosom Res 2006

Control study Kissing study

before after before after

IgE [ng/ml] 2.3 2.5 2.6 1.1 *

IL-4 [pg/ml] 152 135 286 143*

IFN-γ [pg/ml] 203 235 209 134*

Patients with atopic dermatitis or allergic rhinitis spent 30

minutes with their partner without kissing (control study)

or with kissing while listening to music (kissing study)