Targeting grossly elevated IgE: a novel therapeutic option in severe patients

Targeting grossly elevated IgE: a novel
therapeutic option in severe patients
Markus Ollert, MD
Professor of Molecular Dermatology and Immunology
Department of Dermatology and Allergy
Clinical Research Group of Molecular Dermatology and Immunology/ZAUM
Klinikum rechts der Isar, Technische Universität München (TUM) and Helmholtz Center
Munich for Environmental Health, Munich, Germany

Session „Dermatitis Atopica“, XVII Congreso SLaai, Cartagena, Colombia, 25 October 2012

Atopic Eczema / Dermatitis
• Inflammatory, chronically
relapsing, non-contagious and
pruritic skin disorder

• Known since ancient times

Robert Willan, Delineations of
Cutaneous Diseases. 1817
Bieber T. N Engl J Med 2008; 358:1483-1494

Klinik und Poliklinik für Dermatologie Technische
und Allergologie Universität
am Biederstein München

Atopic Eczema / Dermatitis
• Inflammatory, chronically
relapsing, non-contagious and
pruritic skin disorder

30
Taylor, UK
Ninan, UK • Known since ancient times
Schultz-L, DK
25 Varonier, CH

• Up to 10 % of adults in
Aberg, S
Eaton, UK
20
industrialized countries are
Austin, UK
Butland, UK
Yura, J

affected
%

15
Heinrich, J
Schäfer, D
10

5 • Especially for severe cases, no
0
satisfactory treatment option
is available until today
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Bieber T. N Engl J Med 2008; 358:1483-1494


Total IgE levels (U/mL) of
>1,000 – 100,000 are
common in adult
patients


House dust mite
(Encasing, SIT)

Food allergens
(Elimination: cow´s milk,
hen´s egg, wheat, nuts)

Inhalant allergens
(SIT with pollen extract)

S. aureus antigens
(SEA, SEB, FN-BP)

Malassezia sympodialis
(Mala s 1-6)

Autoallergy
(Hom s 1-4)


Targeting IgE antibodies –

A universal therapeutic solution for
allergic atopic disorders with “high IgE
phenotypes” such as atopic dermatitis?


IgE and Atopic Dermatitis

The pathogenetic role of IgE in atopic
dermatitis: a highly controversial issue

Off-label use of anti-IgE antibody
omalizumab in atopic dermatitis: very
ambivalent results

Belloni B et al. JACI 2007; 120: 1223-1225
Bieber T. N Engl J Med 2008; 358: 1483-1494
Heil PM et al. JDDG 2010; 8: 990-998

Patient A: IgE = 12,534 kU/L


Omalizumab

Patient A: IgE = 12,534 kU/L


Case Report: 15-Year-Old Patient with
Severe Asthma
Kerzel et al., Klin Padiatr. 2011;223:356-359

Table 2: Pharmacotherapy on first presentation in our outpatient clinic

Agent Daily dose

Fluticasone / salmeterol 500 µg / 50 µg bid per DPI (Diskus®)

Formoterol 12 µg per pMDI

Prednisolone 50 mg p.o.

Omeprazole 20 mg p.o.

Montelukast 10 mg p.o.

Ipratropiumbromide / fenoterol 20 µg / 50 µg p.r.n per pMDI
(was actually used 10 – 12 times a day)

Cetirizine 10 mg p.o.

NaCl 0.9% 2 ml tid per nebulizer

DPI: dry powder inhaler; pMDI: pressurized metered dose inhaler.


High IgE Asthma Phenotype: Therapy with
Plasmapheresis and Anti-IgE
Table 1: Relevant laboratory findings before plasmapheresis

Actual value Reference range

total IgE 4,170 kU/l [< 100 kU/l]

specific IgE against 35 kU/l [< 0.35 kU/l]
phleum pratense

rye pollen 25 kU/l [< 0.35 kU/l]

cat 209 kU/l [< 0.35 kU/l]

dog 186 kU/l [< 0.35 kU/l]

leukocytes 11.4 G/l [4.5 – 10 G/l]

eosinophils 22% [1 – 4%]



Figure 1: Dynamics of serum IgE during and after plasma exchange

5000

4000

plasma- plasma- plasma-
pheresis pheresis pheresis
3000
IgE
kU/l

2.300 kU/l free IgE
2000

1000

0 80 kU/l
0 24 48 200 700
hour
start omalizumab

Figure 2: Dynamics of total IgE and free IgE during omalizumab therapy

5000

4000 total IgE
free IgE
3000
kU/l

2000
400

300

200

100

0
0 100 200 300
day
start omalizumab Kerzel et al., Klin Padiatr. 2011;223:356-359


Figure 3: Lung function before and after plasmapheresis

300
SR
250
FEV1
200
% predicted

150

100
100

80

60
omalizumab
40
-50 0 50 100 150

days Kerzel et al., Klin Padiatr. 2011;223:356-359
plasmapheresis

Targeting IgE antibodies –

Can we apply an IgE-directed treatment
regimen to atopic dermatitis with “high
IgE phenotype”?


Investigator-initiated pilot study

 Investigator-initiated open-label clinical pilot trial, approved by ethics committee,
government agencies and European Medicines Agency (EMA) (EudraCT #2009-
014582-51)

 10 patients with severe therapy refractory atopic dermatitis and grossly elevated
total IgE-levels ranging from 3,728 kU/L to 69,972 kU/L

Initial immunoadsorption prior to administration of anti-IgE-antibody
omalizumab for 6 months and a 6 months follow-up

Ig-Apheresis Tx with Anti-IgE (Omalizumab) Control period/Follow-up

2-4 days 450 mg s.c. bi-weekly 24 weeks
24 weeks

Investigator-initiated pilot study

Primary endpoint: long-term control of free IgE levels (<150 / <1000 kU/L)

Secondary endpoints:
- severity of AD (rated by SCORAD)
- TARC (CCL 17) levels in serum
- patient’s personal evaluation on severity and pruritus scale
- standardized photography

Sponsor: Klinikum rechts der Isar/TUM

Support: Miltenyi Biotec (supply and materials for Therasorb Ig-apheresis)

Ig-Apheresis Tx with Anti-IgE (Omalizumab) Control period/Follow-up

2-4 days 450 mg s.c. bi-weekly 24 weeks
24 weeks

Conventional plasmapheresis Immune apheresis (Immune adsorption)
Ig-binding specificity/capacity of the
TheraSorb system: IgG > IgM > IgE
Ig-binding specificity/capacity of other
available systems: IgG > IgM >>> IgE

Immunoadsorption with TheraSorb™

Tolerated very well by all patients without
any noteworthy side effects.


IgE during immunoadsorption

IgE during immunoadsorption
120%

100%
Patient 1
Patient 2
80%
Patient 3
Patient 4
IgE

60% Patient 5
Patient 6

40% Patient 7
Patient 8
Paitent 9
20%
Patient 10

0%
beofore IA1 IA1 IA2 IA3 IA4


IgE during omalizumab – first 12 weeks

Free IgE in the course of study
15000
14000
Free IgE levels
13000 continued to drop
12000 during OMZ therapy
11000 Patient 1
reaching free IgE-
10000 Patient 2
levels of
free IgE in IU/ml

9000 Patient 3
8000
<150 kU/L in 5/10
Patient 4
7000 and
Patient 5
6000
Patient 6
<1,000 kU/L in 9/10
5000
Patient 7
patients during the
4000
3000 Patient 8
entire treatment
2000 Patient 9 period of 24 weeks
1000 Patient 10
0
1 3 5 7 9 11 13
= nach IA
week


IgE during omalizumab – first 12 weeks


Control of pruritus and visual
analogue scale
(subjective patient score)


SCORAD
(disease activity)


SCORAD – first 12-25 weeks of IIT


SCORAD – first 12 weeks of IIT


SCORAD / IgE / TARC
(entire study period)


SCORAD and IgE

SCORAD free IgE in kU/L fIgE
14000
free IgE in kU/L
12000

10000

8000

6000
Immune
apheresis
4000

2000

0

End of OMZ Tx

SCORAD and IgE

SCORAD fIgE
80 14000
SCORAD
70 12000
free IgE in kU/L
60
10000
50
8000
40
6000
30 Immune
apheresis
4000
20
10 2000

0 0
week 1 week 3 week 13 week 25 week 49

und Allergologie End of OMZ Tx Universität

TARC Levels

pg/ml
TARC (CCL 17)
2800
2600
2400
2200
2000
1800
Immune
1600
apheresis
1400
1200
1000

am Biederstein End of OMZ Tx München

Clinical Phenotype


Immune
apheresis End of OMZ Tx

Consumption of topical medication (up to week 12)


Conclusion
• Immunoadsorption prior to omalizumab is suitable to
reduce highly elevated serum IgE levels and may
improve clinical symptoms of atopic dermatitis

• Further studies regarding IgE control in atopic dermatitis
are justified and needed due to the given limitations of
our pilot study

• Targeting IgE by apheresis: a promising treatment option
in severely diseased patients with „high IgE phenotype“


Future studies

• Placebo-controlled,
double-blind crossover
study


Muchas gracias por su atención
OLLERT@LRZ.TUM.DE

Targeting grossly elevated IgE: a novel therapeutic option in severe patients

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