This document summarizes the clinical application of Omalizumab, a monoclonal antibody treatment for allergic diseases like asthma and rhinitis. It outlines the drug's mechanism of action by binding to IgE, its dosing guidelines based on patient weight and IgE levels, and its safety profile. Several studies are referenced that show Omalizumab's effects like decreasing free IgE, nasal polyp scores, and exacerbation rates. While generally well tolerated, its cost-effectiveness remains debated. In summary, Omalizumab is a novel targeted therapy for severe allergic asthma and diseases, but its use requires careful consideration.

1. Omalizumab: The Clinical
Application
Theerapan Songnuy M.D.

2. Outlines
• IgE & IgE receptors
• Diseases specific effects of Omalizumab
- Asthma
- Allergic Rhinitis
• Dosing
• Safety
• Take Home Message

3. IgE & IgE Receptors
• In 1967, IgE was described by Ishizaka &
colleagues

4. IgE
•
•
•
•
Smaller amount than IgG, IgM, & IgA
Half-life in serum only 2 days
Up-regulates expression of FcE RI on effector cell
Another receptor: FcERII ( CD 23) that binds with
low affinity to IgE
• If FcERII flow in serum, upregulate IgE production
via interaction with CD 21( B cell co-receptor)
• If binds to cell-surface, FcERII will inhibit IgE
production
Middleton 8th Edition

5. Omalizumab
•
•
•
•
A humanized, monoclonal Ab
Recognizes & binds to Fc portion of IgE molecule
About 95% composed of human sequence
Only 5% from murine sequence that engrafted onto a
human IgG ( IgG 1 K) framework
• Binds to heavy-chain constant ( CH 3 domain) of IgE
molecule
• The same site which IgE bind to FcE RI >>> soluble immune
complex
• Finally, get rid by RES ( i.e., mononuclear phagocyte system)
Middleton 8th Edition

8. Aim:
1. To determine onset of action of omalizumab in regweed-induced change
in nasal volume
2. To determine the kinetics of omalizumab-induced decreases in serum free
IgE & FcERI receptors on basophils

9. Methods
• Patients :
- Aged 19-50 y
- Ragweed SAR > 2 y
- Positive SPT to mixed giant/short/Western
ragweed
- Positive intranasal challenge to ragweed

10. Methods
• Exclusion criteria:
- Asthma
- Past or present immunotherapy
- Omalizumab use
- Severe anaphylaxis or anaphylactoid reaction
- Rhinitis medicamentosa
- Perennial rhinitis
- Structural nasal defect
- On Beta-adrenergic antagonist
- Current sinusitis & URI
- On AH, INS, steroid, decongestant, LTRA etc.
- IgE > 700 IU/ml

11. Methods
• Study design:
- Randomly assigned to 2 gr. as 2:1 ratio
- Omalizumab 0.016 mg/kg/IgE (IU/ml) SC or
placebo on day0 & day28
- Serum total IgE at screening visit
- Serum free IgE on day 3, 28, 42
- FcERI receptor expression on day 0,7,14,28 &
42
- Blood chemistry for adverse events monitoring

12. Methods
• Nasal challenge:
- Baseline acoustic rhinometry, spirometry
- NSS spray, wait for 10 min before measure ( 3-times )
- Ragweed extract; 0.00054 AU, 0.0054 AU, 0.054 AU,
0.54 AU & 5.4 AU ( 1:20 W/V, 66.67 AU/ml ag E)
then 10 min, perform rhinometry & spirometry
- Stop when ; reaching a 30% decrease nasal volume,
final dose, 20% decrease FEV1
- The PD30 : dose that induce a decrease 30% nasal volume
• Free IgE ( solid-phase ELISA) & total IgE (Immulite) measurement
• Basophil cell preparation
• Ab staining & flow cytometry ; basophil expression of FcERI-alpha by mean
fluorescence intensity

20. Conclusion : Clinical Improvement &
Mechanism of Action
• Reduced allergen-induced nasal challenge response within
2 wk ( onset)
- Suggestion: need 2 doses for protection through
the season
• After binding to Omalizumab, free serum IgE decrease 96.1
% within 3 d
• Decreased FcERI expression on basophil ( 7-14 days)
- Mechanism of action of omalizumab
JACI 2004; 113: 297-302

21. Additional Mechanism of Action
• FcERI expressing on dendritic cell, more common
in asthmatics & correlate with serum IgE level
JACI 2003; 112: 1132-8

22. Middleton 8th Edition

23. Markers of Airway Inflammation
• After treatment ; serum IgE, blood eosinophil, &
sputum eosinophil decrease
• Decreased IL-13, IL-5, & IL-8
• Nitric oxide also decreases
Int Arch Allergy Immunol 2003; 131: 46-52
Pediatrics 2004; 113: 308-12

24. Markers of Airway Inflammation
• Decreased tissue & sputum eosinophil
• Decreased cell positive for FcERI
• Reduced CD3, CD4, CD8 & B lymphocyte
Am J Respir Crit Care Med 2004; 170: 583-93

25. Aim:
To assess FENO, peripheral blood eosiniphil count, & serum periostin as
biomarkers of Th2 inflammation & predictors of treatment effects of
omalizumab

26. Methods
• Patients :
- Age 12-75 y
- Severe persistent allergic asthma for > 1 y
- Inadequate controlled despite on ICS & LABA
- Night-time awakening >1 / wk
- Daytime symptom & need > 2 rescue / wk
- Documented as exacerbation > 1 /y
- Documented as allergy to perennial allergens
- Baseline pre-bronchodilator FEV1 40-80% of
predicted value
- Serum IgE 30-700 IU/ml
- BW 30-150 kg

27. Methods
• Exclusion criteria:
- Exacerbation with ETT in prior 12 mon
- Exacerbation with systemic steroid in prior 1
mon
- Active lung diseases
- Treated with omalizumab in prior 12 mon
- Smoking > 10 pack-years
- R/O diseases with high serum IgE

36. Conclusion
• Omalizumab yields benefit in all high-level biomarker
subgroup especially the “first time to exacerbation”
• No consistent trend of secondary endpoint of change at 48
wk as compared to baseline
• Omalizumab is well tolerated, no serious adverse events
• Limitation:
- Overall sample size not sufficient
- Biomarkers not available in all enrolled patients
• Need further study for explore characteristic & prognostic
effects of these biomarkers

38. Evidence that significant over-lap exists on immunopathogenesis of
the atopic & nonatopic variants of asthma
Aim: To investigate biological & clinical effects of
omalizumab in refractory non-atopic asthma
CHEST 2013; 144(2): 411-419

39. Methods
• Patients:
- Aged 18-70 y
- Severe, persistent, non-atopic asthma
- Uncontrolled despite high-dose ICS ( > 1,000 ug
beclometasone dipropionate or equivalent/d )
plus LABA with/with out OCS
- At least 2 exacerbations need systemic steroid
- At least 1 admission or ED visit or both
- Total serum IgE 30-700 IU/ml
- Negative for multi-allergic testing (Aspergillusspecific)
- IgE –radioallergosorbent blood test
CHEST 2013; 144(2): 411-419

40. Methods
• Exclusion criteria :
- Current or former smokers with a > 10 packyear
history
- Smokers who had quit within prior 3 y
- Asthma exacerbation prior 4 wk
- Previous use of omalizumab
- Pregnancy or breastfeeding
- Uncontrolled other chronic diseases
CHEST 2013; 144(2): 411-419

41. Methods
• Study design:
- RPCDB, phase3B
- Ten French centers
- The screening visit ( 2-wk), add-on treatment phase
( 16-wk)
- During Sep 2009-Feb 2011
- Remain previous dose of asthma drugs
- Omalizumab dose depend on the wk0 data ( total
IgE
level & BW )
- F/U at wk 4,8,12, & 16
CHEST 2013; 144(2): 411-419

42. Methods
• Primary end point :
-The change of FcERI expression on basophil &
pDC2s at wk 16 compared to wk0
• Secondary end point:
- PFT
- Asthma control questionnaire score
- physician & patient global evaluation
of treatment effectiveness ( GETE)*
- Exacerbation rate
- FENO
CHEST 2013; 144(2): 411-419
* Allergy 2005; 60(3): 309-316

50. Message from this study
• Decreased FcERI expression on basophils &
pDC2 with Omalizumab treatment in uncontrolled
non-atopic asthma
• Increased in postbronchodilator FEV1
• Trend toward improvement in asthma-exacerbation
rate after 16 wk of treatment
*** The first RCT in non-atopic asthma with omalizumab
But :
1. Why did non-atopic asthma has similar response to
oamalizumab as atopic group?
2. Need more study

51. JACI 2013; 131: 110-6

52. Methods
• Patients :
- Aged > 18 y with chronic rhino-sinusitis with
nasal
polyp and asthma
- Diagnosed by respiratory physician > 2 y
- Total serum IgE 30-700 Ku/ml
- SPT

53. Methods
• Study design :
- RCT,DBPC, 2-centers
- 2007-2008
- Omalizumab used as SC 2 wk/8 injections or
montly/ 4 injections
- Dose based on BW and total serum IgE level
- F/U q 2 wk for 10 visits

54. Methods
• Primary end point :
- Reduction of total nasal endoscopic polyp scores
( TPSs) at wk16
- Sum of both sides of scores were used
• Secondary end point :
- Change in Lund Mackay CT score
- Nasal & asthma symptoms
- Spiro-metry
- QOL questionnaire score

64. Message from this study
• Omalizumab is effective in both allergic &
non-allergic asthma with CRSwNP
• Local IgE level play a role in pathophysiology
of
CRSwNP & asthma

66. Aim: To identify the clinical & economic circumstances
whether omalizumab is cost-effectiveness by using
a mathematic model
JACI 2007; 120: 1146-52

67. Methods
•
•
•
•
Asthma policy model
Target population
Effect of ICS therapy
Effect of Omalizumab therapy

68. • JACI 2007; 120: 1146-52
JACI 2007; 120: 1146-52

69. JACI 2007; 120: 1146-52

70. Omalizumab: Economic Perspective
• Not cost-effectiveness for treating severe
asthma
• Compared to the “ dialysis threshold” need
$ 93,500 per QALY in 2002
• Limitations:
- A model-based
- FEV1 % predicted not represent prognosis

71. Dosing
• FDA approved only Xolair
• Lyophilized powder in doses of 75mg & 150 mg
• Mixed with sterile water for subcutaneous injection
• Liquid formation is forth coming
• Recommended dose = 0.016 mg/kg per 1.0 IU of IgE
q 4 wk , in mod-severe allergic asthma
• Age greater than 12 y

72. Dosing
• Absorbed slowly
• Reaching a peak serum concentration at 7 d
• Average absolute bioavailability 62%
• Serum elimination half-life 26 d
• Clearance average 2.4+- 1.1 ml/kg/d
• After first dose, rising serum IgE ( bound & unbound) due
to a formation of omalizumab-IgE complex
( slower elimination rate)
• At 3 mon after start treatment, total IgE level rising to 8
folds, where as free IgE decrease

73. Dosing
• After discontinuation, need a year to reverse total IgE to be at level
of pre-treatment
• About 40 % of patients not effective
• Free IgE level in non-responder & responder were similar
• May be due to:
- Inexert relationship between free IgE & FcERI expression
- Ratio of sIgE/total IgE inordinately high for
clinically important
- Differences in intrinsic cullular sensitivity ( mast cell,
basophil)
JACI 2009; 123: 107-13

75. Safety
• Well-tolerated both adult & children
• Few adverse reactions:
- Most common is local reaction; pruritus,
burning, pain, swelling, redness, warmth,
hives & bruising
- Cancer not proved as increased risk
http:// www.gene.com/download/pdf/xolair_prescribing.pdf
( accessed Dec 30, 2012)
Ann Allergy Asthma Immunol 2003; 91: 182-8

76. Safety
• Due to decreased serum IgE level, higher
incidence & severity of helminthic infection
• Post marketing reports:
- Severe thrombocytopenia
- Alopecia
- Anaphylaxis ( 2 cases)

78. Take Home Messages
• A selective anti-IgE humanized Mab
• A novel therapy option for patients with severe allergic
asthma & other allergic diseases
• Omalizumab inhibits activation of mast cell, basophil &
decreases effect of eosinophil
• Efficacy; reduce exacerbation in mod-severe allergic asthma
• For other allergic conditions need further studies
• Safety & well tolerated both adult & children
• On daily practice, physicians have to carefully make a
decision on case by case

79. THANK YOU VERY MUCH