Omalizumab presented by Theerapan Songnuy, MD. October15, 2013

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