Anti Immunoglobulin E Therapy

Anti – Immunoglobulin E Therapy
Suda Sibunruang, M.D.

Outline
Immunoglobulin E (IgE) & IgE receptors
Anti – IgE monoclonal Ab (Omalizumab)
• Mechanism of action
• Clinical benefits
• Dosing and administration
• Safety
• Issues in clinical use

Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80
Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition
IgE levels in cord blood are low (<2 kIU/L; < 4.8 mg/L),
gradually increase throughout childhood with a peak
at 10 – 15 yrs of age, and then decrease
throughout adulthood

From www.hindawi.com, access July 2015

Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014
• Large amount of FcεRI on cell surfaces:
- mast cells, basophils
• Other cell types:
- antigen presenting cells
IgE control level of FcεRI expression
- FcεRI not occupied by IgE has a half-life
on mast cell surface of 24 hrs in vitro,
whereas receptors bound to IgE appear to be
expressed for life of cell
- Density of human basophil FcεRI expression
correlates directly with serum IgE levels,
where binding of IgE stabilizes
receptor at cell surface

Picture A. from www.frontiersin.org
Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19

- Ca-dependent lectin
- Consists of a large extracellular domain with lectin head that binds IgE
- Like FcεRI receptor, expression of CD23 is upregulated by IgE and IL-4
- CD23 can be shed from membrane into a soluble form, sCD23, by
endogenous proteases (a disintegrin and metallopeptidase 10-ADAM10)
and exogenous proteases, including dust mite major allergen Der p 1

Boyman O., et al. Allergy 2015;70:727–54

Omalizumab
• Humanized, anti-IgE monoclonal antibody
• Composed of 5% murine sequences that were
engrafted onto a human IgG1κ framework
5% mouse
• Binds to heavy-chain constant CH3 domain
of IgE molecule
• Same site by which IgE binds to FcεRI
Holgate ST. Q J Med 2004;97:247- 57
Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90

Price D. Primary Care Respiratory Journal 2008;17: 62-72
Omalizumab - IgE complexes
Soluble, inert immune complexes that are subsequently cleared
from circulation via interactions with FcγRs of hepatic sinusoidal
endothelial cells of reticuloendothelial system
(half-life 26 days)

Picture from www.what-when-how.com, access July 6, 2015
Owen CE. Pharmacology & Therapeutics 2007;113:121–33
As IgE upregulates IgE receptors on mast cells, reduction
in amount of free IgE in circulation also results in a decrease
in number of IgE receptors on surface of mast cells

Holgate ST. and Polosa R. Nature Reviews Immunology 2008;8:218-30

Holgate S., et. al. J Allergy Clin Immunol 2005;115:459-65

Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36

Owen CE. Pharmacology & Therapeutics 2007;113:121–33
- 99% reduction in free serum IgE levels has occurred within 2 hrs
after omalizumab administration
- Omalizumab administration reduces allergen-induced nasal challenge
responses and expression of FcεRI on basophils within 7 days
- Within 3 months, human basophil responsiveness
(i.e., histamine releasability) was reduced by 90%

Total IgE levels generally increase by up to 5-fold after omalizumab
treatment because of increased stability of omalizumab-IgE complexes,
whereas free IgE levels decrease by up to 95%. There is great variability in
accuracy of different systems for total IgE measurements in presence of omalizumab

Picture from www.xolair.com, access July 2015

Djukanovic R, et. al. Am J Respir Crit Care Med 2004;170:583-93
Bronchial biopsy specimens obtained from patients with mild steroid-naive
asthma and who received omalizumab show a marked decrease in
inflammatory cells (eosinophils, IgE+cells, FceRI+ cells, IL-4-secreting cells,
and CD3+ T lymphocytes) within epithelium and submucosa
Indicate additional modulatory effects of omalizumab

Hoshino M, et. al. Respiration 2012;83:520-8
Effects of Adding Omalizumab, an Anti-Immunoglobulin E
Antibody, on Airway Wall Thickening in Asthma
Obj: To assess effects on airway wall thickness using CT
Methods: 30 severe persistent asthma pt were
randomized to conventional therapy with (n = 14) or
without omalizumab (n = 16) for 16 wks
Airway dimensions were assessed at
right apical segmental bronchus by CT:
- airway wall area corrected for BSA (WA/BSA)
- percentage wall area (WA%)
- wall thickness (T)/ BSA
- luminal area (Ai)/BSA
% of eosinophils in induced sputum
Pulmonary function
Asthma Quality of Life Questionnaire (AQLQ)
Results: Significantly decreased WA/BSA, WA%, T/ BSA
and increased Ai/BSA, whereas conventional
therapy resulted in no change
-Decrease % of sputum eosinophils
-Improved FEV 1
-Improved AQLQ score

Hoshino M, et. al. Respiration 2012;83:520-8
Effects of Adding Omalizumab, an Anti-Immunoglobulin E
Antibody, on Airway Wall Thickening in Asthma
Obj: To assess effects on airway wall thickness using CT
Methods: 30 severe persistent asthma pt were
randomized to conventional therapy with (n = 14) or
without omalizumab (n = 16) for 16 wks
Airway dimensions were assessed at
right apical segmental bronchus by CT:
- airway wall area corrected for BSA (WA/BSA)
- percentage wall area (WA%)
- wall thickness (T)/ BSA
- luminal area (Ai)/BSA
% of eosinophils in induced sputum
Pulmonary function
Asthma Quality of Life Questionnaire (AQLQ)
Results: Significantly decreased WA/BSA, WA%, T/ BSA
and increased Ai/BSA, whereas conventional
therapy resulted in no change
-Decrease % of sputum eosinophils
-Improved FEV 1
-Improved AQLQ score
Omalizumab reduced airway wall thickness
and airway inflammation

Allergic asthma
Clinical efficacy of omalizumab in patients
with moderate to-severe and severe allergic asthma
has been well documented in several large-scale
clinical trials that involved adults, adolescents,
and children

Humbert M., et. al. Allergy 2005:60:309–16
Double-blind, parallel-group, multicentre study
Obj: Determined effect of omalizumab on clinically significant
asthma exacerbations (requiring systemic corticosteroids)
Participants: Patients (12-75 yrs) with severe persistent asthma
who are inadequately controlled despite Global Initiative for
Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA)
Method: randomized to receive omalizumab
or placebo for 28 wks
Omalizumab significantly improved asthma-related
quality of life, morning PEF and asthma symptom
scores

Humbert M., et. al. Allergy 2005:60:309–16
Double-blind, parallel-group, multicentre study
Obj: Determined effect of omalizumab on clinically significant
asthma exacerbations (requiring systemic corticosteroids)
Participants: Patients (12-75 yrs) with severe persistent asthma
who are inadequately controlled despite Global Initiative for
Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA)
Method: randomized to receive omalizumab
or placebo for 28 wks
Omalizumab significantly improved asthma-related
quality of life, morning PEF and asthma symptom
scores
Omalizumab significantly reduced rate of
clinically significant asthma exacerbations,
severe exacerbations and emergency visits

Bousquet J., et. al. Allergy 2005:60;302–8
Pooled data from 7 studies to examine effect of omalizumab on exacerbations
n = 4,308 (2,511 treated with omalizumab), 93% severe persistent asthma
Omalizumab was added to current asthma therapy, duration 24 – 52 wks
- compared with placebo (5 double-blind studies) or
- with current asthma therapy alone (2 open-label studies)

Hanania NA, et. al. Ann Intern Med 2011;154:573-82
(EXTRA)
Prospective, multicenter, randomized,
double-blind, placebo-controlled trial
193 sites in USA and 4 sites in Canada
Obj: To evaluate efficacy and safety of omalizumab in
(850) patients (12-75 yrs) with inadequately controlled
severe asthma who are receiving high-dose ICS and
LABAs, with or without additional controller therapy
Duration: 48 wks
Primary end point: Rate of protocol defined
exacerbations
Results: Rate of protocol-defined asthma
exacerbations was significantly reduced for omalizumab
compared with placebo (25% reduction), increase time
to first asthma exacerbation, improved mean AQLQ(S)
scores, reduced mean daily albuterol puffs, decreased
mean asthma symptom score.
Incidence of adverse events were similar.
Protocol-defined asthma exacerbation was worsening asthma symptoms
requiring treatment with systemic corticosteroids for 3 or more days;
for patients receiving long-term OCS, an exacerbation was a 20-mg or
more increase in average daily dose of oral prednisone

Hanania NA, et. al. Ann Intern Med 2011;154:573-82
(EXTRA)
Prospective, multicenter, randomized,
double-blind, placebo-controlled trial
193 sites in USA and 4 sites in Canada
Obj: To evaluate efficacy and safety of omalizumab in
(850) patients (12-75 yrs) with inadequately controlled
severe asthma who are receiving high-dose ICS and
LABAs, with or without additional controller therapy
Duration: 48 wks
Primary end point: Rate of protocol defined
exacerbations
Results: Rate of protocol-defined asthma
exacerbations was significantly reduced for omalizumab
compared with placebo (25% reduction), increase time
to first asthma exacerbation, improved mean AQLQ(S)
scores, reduced mean daily albuterol puffs, decreased
mean asthma symptom score.
Incidence of adverse events were similar.
Protocol-defined asthma exacerbation was worsening asthma symptoms
requiring treatment with systemic corticosteroids for 3 or more days;
for patients receiving long-term OCS, an exacerbation was a 20-mg or
more increase in average daily dose of oral prednisone
Omalizumab provided additional clinical benefit
for patients with severe allergic asthma that is
inadequately controlled with high-dose ICS and
LABA therapy

Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8
Randomized, double-blind, placebo-controlled trial
Obj: Evaluated ability of omalizumab to improve disease control
sufficiently to enable ICS reduction in patients with
severe allergic asthma
Omalizumab improved asthma symptoms and asthma related QoL ,
and reduced rescue medication requirements compared to placebo

Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8
Randomized, double-blind, placebo-controlled trial
Obj: Evaluated ability of omalizumab to improve disease control
sufficiently to enable ICS reduction in patients with
Omalizumab improved asthma symptoms and asthma related QoL ,
and reduced rescue medication requirements compared to placebo
Omalizumab improves asthma control in severe
allergic asthma, reducing ICS requirements without
worsening of symptom control or increase in
rescue medication use

Vignola AM, et. al. Allergy 2004;59:709-17
Multicentre, randomized, double-blind,
placebo controlled trial
Obj: To evaluate efficacy and safety in patients with
concomitant moderate-to-severe asthma
and persistent allergic rhinitis
Method: 405 pts (12–74 yrs) with a stable treatment
(400 µg budesonide Turbuhaler) and  2 unscheduled
medical visits for asthma during past year
or  3 during past 2 years were enrolled to receive
omalizumab or placebo for 28 wks
Fewer patients experienced asthma exacerbations
(20.6%) than placebo-treated patients (30.1%)
Clinically significant ( 1.0 point) improvement in
both Asthma Quality of Life Questionnaire
and Rhinitis Quality of Life Questionnaire occurred in
57.7% of omalizumab compared with 40.6% of placebo
Serious adverse events were observed in 1.4% of
Omalizumab and 1.5% of placebo

Tsabouri S. et. al. J Allergy Clin Immunol Pract 2014;2:332-40
Obj: To assess efficacy and safety in poorly controlled AR
11 studies (1997-2010) of 2870 patients were finally included
Result: Significant reduction in daily nasal symptom severity score, daily nasal rescue medication
score and improvement QoL
Efficacy of omalizumab in reducing DNSSS

Braunstahl GJ, et. al. Respir Med 2013;107:1141-51
The eXpeRience registry: The ‘real-world’
effectiveness of omalizumab in allergic asthma
2-year, single-arm, open-label, observational
943 pts with uncontrolled persistent allergic asthma
Evaluate effectiveness variables (physician’s Global
Evaluation of Treatment Effectiveness [GETE], change
from baseline in exacerbation rate, symptoms,
rescue medication use, and oral corticosteroid [OCS] use
69.9% responded after 16 (±1) wks
Proportion of patients with no clinically significant
exacerbations increased
Symptoms and rescue medication use at Month 24
were reduced by >50% from baseline.
Maintenance OCS use was lower at Month 24 (14.2%)
compared with Month 12 (16.1%)
and baseline (28.6%)
Acceptable safety profile
GETE: overall clinical evaluation of asthma control at 16 weeks,
based on all available information: patient interview and
physical examination, and review of patient notes and diary

Poachanukoon O.,et. al. J Allergy Clin Immunol 2014;AB2 abstract
METHODS: Multi-center, observational study in severe allergic asthma patients
RESULTS: 61 patients were reviewed
- ACT score increased from 13.8 baseline to 16.4 at Wk 16 (p=0.201) and
increased to 20.6 at Wk 52 (p=0.005)
- Proportion of patients with controlled asthma (ACT score >20) increased from
17% baseline to 52.8% and 72.2% at Wk 16 and 52
- Mean annualized rate of asthma exacerbations was reduced
- Mean hospitalization rate was reduced
- Reduction in ER visits
- Mean daily dose of ICS equivalent to fluticasone was reduced slightly
- 78.7% patients continued omalizumab for at least 1 year
- Of the 9 patients who discontinued omalizumab, 55.5% had relapse
within 3 months and needed to restart treatment

Remark
• Limited data are available on efficacy of
omalizumab for active smokers and for
exsmokers with substantial pack-year histories
because these patients often are excluded
from clinical trials
• But it is suggested that efficacy is likely to be
similar to that in nonsmokers

Global Initiative for Asthma (GINA), 2015 update

Indication in the United States
• Approved in 2003 for treatment of patients
 12 yrs with moderate-to severe persistent
allergic asthma despite treatment with ICS

Indication in the European Union
Approved in 2005 as add-on therapy in patients
>12 years with severe persistent allergic asthma:
• Positive skin test or serum IgE to a perennial
aeroallergen
• Reduced lung function (FEV1 <80%)
• Frequent daytime symptoms or night-time
awakenings
• Multiple documented severe asthma
exacerbations (PEF/FEV1 <60% of patients’ maximum recorded)
despite receiving daily high-dose ICS plus a LABA
‘Multiple severe asthma exacerbations’ is defined as either two or more severe exacerbations
of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of
asthma within the previous year, at least one of which required admission to hospital

Holgate S., et. al. Respiratory Medicine 2009;103:1098-113

แนวทางการให้ยา Omalizumab (asthma)
ผู้ป่วยต้องมีเกณฑ์ทุกข้อดังนี้
• ต้องอยู่ในการดูแลของแพทย์ผู้เชี่ยวชาญด้านโรคปอดและภูมิแพ้
• ผู้ป่วยต้องใช้ยาตามแพทย์สั่งได้ถูกต้องสม่าเสมอ
• ต้องมีการสืบค้นว่าผู้ป่วยไม่มีภาวะ/โรคอย่างอื่นที่เป็นสาเหตุทาให้ ควบคุม โรคหืดไม่ได้
และหลีกเลี่ยงสิ่งกระตุ้น
• มีระดับ Total lgE 75-1,300 IU/mL
• มีการตรวจสารก่อภูมิแพ้ด้วยการตรวจสอบ skin prick test หรือ specific IgE ต่อ
สารก่อภูมิแพ้ในอากาศ (aero-allergen) ให้ผล บวก
• ได้รับการรักษาโรคหืดตาม ระดับที่ 4 มาเป็นเวลาอย่างน้อย 6 เดือนแล้ว ยังคุมอาการ
(Uncontrolled ตาม GINA) ร่วมกับประเมิน PEF variability > 20%
• มีอาการกาเริบของ (Exacerbation) อย่างรุนแรงโดยต้องได้systemic
corticosteroids มากกว่าหรือเท่ากับ 2 ครั้งในช่วง 1 ปีที่ ผ่านมา หรือมีประวัติการ
ใช้สเตียรอยด์ชนิดรับประทาน (Prednisolone) มากกว่าหรือเท่ากับ 10 มิลลิกรัมต่อวัน
ติดต่อกันนานเกินกว่า 30 วัน
แนวทางการวินิจฉัยและรักษาโรคหืด ในประเทศไทย V.5 สาหรับผู้ใหญ่และเด็ก พ.ศ. 2555/ สมาคมสภาองค์กรโรคหืดแห่งประเทศไทย

การประเมินผู้ป่ วยหลังได้รับยา Omalizamab
หลังได้รับยา Omalizamab เป็นเวลา 16 อาทิตย์แล้วประเมินผู้ป่วย
อยู่ในระดับ controlled ตาม GINA ยกเว้น ผลการตรวจสมรรถภาพ
ปอด (ในตารางที่ 3) ร่วมกับมีค่า PEF variability < 15% ให้ยาต่อ
จนครบ 6 เดือน แล้วให้หยุดยา แต่ถ้าประเมินผู้ป่วยหลังได้เป็นเวลา 16
อาทิตย์ ไม่อยู่ในระดับ controlled ให้หยุดยาไม่ให้ยาต่อ ในกรณีที่
หยุดยา หลังที่ ให้ยาครบ 6 เดือนแล้วผู้ป่วยมีอาการกาเริบ พิจารณาให้ยา
ใหม่ตามข้อ บ่งชี้ข้างต้น

Garcia G., et. al. Chest 2013;144:411–9

Chang T.et al. J Allergy Clin Immunol 2014

Casale TB., et. al. J Allergy Clin Immunol Pract 2015 article in press

Maurer M. et. al., J Eur Acad Dermatol Venereol 2015;29:s16-32

Zuberbier T. et al. Allergy 2014; 69: 868–87

แนวทางการให้ยา Omalizumab (urticaria)
• ผู้ป่วยต้องอยู่ในการดูแลของแพทย์ผู้เชี่ยวชาญด้านโรคผิวหนัง และ/หรือ โรคภูมิแพ้
• มีอายุ 12 ปี ขึ้นไป
• ได้รับการตรวจวินิจฉัยเพิ่มเติมว่าไม่มีสาเหตุหรือปัจจัยกระตุ้นอื่นที่ทาให้เกิดโรคลมพิษ
- การตรวจทางห้องปฏิบัติการที่จาเป็น คือ CBC, UA, ANA
• ได้รับการวินิจฉัยจากแพทย์ผู้เชี่ยวชาญว่าเป็น chronic spontaneous urticaria
และไม่ตอบสนองต่อการรักษาพื้นฐาน มีความรุนแรงของโรคระดับปานกลางถึงรุนแรง
• ผู้ป่วยมีอาการของโรคมาอย่างน้อย 3 เดือน แต่ยังไม่ตอบสนองต่อการรักษา
ถึงแม้จะได้รับการรักษาตามขั้นตอนการรักษามาตรฐาน (อ้างอิงแนวทางการรักษาโรคลมพิษ
แห่งประเทศไทย 2557 ) จึงจะมีการพิจารณาให้ยา omalizumab
Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/
สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย

Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/
สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย

Omalizumab beyond
asthma/urticaria

Boyman O., et al. Allergy 2015;70:727–54
A number of trials are underway…

• Rhinitis
• Atopic dermatitis
• Hymenoptera allergy
• Mastocytosis
• Idiopathic anaphylaxis
• Ocular allergy
• Eosinophilic
gastrointestinal diseases
• Food allergy
• Latex allergy
• Mieniere’s disease
• Churg-Strauss Syndrome
• Hyper IgE syndrome
• Bronchopulmonary
aspergillosis
Omalizumab beyond asthma/urticaria
Sanchez J. et. al. Allergol Immunopathol (Madr) 2012;40:306-15

75 mg
150 mg
Lyophilized product
takes 15 to 20 min
to dissolve
From www.xolair.com, access July 2015

Subcutaneous injection every 2 or 4 weeks,
with dose being based on pretreatment serum total IgE levels and body weight

Patients whose baseline IgE levels or BW
are outside limits of dosing table should not
receive omalizumab

Dosage & body weight
• Doses should be adjusted for significant
changes in body weight
• Calculate from total body weight, not ideal
body weight
เอกสารกากับยา
Ledford DK, et. al. Expert Opin Biol Ther 2009;9:933-43

Dosage & IgE level
• Total IgE levels are elevated during treatment and
remain elevated for up to 1 yr after
discontinuation
• Therefore, re-testing of IgE levels during Xolair
treatment cannot be used as a guide for dose
determination
• Interruptions lasting < 1 yr: Dose based on serum
IgE levels obtained at the initial dose
determination
• Interruptions lasting ≥ 1 yr : Re-test total serum
IgE levels for dose determination

Use solution for sc administration within 8 hrs following reconstitution
when stored in the vial at 2 - 8°C, or within 4 hrs of reconstitution when
stored at room temperature.
Reconstituted Xolair vials should be protected from direct sunlight
From www.xolair.com, access July 2015

Other concerns (1)
Xolair has not been studied or inadequately
studied:
• Patients < 6 yrs or > 65 yrs
• Patients with autoimmune diseases
• Patients with pre-existing renal or hepatic
impairment

Other concerns (2)
• One 150 mg Xolair powder vial and solvent for
solution dose contains 108 mg of sucrose
• Not indicated for relief of acute bronchospasm
or status asthmaticus
• No formal drug interaction studies have been
performed with Xolair

Other concerns (3)
• Maximum tolerated dose of Xolair has not
been determined.
• Single IV doses of up to 4,000 mg have been
administered to patients without evidence of
dose limiting toxicities
• Highest cumulative dose administered to
patients was 44,000 mg/20 wk period

Corren J, et. al. Clin Exp Allergy 2009;39:788-97
Safety and tolerability of omalizumab
Analyzed safety using data from clinical studies involving > 7,500 patients as well as
post-marketing data in 2003 – 2006 (57,300 patients)
Overall incidence of adverse events with omalizumab
similar to that in placebo or control groups

Most common systemic adverse events
Adults
• Nasopharyngitis
• Headache
• Upper respiratory tract
infection
• Sinusitis
Children
• Nasopharyngitis
• Upper respiratory tract
infection
• Headache
• Sinusitis

Cox L, et. al. J Allergy Clin Immunol 2007;120:1373-7
Summary of recommendations
• Informed consent
• Anaphylaxis education
• Epinephrine autoinjector
- 24 hrs after administration
• Preinjection health assessment
- V/S, lung functions
• Wait period after injection
- 2 hrs for first 3 injections and
30 min for subsequent injections
(captured 75% of anaphylactic reactions)
Obj: reviewing data on anaphylaxis and anaphylactoid reactions
Duration: 2003 – 2005
Results: 35 patients had 41 episodes from 39,510 patients ( 0.09%)

Cox L, et. al. J Allergy Clin Immunol 2011;128:210-12
Duration: 2006 – 2008

Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5
Omalizumab
Omalizumab antibody
Excipients:
- Sucrose
- L-histidine
- Polysorbate 20
Obj: to examine whether omalizumab skin
testing is safe and to establish an appropriate
nonirritating concentration for prick and
intradermal testing
Participants: no prior exposure to omalizumab
or other biologic therapies
Positive reaction: 3-mm wheal or larger and/or
10-mm or larger erythema over negative control
Antiomalizumab IgG was analyzed 10 weeks
after skin testing

Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5
Intradermal Test in Healthy Volunteers (First Cohort, n=30) and
Allergic Asthma Patients (Second Cohort, n=30)
1:10,000 contains 12.5 g/mL of protein
SPT with all concentrations diluted with
NSS did not elicit any nonspecific reactions
No detectable IgG ab to omalizumab

Shankara T. and Petrov A. Curr Opin Allergy Clin Immunol 2013;13:19–24

Malignancy
Analysis of pooled data from omalizumab phase I to III
clinical studies showed a numerical imbalance in incidence
of malignancy between placebo (0.18%) and omalizumab (0.5%)

Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9
Obj: Examine incidence of malignancy
using pooled data from clinical trials
No cluster of histologies was identified

Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9
A causal relationship between omalizumab therapy
and malignancy is unlikely

Long A. et. al. J Allergy Clin Immunol 2014;134:560-7
Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness
and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS)
- Request of FDA
- 5-year observational cohort study
conducted in patients  12 yrs
with moderate-to-severe asthma
(approximately 5,000 pts treated
with omalizumab and 2800 control)
- Obj: Evaluate long-term safety of
omalizumab, primarily risk of
malignancy
Time to first study-emergent primary malignancy
- Crude malignancy rates were similar (16 & 19/1000 patient-years)
- Time to study-emergent primary malignancy were similar
- Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for
all malignancies and 1.15 for all malignancies excluding NMSC
- Overall frequency and frequency of individual cancer
are consistent with expectations for general population

- Pooled clinical trial data in 2003
showed malignancies in 0.5% of
omalizumab- treated patients
compared with 0.2% of control
malignancy
- Time to first confirmed study-emergent primary malignancy
were similar

- Pooled clinical trial data in 2003
showed malignancies in 0.5% of
omalizumab- treated patients
compared with 0.2% of control
malignancy
- Time to first confirmed study-emergent primary malignancy
were similar
Omalizumab is not associated with
an increased risk of malignancy

Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12
Prospective, observational study of pregnant women
exposed to ≥1 dose of omalizumab within 8 wks
prior to conception or at any time during pregnancy

Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12
Do not increase risk of preterm birth or SGA infants
and prevalence of major congenital defects in
general population with asthma
Omalizumab is classified as a Pregnancy
Category B medication

Nursing mother
• In monkeys, milk levels of omalizumab were measured
at 0.15% of the maternal serum concentration
• It is not known whether Xolair is present in human
breast milk; however, IgG is present in human milk in
small amounts
• Developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical
need for Xolair and any potential adverse effects on
breastfed child from Xolair or from underlying
maternal condition
• Exercise caution when administering Xolair to a
nursing woman

Parasitic (Helminth) Infection
• Monitor patients at high risk of geohelminth infection
while on Xolair therapy
• Insufficient data are available to determine length of
monitoring required for geohelminth infections after
stopping Xolair treatment
• 53% (36/68) of Xolair-treated patients experienced an
infection, as diagnosed by standard stool examination,
compared to 42% (29/69) of placebo, odds ratio for
infection was 1.96
• Response to appropriate anti-geohelminth treatment
of infection as measured by stool egg counts was not
different

Other adverse events
• None of omalizumab recipients developed
measurable antiomalizumab antibodies
• Although thrombocytopenia was noted in preclinical
studies, a decrease in platelet counts of 100 x 10⁹/L
was seen in only 3.4% of omalizumab and 2.3% of
controls

Predictors of response
Not all patients respond to omalizumab !

Predictors of response
• It was difficult to reliably predict by using
pretreatment characteristics
• Physician’s GETE at 16 wks was the most meaningful
measurement of treatment response and the best
discriminator of treatment outcomes

1. Overall physician assessment

1. Overall physician assessment
2. Composite measure of asthma control
AQLQ: Asthma related quality of life

UK responder algorithm
Holgate S., et. al. Respiratory Medicine 2009;103:1098-113

Baseline levels of fraction of exhaled nitric oxide (FeNO),
peripheral blood eosinophils, and serum periostin
Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was
significantly greater in patients with high versus low baseline levels of all 3 biomarkers

Baseline levels of fraction of exhaled nitric oxide (FeNO),
peripheral blood eosinophils, and serum periostin
Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was
significantly greater in patients with high versus low baseline levels of all 3 biomarkers
Stratified approach to treatment,
and to determine value of these biomarkers for
guiding decisions on initiation of omalizumab
which may potentially enhance cost- effectiveness

Duration of therapy
Optimal duration has yet to be determined

Nopp A, et. al. Allergy 2010;65:56-60
Obj: Report clinical and immunological state of patients
3 yrs after a 6-year period of Xolair treatment for
Participants: 18 cat allergen sensitivity pt with asthma
Results: 12/18 patients reported improved or unchanged
asthma compared with ongoing Xolair treatment
-Most patients were in stable clinical condition
-16/18 had not increased nightly asthma attacks
-14/18 little or no increase in medication
-CD-sens to cat was still significantly lower than
untreated patients with allergic asthma and lower than
expected from their serum IgE antibody levels
-Considerable, downregulation of basophil allergen sensitivity

Most patients had good asthma control
for up to 3 yrs after omalizumab withdrawal

Pro: Most patients had good asthma control
for up to 3 yrs after omalizumab withdrawal
Con: Slavin et. al. found that reducing dose of
omalizumab at 6 months led to a recurrence of asthma
symptoms in patients assessed as responders by
physician evaluation at 16 wks

Pharmacokinetic-pharmacodynamic modelling
• IgE production decreases with duration of treatment
by approximately 54%/yr, reaching a new equilibrium
after 5 years of treatment
• After withdrawal, IgE production is predicted to
increase slowly, potentially taking 15 years to return
to baseline, which suggests that patients may not
need to continue omalizumab indefinitely
• Further research into appropriate duration of
treatment is required

Access from www.clinicaltrials.gov/ct2/show/NCT01125748, July 9, 2015
-Study of patients who received omalizumab continuously for up to 5 or more years
and who were randomized to either continue or discontinue omalizumab, with
follow up for a further year
-Results will help to clarify effects of omalizumab withdrawal after successful
long term therapy

Monitoring requirements
• Anaphylactic reactions
sometimes occurs for the first time after multiple
administrations
• Assessment of responses at 16 wks by
using GETE

ธนะวัฒน์ วงศ์พัน/การศึกษาความคุ้มค่าทางเศรษฐศาสตร์และข้อเสนอเพื่ อปรับราคายา Omalizumab ที่เหมาะสมสาหรับผู้ป่วยหอบหืดในประเทศไทย/2556

Take home messages
• Omalizumab is humanized anti-IgE mAb
• Important treatment option for patients with
moderate-to-severe or severe allergic asthma
who remain uncontrolled despite current
standard therapies
• A number of trials are underway that are
investigating efficacy, safety and roles in
conditions other than asthma and urticaria

Anti Immunoglobulin E Therapy

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to Anti Immunoglobulin E Therapy

Similar to Anti Immunoglobulin E Therapy (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Anti Immunoglobulin E Therapy