Antiimmunoglobulinetherapy 150712105317 Lva1 App6892

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
TABLE 5- Human Antibody
2 lsotypes
Isotope Subtype Concentratio
Serum Serum Half-
of s n life Secreted Functions
Antibody (H (mg/ml) (days) Form
Chain) Mucosa I
lgA 3.5 6 Mainly immunit
lgA1,2 dimer; 1 y
(a1 or also U"U
a2) monomer,
Q \ C"2 Ca3
trimer
\Jchain
lg Non Trac 3 Monome Naive B

D e e r cell
(6) antigen
recepto
lg Non 0.0 2 Monome r
E e 5 r
(E) Defense against
CE2 helminthic
Ce3
parasites, immediate
hypersensitivity
Ce4
lg lgG1-4 13. 2 Monome Opsonization,

G (y1, y2, 5 3 r complement
y3, activation, antibody-
ory4) dependent cell-
mediated
cytotoxicity, neonatal
immunity, feedback
inhibition of B cells
lgM Non 1. 5 Penta Naive B cell antigen
e 5 mer recep-
() tor (monomeric form),
complement
activation
Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition
TABLE 5- Human Antibody
2 lsotypes
Isotope Subtype Concentratio
Serum Serum Half-
of s n life Secreted Functions
Antibody (H (mg/ml) (days) Form
Chain) Mucosa I
lgA 3.5 6 Mainly immunit
lgA1,2 dimer; 1 y
(a1 or also U"U
a2) monomer,
Q \ C"2 Ca3
trimer
\Jchain
lg Non Trac 3 Monome Naive B

D e e r cell
(6) antigen
recepto
lg Non 0.0 2 Monome r
E e 5 r
(E) Defense against
CE2 helminthic
Ce3
parasites, immediate
hypersensitivity
Ce4
lg lgG1- 13. 2 Monome Opsonization,

G 4 y2, y3,
(y1, 5 3 r complement
activation, antibody-
IgE lev e l s in cord blood are low (<2 kIU/L; < 4.8 m g / L
o ry 4) dep ende nt c ell -d
cytotoxicity,
),
m ed iate
gradually increase throughout childhood with a p e
neonatal
in hibiti feedback
immunity, on of
lgM at 15 y rs of age , a then decreas
None
() ak e
5 Pen ta m er N aive B cell antigen
B ce lls tor (monomeric
lgM
10at 10 15 y rs ofnd
None1.5 age , a nd then decreas e
1.5 5 Pen ta m er recep- form),N aive B cell
antigen rece
throughout adulthood
Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80
complement
From www.hindawi.com, access July 2015
IgE control level of FcRI expression
- FcRI 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 FcRI expression
correlates directly with serum IgE levels,
where binding of IgE stabilizes
receptor at cell surface
Large amount of FcRI on cell surfaces:

- mast cells, basophils
Other cell types:
- antigen presenting cells

Oettgen H. Middletons Allergy Principle and Practice. 8th edition, 2014
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 FcRI 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;70:72754
Omalizumab
Humanized, anti-IgE monoclonal antibody
5% mouse
Composed of 5% murine sequences that were

engrafted onto a human IgG1 framework
Binds to heavy-chain constant CH3 domain

of IgE molecule
Same site by which IgE binds to FcRI
Holgate ST. Q J Med 2004;97:247- 57

Stokes JR. and Casale TB. Middletons Allergy 8th edition, 2014, 1480-90
Omalizumab - IgE complexes
Soluble, inert immune complexes that are subsequently cleared

from circulation via interactions with FcRs of hepatic sinusoidal
endothelial cells of reticuloendothelial system
(half-life 26 days)
Price D. Primary Care Respiratory Journal 2008;17: 62-72
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
Picture from www.what-when-how.com, access July 6, 2015
Owen CE. Pharmacology & Therapeutics 2007;113:12133
Holgate ST. and Polosa R. Nature Reviews Immunology 2008;8:218-30
Holgate S., et. al. J Allergy Clin Immunol 2005;115:459-65
Airway lumen Allergen
0
()
Epithelium
Dendritic cell
e
Circulation
IL-4, 9, 13

Histamine
Eosinophil
8/ :
Leukotrienes
: Prostaglandins

: Cytokines (IL-3, 4)
: GM-CSF

IL-13?
,.
.
Smooth
muscle
X direct effect
e- indirect effect Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
- 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 FcRI on basophils within 7 days
- Within 3 months, human basophil responsiveness
(i.e., histamine releasability) was reduced by 90%
Owen CE. Pharmacology & Therapeutics 2007;113:12133

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

Clinical benefits
Moderate to severe
Chronic persistent
Idiopathic Allergic
Urticaria Asthma
(CIU) not controlled by
inhaled steroids
not controlled by H1
antihistamine Limitations of Use:
XOLAIR is not used to
treatment
Limitations of Use:
treat other allergic
XOLAIR is not used to treat
other forms of urticaria conditions, acute
bronchospasm or status
asthmaticus.
Goto the Go to the

H.....e....a...l..t...h....c...a...r...e...... .H....e....a...l..t..h.....c...a...r...e......
P...r....o...v....i.d....e....r.....S...i..t.. P...r...o....v....i.d....e....r.....S...i..t..
e.... e....
Picture from www.xolair.com, access July 2015

Allergic asthma
Effect on airway inflammation
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
Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36

Djukanovic R, et. al. Am J Respir Crit Care Med 2004;170:583-93
Effect on remodelling
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
Omalizumab reduced airway wall thickness
Airway dimensions were assessed at
right apical segmental bronchus by CT:
and airway inflammation

- airway wall area corrected for BSA (WA/B SA)
- 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

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

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 2005:60:30916

Benefits of omalizumab as add-on therapy in patients with severe
persistent asthma who are inadequately controlled despite best
available therapy (GINA 2002 step 4 treatment): INNOVATE
A P= 0.042
1.0 026% I
0.91 (0.7 3, 1.14) Double-blind, parallel-group, multicentre study
.'!
c
.Q
!!.'!
0.68 (0.53, 0.87)
Obj: Determined effect of omalizumab on clinically significant
0.8
asthma exacerbations (requiring systemic corticosteroids)
0.6
0)

'U)
0.4
Participants: Patients (12-75 yrs) with severe persistent asthma
uO:ss:
Cl)
0.2 who are inadequately controlled despite Global Initiative for
E gj Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA)
Omalizumab Placebo
O m a l i z u i g f i c Method: reduced
Table 3. Freque ncy of em erge n cy vis its
mary intent-to-treat, PITI
rate of P o isson regr es si on
randomized to receive omalizumab
m a clinically
b s
population)
signi fai cntly
for ast hma usin g
Type of
a nt a stohr pm lacea boefox
r 2a
Statisti
8cwke
s (pri
O m al izum ab
(n = 209) (n =
Plac ebo
visit
s e ve r e
rbations,
Total emergenc y v isits tion aOnmdalizeummab esigrngificea
c
N um ber
0.2
210)
93
0.4
quality of life, morning PEF and asthma symptom
exacerb a s n
5 0 ciympvroviesdiatssthma-related
tly
scores
P-value for ratio
-:S611([325=Cf9681--------------------'
4
0.03
3
Hospital Number 0.24

13 8 25 0.43 quality of life, morning PEF and asthma s
admissions Rate per treatment 0.0 0.1
period 60.540 (0.250-
2
Ratio of rates (95% 1.166)
Emergency room Cl) 9 0.117 14
visits P-value for ratio 0.0 0.0
Number 40.659 (0.208-
6
Rate per treatment 2.094)
Unscheduled doctor period 28 0.480 54
visits Ratio of rates (95% 0.1 0.2
Cl) 30.546 (0.271-
4
P-value for ratio 1.100)
Number Humbert M., et. al. Allergy 2005:60:30916
0.090
The effect of treatment with omalizumab, an anti-IgE antibody,
on asthma exacerbations and emergency medical visits in patients
with severe persistent asthma
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)
Table 2. Pooled analysis: reductions in exacerbations and emergency visits58 and increased quality of life59
with omalizumab.
Omalizumab Control Difference Ratio p-value

(n=2,511) (n=1,797) (%) (95% Cl)
Exacerbation rate* 0.91 1.47 38% 0.617 (0.535-0.712) <0.001
Total emergency visit rate* 0.33 0.62 47% 0.533 (0.401-0.709) <0.001
AQLQ (change from baseline, (n=1,221) (n=1,032)

LSM) 1.01 0.61 <0.001
Overall 1.03 0.65 <0.001
Activity 1.04 0.62 <0.001
Emotions 0.97 0.54 <0.001
Symptoms 1.01 0.60 <0.001
Environment
* Annualised; AQLQ = Asthma Quality of Life Questionnaire
Bousquet J., et. al. Allergy 2005:60;3028

P < .001 Omalizumab (n = 2511)
Control (n = 1797)
0.7
0.623
0.6
P< .001
0.5
0.443
( I
. .. .
.)..
c:: 0.4
s
0.332
-
"'O
i-
N
" d)
@ 0.3
0.252
1 P= .041
P = .013
0.2
0.1 !]
0 -----
Total emergency Hospital admissions
66
Emergency room Unscheduled doctor
0.026
visits visits visits

(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

Omalizumab in Severe Allergic Asthma
Inadequately Controlled
Standard (EXTRA) With
Therapy
Table 2. Protocol-Defined Asthma Exacerbations Over Prospective, multicenter, randomized,
the
double-blind, placebo-controlled trial
48-Week Treatment Period
193 sites in USA and 4 sites in Canada
Analysis of Primary End Point Omalizumab Group Placebo Group
(n = 427) (n = 421) Obj: To evaluate efficacy and safety of omalizumab in
Frequency of protocol-defined (850) patients (12-75 yrs) with inadequately controlled
asthma exacerbations,
severe asthma who are receiving high-dose ICS and
Omalizum
Omalizumaabbprov provi di deead d ad d i tdi o i tni oanl ac l icnli cnai cl a l
n (%)
0 27 27
5 ( 564.4)
( 64.4) 2 422 42
(57 (57
.5) .5) LA BALA s, BA
w i s,thwor
i thwior
th wi
outh
t aou
ddt iatio
ddna l na l
i tio
1 94 (22.0) 107 (25.4)
Duration: 48 wks
3
?:4
2
d b e nb e fni te f i t
11 (7.3)
(2.6)
c on troc lle
15 (8.1)
(3.6)
on rtro
t hlle
e rap
r t h e rapy
31 34
Rat
for patienytscwith
inadequatel o slled evere Rew sula
Pri
i al: rlyRate
tst
m
16 (3 .7)
h eernhdgopifiogcprintha:otoRsa-tctdeol-hofom
2 3 ( 5.5)
aoco
desfin
prot
e tl
ed
h
dea
fint dis
Inci 0 .75 ( 0.6 1-
P value eexacerbations was significantly reduced for omalizumab
"O
n t ro
100
e of0.protocol-defined
92); 0. 00 6 asthmaLABA IaCsthStma
0.66 chand
omepraraedpwyith placebo reduction), increase time
exacerbations 0.88
Q)
c
90
exacerbations per patient to first asthma exacerbation, improved mean AQLQ(S)
Q) dence rate ratio (95%
0

80
Cl);
(25%
scores, reducedwas
exacerbations mean daily albuterol
significantly puffs,
reduced for decreased
omal
P value
--- LABA t h e r a p y
I
r: 70
-, .
0
mean
c om pasthma
ar ed symptom score.(25% reduction),
-
u
0
.. . ns
0
:p
60

w ith placebo
Incidence of adverse events were similar.
-
.. .. ..
;-
0
:::: ..
,
.s:
0
ns
Q)
u
w
x
50
40
increase ti
ns Protocol-defined asthma exacerbation was worsening asthma symptoms
--
:
VI
c
nQ.
u
s
E
..c
VI
-c
30
20 --- Placebo (n = 421)
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
:n 10 Omalizumab (n =
es
0..
0 427)
0 4 8 12 16 24 28 32
20
Time Since Day 0, wk Hanania NA, et. al. Ann Intern Med 2011;154:573-82
Efficacy and safety of a recombinant anti-immunoglobulin E antibody
(omalizumab) in severe allergic asthma
(a) 0-0 Omalizumab
2.0 .... Placebo
Randomized, double-blind, placebo-controlled trial
1.5 Obj: Evaluated ability of omalizumab to improve disease control
rJ)
E
sufficiently to enable ICS reduction in patients with
a0. 1.0 severe allergic asthma
iE
s:
O Omalizumab improved asthma symptoms and asthma related QoL ,
'in
S
<( 0.5
! Corticosteroid I and reduced rescue medication requirements compared to placebo
reduction
0 4 8 12 16 20 24 28 32
Table 3. Reduction in inhaled corticosteroid (fluticasone) at the end of treatment (week 32) (intention-to-treat population)
Outcome Placebo (n = 120) Omalizumab (n = 126)
Reduction in fluticasone dose (%)

Median (95% Cl) 50.0 (33.3-50.0) 60.0 (50.0-75.0)
Mean (SD) 43.3 (38.6) 57.2 (36.7)
Patients with 100% reduction in fluticasone dose (%) 15.0 21.4
Patients with ;;::: 50% in fluticasone dose (%)
reduction
50.8 73.8
All patients 53.8 (n = 52) 72.6 (n = 62)
Patients receiving LABA 48.5 (n = 68) 75.0 (n = 64)
Patientsreduction
Absolute not receiving LABA dose (g/day)
in fluticasone
Median (95% Cl) 500 (500-750) 750 (750-1000)
Mean (SD) 596 (539) 782 (519)
Patients reduced to 500 g/day
Fluticasone (%) 45.8 60.3
Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8
Efficacy and safety of a recombinant anti-immunoglobulin E antibody
(omalizumab) in severe allergic asthma
(a) 0-0 Omalizumab
2.0 .... Placebo
Randomized, double-blind, placebo-controlled trial
1.5 Obj: Evaluated ability of omalizumab to improve disease control
sufficiently to enable ICS reduction in patients with
E
% severe allergic asthma
1.0
i'in
s: Omalizumab improved asthma symptoms and asthma related QoL ,
OS
E and reduced rescue medication requirements compared to placebo
Patients with 100% reduction in fluticasone dose (%} 15.0 21.4

Patients with ;;::: 50% in fluticasone dose (%}
reduction 50.8 73.8
All patients 53.8 (n = 52) 72.6 (n = 62}
Patients receiving LABA 48.5 (n = 68) 75.0 (n = 64)
Patientsreduction
Absolute not receiving LABA dose (g/day)
in fluticasone
Median (95% Cl) 500 (500-750) 750 (750-1000)
Mean (SD) 596 (539) 782 (519)
Patients reduced to 500
Fluticasone (%} g/day 45.8 60.3
Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8
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 (1274 yrs) with a stable treatment
(400 g 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
Vignola AM, et. al. Allergy 2004;59:709-17

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
Tsabouri S. et. al. J Allergy Clin Immunol Pract 2014;2:332-40

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 (physicians 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
Braunstahl GJ, et. al. Respir Med 2013;107:1141-51 physical examination, and review of patient notes and diary
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
Poachanukoon O.,et. al. J Allergy Clin Immunol 2014;AB2 abstract
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

.........................................................................
.........................................................................
Diagnosis ./'l.:
.................................................................... ":'<(i !
Symptom control risk factors :/)
(including lung
& !
function)
Inhaler technique & adherenc{/ j
,,.
Patient preference i

Symptoms
Exacerbations I
Side-effects
Palienl satisfaction
Asthma medico i
Non-phgical strategies
Lung function Treaabi.e risk factors

jSTEP
5
STEP4 l:
STEP3 '
PREFERRE STEP ' Refer
for
D 1 i add-
CONTROLLE Medlhigt on
R 1 '!
CHOICE ICS/LABA treatment
eg
anti-lgE
Other
conlroller
options
As-needed SABA or
RELIEV As-needed short-acting etnist (SABA) low dose ICS/formoterol..
ER
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
Severe asthma?
yes
Patient 2:.12 years?

yes
Controlled with ICS plus LABA?
no
Multiple documented severe exacerbations?

yes
Frequent daytime and nocturnal symptoms?
yes
FEY, <80% predicted

yes
Skin-prick test positive?

yes
RAST test positive?
yes
Bodyweight 20-150 kg and total lgE 30-700 IU/mL?
Consider treating with omalizumab Patient not suitable for omalizumab
Holgate S., et. al. Respiratory Medicine 2009;103:1098-113

Omalizumab
(asthma)

Total lgE 75-1,300 IU/mL
skin prick test
specific IgE
(aero-allergen)

corticosteroids 4 2
1 6

(Uncontrolled GINA)
(Prednisolone) PEF
variability >
V.5 .. 2555/
10
20%

Omalizamab
Omalizamab 16
GINA
controlled

( 3) PEF variability <

15% 6
16

6controlled

V.5 .. 2555/

V.5 .. 2555/
A Proof-of-Concept, Randomized,
Controlled Trial of Omalizumab in
Patients With Severe, Difficult-to-Control,
Nonatopic Asthma
3
p=0,029 --.
0
35
Placebo
0
;::
30
.,. ..
.., ,r
.
,c-
" 25 11.
'
Cl)
.J
).S p. .,....

Cl)
1,1
0..
"' )(
20
....
,0 .....
Omolizumob
.
Cl)
15 :
1}.

....
u.
t;t..a
i 10
:::
.Q
E
, :
u,
c ...
.... u,
c

1l
Cl) 10
Q)
:::,
!!E .. C)
!:::
u,
5 ' 0
-0.2%
o + 9.72%
0 10 20 30 40 SO 70 80 90 100 110 120
Start of 60
Trotmont Day
-10 Omalizumab Placebo
Garcia G., et. al. Chest 2013;144:4119

Urticaria
Chang T.et al. J Allergy Clin Immunol 2014
c Efficacy endpoint, week 12
l Every 4 weeks injection
0
CIU/CSU Background
Therapy l l l l l l
Approved doses of 24-week treatment period 16-week
ASTERIA I H1 -antihistamines Omalizumab 75, 150, 300 mg vs placebo follow-up
l l l
12-week treatment
0
Approved doses of period
ASTERIA II Omalizumab 75, 150,
H1 -antihistamines
300 mg vs placebo
0
Up to 4X approved dose of
l l l l l
H1 -antihistamine plus
24-week treatment period
GLACIAL LTRA or H2 -antihistamine, Omalizumab 300 mg vs placebo
or all 3 in combination
Casale TB., et. al. J Allergy Clin Immunol Pract 2015 article in press
Table 1 Summary of phase Ill data with omalizumab in
chronic
spontaneous urticaria: % reduction in itch, hives and overall DLQI
score.
ASTERIA 116 ASTERIA 111 GLACIAL15
4
% Reduction*
Itch Severity 67 71 62
Score (ISS) P < 0.0001 P < 0.001 P < 0.001
Weekly Hives Score 67 74 62
P < 0.0001 P < 0.001 P < 0.001
DLQI (overall score) 74 78 73
P < 0.0001 P < 0.001 P < 0.001
Responder(%)
UAS7 < 6 52 66 52
P < 0.0001 P < 0.001 P < 0.001
*From baseline to week 12 with omalizumab 300 mg.
Maurer M. et. al., J Eur Acad Dermatol Venereol 2015;29:s16-32

Zuberbier T. et al. Allergy 2014; 69: 86887
Omalizumab
(urticaria)
/

12

- CBC, UA, ANA

chronic
spontaneous urticaria

3
Clinical Practice Guideline 2557
(
/

(chronic spontaneous urticaria)
,r
,
,
'Wl'HUl!'lJcJl nonsedatingl HI-antihistamines
<:! I
innrri:d 1 6lf'W .,, I 3)
111elcJ1 modem .,,- I
second-
1
I o'
generation
3,1.,,
HI-antihistamines 61J'Wl 0Jlfltl 4 !l'1161Jel61J'Wll'l 'HJfll'J'J1J'Jel)

'Wl'WelcJl'WelcJ 4 'fflJl'n
, r

/
/
,,. d
.
'lr&flW'Y
I
Urticaria Activity Score 7 (UAS7) :::_16 Urticaria Activity Score 7 (UAS7) :::_16
"...'I V1V ,, tl '

i'Uf:!u1 u mss fl'lfl1>11lJ'l
Q.I
f 1Jl!nl1
l>l'
,,
tl'l.HY'U l>lt
v 1U
'
lJl>l tl.:J l
flI u'1:i'.J1vihin1;1ru:i.:ie:J
m
fl1Jfo1;11
h.J
.,
I. ii absolute contraindications tltn ciclosporin"
.. I '
!ntl!Cfl UAS7
16
... "-'1 d tl ,,.. v
* i unrn!f:!u1 n 'Utl .:J'i11n l,j'1uJ ff
=
'6flWI 1. Ciclosporin
.d lJlJ'\Jtl =
m ! -I : V1 .. .
'lJ tl.:JV1 ciclosporin i'U1ne:J11n11 18 iJ ms - l J fl11: ciclosporin dependence
11lJff11J1Jt1'11QV1
i;V1'f11J
1
2.
..
ii absolute contraindications tltn systemic
I
-
\1
ciclospori.t1 l;mi.:ii;u11J11unm31${tl'U
I 3}
Q.I '117tl
lJl>ltl1Jff'Utl.:Jl>ltlfll'nn1;111vv1 ciclosporin
I
(lJ'f'l:U'U'U
3
corticosteroids tJJ:!ilu UAS7 "".:ihici.:i 30% 'i11n11i1J1Piumi.:i'i11n
1 1
l;f1Jv1i'U'U'U1 h11n'U 3 lJn./nn./1'U 'U1'UtlV1.:Jtfov 4
tirtJJ :d'.ium1lJiuuJ .:J'\Jtl.:J1J'f'l'i11n111J1JtJ J:!'Utll fllJ'U irtJ111)

'117tl
. '
'1lJVj'l;l\91'1tlJ:U:!1m 7 1'U (Urticaria Activity Score 7; UAS7) - .lJfl11: ciclosporin treatment intolerance !'lf'U lJ'f1111J
. ...
'\i'V'i1: i'1V1'=W'i11JOA1fl1'n.,n'l;l1V1VV1 omalizumab 1
tJn'IJtl.:J l1>1u'1:/'117tl'fl 111Ji'Ul'1'ttl>l'g'.:J'tt
I i'UJlVV"'l"lJ'
I Q.I G
/1;r1Jv11v
.. .
lJ blood pressure>140 nunHg systolic '11Jtl >90 nunHg
. ...
'f'l:uuu UAS7 ummnrsermnu 16 neuuu ('i11n'f'l:uuu11>11J diastolic tlf1'U'Ul'U 2
irtJ111
2. Corticosteroids
'111JlV!'l11iJ: niiu1e1'1.:itl.:J!lJ!lJimh'U'lltl.:J
tl I I
Relative J1J oral prednisolone 'IJ'Ul1J1nm1wrnm1n1J 10
Q.I
-
contraindications tlV1 ciclosporin2 U'1: systemic !i}o.,
"nfoe:J1'Ue:Jnummnu 30 iu
corticosteroid/
. ..
- 1 J fl11: corticosteroid dependence tl1J''ff11JlJt1'1u- Fr-n1ruvi
.. . 'l, .,
'11 J tl'l1Ml
'l'1V1'=W'i1UW1 'l '1V101

omalizumab
/
/

Omalizumab beyond
asthma/urticaria
A number of trials are underway
Boyman O., et al. Allergy 2015;70:72754

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

Dosing and administration
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
75 75 75 150 150 150 150 150 300 300 225

150 150 150 300 300 300 300 300 225 300 375
150 150 225 300 300 225 225 225 300 375
225 225 300 225 225 225 300 300
225 300 225 225 300 300
300 225 300 300 375

225 225 300
225 300 375

>800-900 225 225 300
.>900-1000 225 300 !175
,1000-1100 225 300 375
>1100-1200 300 300
>1200-1300 300 375
> 1300-1500 300 375

75 75 75 150 150 150 150 150 300 300
150 150 150 300 300 300 300 300 225 300
150 150 225 300 300 225 225 225
225 225 300 225 225 225 300 300
Patie nts wh ose baselin e IgE levels or BW

225 300 22 225 3 0 0 30 0
300 225 300 300 875
are outsid e li mit s of dosing table should not

5
22 2 2 3 00
5
225
receive omalizumab
225
225
5
300 875
225 300 875

300
225 300
300 300
300 875
300 B75

Dosage & body weight
Doses should be adjusted for significant
changes in body weight
Calculate from total body weight, not ideal
body weight

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
Dosing Guide for
cur and
Number of Injections Injection Two 150-mg vials= 300 mg.
Product not shown to scale.
Total
XOLAIR Number Volumes
dose, mg of Total
injections" volume
injected, ml'
BY SUBCUTANEOUS INJECTION EVERY 4 WEEKS'

"Doses of more than 150 mg are divided among more than one
injection site to limit injections to not more than 150 mg per site.
1 .2 ml maximum delivered volume per vial aher reconstitution.
1
Administer XOlAIR only in a healthcare setting by healthcare

providers prepared to manage anaphylaxis that can be life-
threatening
Use solution for sc administration within 8 hrs following reconstitution

when stored in the vial at 2 - 8C, 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

Safety
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
Corren J, et. al. Clin Exp Allergy 2009;39:788-97

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

Obj: reviewing data on anaphylaxis and anaphylactoid reactions
Duration: 2003 2005
Results: 35 patients had 41 episodes from 39,510 patients ( 0.09%)
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)
Cox L, et. al. J Allergy Clin Immunol 2007;120:1373-7

A111erican Acade111y of Allergy, Asth111a & l111
111unology/A111erican College of Allergy, Asth111a -
& Imrnunoloqv Omafizumab-Associated Ana
phylaxis Joint Task Force follow-up report
Duration: 2006 2008
TABLE Ill. Summary of reaction timing in comparison with
omalizumab (Xolair) dose and recommended wait period
Reactions Reactions
Total
.
occur nn g
.
occur nn g
with within the beyond the
known recommended recommended Timing
Dose Patients* timing wait period+t wait period] unknown
1-3 44 40 33 (82%) 7 (18%) 4

4 and 33 29 20 (68%) 9 (32%) 4
subsequent
Total 77 69 53 (77%) 16 (23%) 8
Cox L, et. al. J Allergy Clin Immunol 2011;128:210-12

Omalizumab Obj: to examine whether omalizumab skin
Omalizumab antibody testing is safe and to establish an appropriate
nonirritating concentration for prick and
Excipients:
intradermal testing
- Sucrose
- L-histidine Participants: no prior exposure to omalizumab
- Polysorbate 20 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

Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5
Table 1. Example of omalizumab desensitization
protocol. Target dose should be split in half with a
plan for weekly or biweekly injections dependent
on a total dose
Stock solution Dose

Step (S.S.) (mg/ml)
concentration
1 1.5 mg/1.2 ml 0.0625
2 1.5 mg/1.2 ml 0.625
3 15 mg/1.2 ml 1.25
4 15 mg/1.2 ml 2.5
5 15 mg/1.2 ml 5
6 15 mg/1.2 ml 10
7 150 mg/1.2 ml 20
8 150 mg/1.2 ml 37
9 150 mg/1.2 ml 37
10 150 mg/1.2 ml n/a
Cumulative 113.38
dose
(mg) Shankara T. and Petrov A. Curr Opin Allergy Clin Immunol 2013;13:1924
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%)

Omalizumab and the risk of malignancy: Results from a
pooled analysis Obj: Examine incidence of malignancy
All clinical trials using pooled data from clinical trials
67 trials
Omalizumab-treated, n = 7789
TABLE Ill. Summary of primary malignancy type (RDBPC trials,*
Control, n = 4252 including events identified from the ARGUS database)
Primary malignancy Omalizumab (n = 4254) Placebo (n = 3178)

Excluding uncontrolled single-dose or
omalizumab arm(s) only studies 14 (0.33) 11 (0.35)
Any event, no. (%)
MSC 5 (F30, F46, F66, F75, M74) 2 (F56, M66)
Controlled clinical trials
40 trials =
Omalizumab-treated, n 6246
Breast
Melanoma
l t.
(F47)
Control, n = 4252 Prostate 2 (F39, F44)
Colon 1 1
Excluding unblinded, allocated and/or
t.
L
active control studies Salivary gland 1(M74) (M57)

"
RDBPC trials
No cluster of histol o g ie s was identified
eo pla srn
Pancreatic cancer
1 (F 38 )
(M44)
1
32 trials Rectal cancer (M68)
1 (F44)
Omalizumab-treated, n = 4254 Brain neoplasm I
Placebo, n = (F27)
3178
Gastric cancer
Lung adenocarcinoma 1
TABLE II. Incidence of primary malignancy in RDBPC trials
Esophageal carcinoma (M64)
(primary analysis, including events identified from the ARGUS
Renal neoplasm I
database)
(M36)
Medulloblastorna
Omalizumab vs placebo 1
Omalizumab Placebo Difference Rate
Bladder 1 t. (M56)
(n= 4254) (n = 3178) in rates ratio Testicular neoplasm (M47) 2(M21,M34)
1
No. of patients 14 11 (F6)
with primary 1
malignancy (M7)
Observation 3382.40 2473.79
time (y)
Incidence rate':' 4.14 4.45 -0.31 0.93
95% CI 2.26 to 6.94 2.22 to 7.94 -4.47 to 3.35 0.39 to 2.27
*Incidence rates presented are per IOOO patient-years of observation time (number of
patients with malignancies/observation time in patient-years censored at the date of Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9
primary malignancy).
A causal relationship between omalizumab therapy
and malignancy is unlikely
Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9
Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness
and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS)
Time to first study-emergent primary malignancy
- 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
- 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
Long A. et. al. J Allergy Clin Immunol 2014;134:560-7 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
Long A. et. al. J Allergy Clin Immunol 2014;134:560-7
- Pooled clinical trial data in 2003
showed malignancies in 0.5% of
omalizumab- treated patients
Omalizumab is not associated with
compared with 0.2% of control
an increased risk of malignancy
malignancy
- Time to first confirmed study-emergent primary malignancy
were similar
Long A. et. al. J Allergy Clin Immunol 2014;134:560-7
The Xolair Pregnancy Registry (EXPECT): The safety
of omalizumab use during pregnancy
TABLE Ill. Omalizumab exposure in registrants
All registrants
(N = 191)
Prospective, observational study of pregnant women
exposed to 1 dose of omalizumab within 8 wks
Dose (mg),*" n (%)
150 37 (21.5) prior to conception or at any time during pregnancy
225 23 (13.4)
300 56 (32.6)
375 31 (18.0)
Other 25 (14.5)
Dosing interval," n (%) TABLE IV. Known pregnancy outcomes for registrants*
Every 2 weeks 83 (48.0)
Outcome Pregnancies (N = 169)
Every 4 weeks 84 (48.6)
Other 6 (3.5) Live birth, n 156t
Earliest exposure, n (%) Percentage of registrants (95% CI) 92.3 (87.2, 95.8)
First trimester 188 (98.4) I
Elective termination, n
Second trimester 3 ( 1.6)
Percentage of registrants (95% CI) 0.6 (0.0, 3.3)
Third trimester 0 (0.0)
Stillborn/fetal death (20 wk), n 1
Timing of exposure," n (%)
First trimester 21 (12.7) Percentage of regi trants (95% CI) 0.6 (0.0, 3.3)
Second trimester 0 (0.0) 11
Spontaneous abortion (<20 wk)
Third trimester 0 (0.0) Regi trants enrolled prior to 20 wks, n
128
First and second trimesters 4 (2.4) Percentage of registrants (95% Cl) 8.6 (4.4, 14.9)
First and third trime ter 2 ( 1.2)
Second and third trimesters 3 ( I. 8) "One pregnancy per woman.
All trimester 135 (81.8) +One hundred fifty-two singleton infants and 4 pairs of twins.
Exposure duration (mo) during pregnancy"
Mean (SD) 7.3 (2.7)
Median (range) 8.8 (1.1-9.9)
Infant exposure via breastfeeding, n (%l
Delivery through mo 6 98 (100)
Month 6 through mo 12 43 (43.9)
Beyond mo 12 16 (16.3)
Exposure duration (mo) in breastfed infants"
Mean (SD) 5.4 (5. l)
Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12
Median, range 3.9 (0.1-20.4)
The Xolair Pregnancy Registry (EXPECT): The safety
of omalizumab use during pregnancy
TABLE I. EXPECT findings compared with those from studies of adverse pregnancy outcomes in the general population and in women with
asthma
Preterm Spontaneous
M_
ajo_
r ,,_!!:b) ---Sm-all for Low birth
Fetal death abortion
'- ks)
ir
-------'-' -.....1 ...--l
th-
Data
-
EXP 14.9)
PR Pasternak 2013 5.2 9.2 3.7 0.40

Martin 201324 ; MMWR23; 11.724 10.523 8.124 0.6119
1
9
LABA 9.117
OTIS Network Bakhireva 200715
13i-agonists 3.9 11.8 3.9 0 5.6
LTRAs 6.0 9.8 6.1 I. I 5.6
Sheiner 200527
Soroka Univ Med Ctr 3.8 9.5
Sarkar 200926
Int'I Teratogen 2.7 18.2 9.4
Information Services
Health Improvement etwork Tata 200720 I. I
Database (UK)
Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12
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 mothers 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 10/L
was seen in only 3.4% of omalizumab and 2.3% of
controls

Issues in clinical use
Predictors of response
Not all patients respond to omalizumab !

Predictors of response
It was difficult to reliably predict by using
pretreatment characteristics
Physicians 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

Time Patient assessment
Key assessments: ACP, Mini-AQLQb UK responder algorithm
-4 weeks Supportive assessments: PEFd, exacerbations", HCUf
_J_ _L-
Baseline: Patient assessment (baseline)
initiate Key assessments: ACT, Mini-AQLQ Supportive
omalizumab assessments: PEF, exacerbations, HCU
_J L
-
Patient assessment
Key assessments: ACT, Mini-AQLQ Supportive
assessments: PEF, exacerbations, HCU
Decision point - assessment of response compared with baseline
Key response indicators

Must achieve at least one of the following
+16 weeks: ACT .O improvement
decision point Mini-AQLQ 0.5 improvement
with no deterioration in either assessment
Supportive response indicators

PEF chart
Incidence of exacerbations
Incidence of unscheduled HCU
AND
Patients must achieve excellent/good overall evaluation score in
Physician Global Evaluation of Treatment Responsec
I I
J l
ONLY CONTINUE OMALIZUMAB THERAPY IF ABOVE
CRITERIA ARE MET
I I
Patient on-going assessment
+52 weeks Ensure further follow-up assessment, minimum at 1 year
Key assessments: ACT, Mini-AQLQ Supportive
assessments: PEF, exacerbations, HCU
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
Stratified approach to treatment,

and to determine value of these biomarkers for
guiding decisions on initiation of omalizumab
which may potentially enhance cost- effectiveness
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

Duration of therapy
Optimal duration has yet to be determined

Obj: Report clinical and immunological state of patients
3 yrs after a 6-year period of Xolair treatment for
severe allergic asthma
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
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
severe allergic asthma
Most patients had good asthma control

Participants: 18 cat allergen sensitivity pt with asthma
Results: 12/18 patients reported improved or unchanged

for up to 3 yrs afterasthma
omalizumab withdrawal
compared with ongoing Xolair treatment
-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
-Considerable, downregulation of basophil allergen sensitivity

After 6 years with Xolair; a 3-year withdrawal follow-up
160
-Cl) 140 Obj: Report clinical and immunological state of patients

C')
c: 3 yrs after a 6-year period of Xolair treatment for
12 0
0
P ro: Most patients h a d g o o d asthma se ve re aller ic as thm a

100
LL
-control
80
for up to 3 yrs aftePResults:
60
rasthma
arto
icipm anta
12/18 s: 1l8iczatreported
patients ualmlergean sb
ensiw
improved
compared with ongoing Xolair treatment
ortivitiytpthwd
unchanged ith
rasa
thw
ma al
1 6 12 36
Months after last injection
Con: Slavin et. al. found t-1h6a/1t8 hraed dnout icncirneagseddnoighstely
P < 0.0001
omalizumab
1000
a t months a o
-1 l4e
P< 0 .001
sth f
-CD-sens
/1d8 litttole oar
ma attacks
P < 0.001 to cat was still significantly lower than
6
symptoms
100
in pat nroeinccruearsruee
ie n ass inn
nt s cede
remsate e ica
d o
P < 0 .02
pa
0
tiotifnent
a s asthma
r sewsithpaollenrgdic e
asrthsmb a
n ev aluation aty11-lower
0 0
u,
physicia
ts
10
00
00 a nd
00
6-6Con
Conw
000
sidkersable,
than 00
able, downregulation
downregulationof of basophil
basophilallergen
allergen
c: 000 oo'b oo 0 00
Cl) sensitivit
0 880 0 9' sensitivity
u, 1 o0o 0
I 0 0
c 0
0
08 0
0 0.1 00 00
00 0
0
0.01
0.001 'ii
1 6 12 ' 36 Control
Months after last injection
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

Ex,
ClinicalTrials.gov Search for studies: [
A service of the U.S. National Institutes of Health Ad
Find Studies About Clinical Studies Submit Studies Resources About This Site
Home > Find studies > study Record

Detail
A Study Evaluating the Persistency of Response With or Without Xolair (Omalizumab) After Long-term Therapy (XPORT)
This study has been completed. ClinicalTrials.gov Identifier:

NCT01125748
Sponsor:
Genentech, Inc. First received: May 14, 201 O
Last updated: October s, 2014
Information provided by (Responsible Party): Last verified: October 2014
Genentech. Inc. History or Changes
Full Text View Tabular View Study Results Disclaimer D How to Read a Study Record
.....
Purpose
This was a randomized, ooume-ojno, placebo-controlled, z-arm, t-year study of participants Who completed the EXCELS study (NCT00252135) and had received
did not participate in the EXCELS study but received long-term (-5 years) treatment with xoiair were allowed to enter the study.
-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
Access from www.clinicaltrials.gov/ct2/show/NCT01125748, July 9, 2015

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

Cost: a major obstacle
/ Omalizumab
/ Omalizumab
l) f11'i,a;lJf11'iL"ll1i1-l inhaled corticosteroid 'el-lvi1'lvf
I
LUU
'iUfi'i'ilJ
'IJ
llR::ijiJ'i::Vlfifl1YilJ1f1f111Vhuu'elLUUuu
'IJ q
'i1lJVl-J1(?lt-JRrl11lJ
V
i1 uruvt11'irivt'eluiirn6llu'iuLl'i-J
q
L-w'elu'i::
LiJur111lJ1Luu"1J'el-J
l; 1lgE
Anti 'el11.J"1
urnsu m
J 2) Vl1f1:: 1'iill1U1 Omalizumab lJ'i'i Luuru;u1V1in LL1'1'16ll1
q
I
'lUf1'illiU1U severe uncontrolled asthma vi11J [;)'ellJU'el-J 'el

" f11'iff1H1 I
[;11lJ lllJ1JlJ1 rl1'if11V1Urn'lvf ij Lf1illf11'iL'li81 LLR:: inHru:: "ll'el-J ,,

u1uvi
..
[;)'i 1U
/ Omalizumab
/ Omalizumab
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
Thank you for your attention

Antiimmunoglobulinetherapy 150712105317 Lva1 App6892

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Antiimmunoglobulinetherapy 150712105317 Lva1 App6892

Uploaded by

Copyright:

Available Formats

Anti Immunoglobulin E Therapy

Suda Sibunruang, M.D.

lg Non Trac 3 Monome Naive B

lg lgG1-4 13. 2 Monome Opsonization,

lg Non Trac 3 Monome Naive B

lg lgG1- 13. 2 Monome Opsonization,

Large amount of FcRI on cell surfaces:

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80

Composed of 5% murine sequences that were

Binds to heavy-chain constant CH3 domain

Same site by which IgE binds to FcRI

Holgate ST. Q J Med 2004;97:247- 57

Soluble, inert immune complexes that are subsequently cleared

Owen CE. Pharmacology & Therapeutics 2007;113:12133

Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80

Goto the Go to the

Picture from www.xolair.com, access July 2015

Indicate additional modulatory effects of omalizumab

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

Obj: To assess effects on airway wall thickness using CT

Results: Significantly decreased WA/BSA, WA%, T/ BSA

Hoshino M, et. al. Respiration 2012;83:520-8

Obj: To assess effects on airway wall thickness using CT

and airway inflammation

Results: Significantly decreased WA/BSA, WA%, T/ BSA

Hoshino M, et. al. Respiration 2012;83:520-8

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

Method: randomized to receive omalizumab

Omalizumab significantly improved asthma-related

Humbert M., et. al. Allergy 2005:60:30916

Hospital Number 0.24

Omalizumab Control Difference Ratio p-value

Exacerbation rate* 0.91 1.47 38% 0.617 (0.535-0.712) <0.001

AQLQ (change from baseline, (n=1,221) (n=1,032)

Bousquet J., et. al. Allergy 2005:60;3028

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

Protocol-defined asthma exacerbation was worsening asthma symptoms

Hanania NA, et. al. Ann Intern Med 2011;154:573-82

Outcome Placebo (n = 120) Omalizumab (n = 126)

Reduction in fluticasone dose (%)

Patients with 100% reduction in fluticasone dose (%} 15.0 21.4

Fewer patients experienced asthma exacerbations

Serious adverse events were observed in 1.4% of

Vignola AM, et. al. Allergy 2004;59:709-17

Efficacy of omalizumab in reducing DNSSS

Tsabouri S. et. al. J Allergy Clin Immunol Pract 2014;2:332-40

943 pts with uncontrolled persistent allergic asthma

Evaluate effectiveness variables (physicians Global

69.9% responded after 16 (1) wks

Symptoms and rescue medication use at Month 24

Acceptable safety profile

GETE: overall clinical evaluation of asthma control at 16 weeks,

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

Price D. Primary Care Respiratory Journal 2008;17: 62-72

Patient 2:.12 years?

Multiple documented severe exacerbations?

FEY, <80% predicted

Skin-prick test positive?

Consider treating with omalizumab Patient not suitable for omalizumab

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

-10 Omalizumab Placebo

Garcia G., et. al. Chest 2013;144:4119