anti-ige treatment in severe asthma
TRANSCRIPT
AntiAnti --IgE Treatment In Severe AsthmaIgE Treatment In Severe Asthma
Thomas B. Casale, MDProfessor of Medicine
Chief, Allergy/ImmunologyCreighton University
Omaha, NE
Relevant DisclosuresRelevant Disclosures
•Financial Relationship/Consulting Fees:
Value< $10,000: MedImmune,
• Research: All grants to Creighton University: Amgen, Novartis, Genentech, NIH, State Of Nebraska
• Legal Consult/Expert Witness: None
• Organizational: EVP of AAAAI and BOD WAO• Gifts: None
• Other: N/A
Objectives
� To explain the rationale behind IgE blockade
� To consider which patients benefit
� To address how to assess response to treatment
The First Question
• What is severe asthma?
• Answer: –Depends upon who is asking and why
WHO Definition Of Severe AsthmaWHO Definition Of Severe Asthma
• Defined by the level of current clinical control an d risks which can result in frequent severe exacerbations and/or adverse reactions to medications and/or chronic morbidity.
• 3 groups, each carrying different public health messages and challenges. – Untreated severe asthma– Difficult to treat asthma– Treatment resistant severe asthma
• Controlled on high dose medication • Not controlled on high dose medication
Bousquet et al, JACI 2010
2009 ATS/ERS Task Force On Severe Asthma Definition
• Asthma which requires treatment with high dose ICS (fluticasone > 1000 mcg/d or equivalent) plus a 2 nd controller (and/or systemic CS) to prevent a patient from becoming “uncontrolled” or which, despite high dose therapy, remains “uncontrolled“.
Uncontrolled Asthma– Any one of the following:
• Poor symptom control: ACQ consistently >1.5 (or “not well controlled” by NAEPP guidelines)
• Frequent exacerbations: 2 or more bursts of systemic CSs (>3 days each) in previous year
• Severe exacerbations: at least 1 hospitalization, ICU stay or mechanical ventilation in previous yr
• Persistent airflow limitation: pre-short and long acting bronchodilator FEV1< 80% predicted (in the face of reduced FEV1/FVC)
2009 ATS/ERS Task Force On Severe Asthma Definition
Second Question
What Is the Role of IgE in Severe Asthma?
Secretion and
Epithelial Permeability
AllergensBacteria
Histamine,
LTC4
and
PGD2
IgE
Immune-cell
Recruitment
and
activation
Neutrophil
Mast Cell
Histamine,
LTC4,
Chymase, and
heparin
Histamine, PGD2,
and proteases
Epithelium
TNF TGFβ and FGF
Fibroblasts
Wound healing
and fibrosis
ILs-3,4, 5,6,8,9,11,13TNF-αααα, MIP1, MCP
Blood flow
coagulation
and vascular
permeability Blood vessel
endothelium
Eosinophil B-cell T-reg Cell
Nerve cellSmooth
Muscle
Cell
Immune cell
activation and recruitment
Neuroimmune interactions,
Peristalsis bronchoconstriction
and pain
IgEIgEIgEIgEIgEIgEIgEIgE-------- Mediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic ReactionsMediated Allergic Reactions
Adapted from Bischoff, Nature Immunol, ‘07
Prevalence of Asthma Related to Serum Prevalence of Asthma Related to Serum IgE Level Standardized for Age and GenderIgE Level Standardized for Age and Gender
Age 6 to <35 years
Age 35 to <55 years
Age 55+ years
< -1.5 -1.5 to <-0.5 -0.5 to <0.5 0.5 to <1.5 ≥≥≥≥1.5
Ranges of serum IgE Z score
0
10
20
30
40
Pre
vale
nce
of A
sthm
a (%
)
Burrows B, et al. N Engl J Med 1989; 320: 271-7.
Longitudinal Association Between IgE & Lung Function in Adult Asthmatic Non-Smokers
Sherrill DL, et al. Am J Respir Crit Care Med 1995;152:98-102.
Log IgE = 0.8Log IgE = 1.75
55
65
70
75
80
85
35 75
Age (yrs)Age (yrs)
FE
V1/
FV
C (
%)
The Relationship between IgE and FcεεεεRI Expression
Fractional increase over Day 21
0
3.0
0
Incubation time (days)
2.5
2.0
1.5
1.0
0.5 Log fluorescence
Cou
nt
IgE (500 ng/mL)
IgE absence
1 2 3 4 5 6 7
MacGlashan D, et al. Blood 1998;91:1633-43.
Atopicasthmatics
Non-atopicasthmatics
Atopiccontrols
Non-atopiccontrols
180
160
140
120
100
80
60
40
20
0
Fc εε εε
RI+
(22
E7)
cel
ls/m
m2
p=0.001p=0.006
p=0.0006
p=0.02
170
160
30
20
10
0
Asthma Patients
Controls
Saline Allergen Saline Allergen
Fc εε εε
RI αα αα
mR
NA
+ ce
lls (
x 10
6ce
lls)
FcFcεεεεεεεεRI Expression Upregulated in AsthmaRI Expression Upregulated in Asthma
Rajakulasingam K, et al. Am J Respir Crit Care Med 1998;158:233-40.Humbert M, et al. Am J Respir Crit Care Med 1996;153:1931-7.
Expression of High-Affinity IgE ReceptorIncreased in Fatal Asthma
302328
Fatal Asthma(n=10)
Non-Pulmonary Deaths(n=9)
Fc εε εε
RI r
ecep
tor
expr
essi
on in
la
min
a pr
opria
(+
cells
/mm
2 )
Mild Intermittent Asthma †
(n=16)
1200
1000
800
600
400
200
0
1085*
*P<0.05 vs other groups.†Biopsy
Fregonese L, et al. Am J Respir Crit Care Med. 2004;169:A297.
Mechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of OmalizumabMechanisms Of Action of Omalizumab
���� airway eosinophils, mast cells,
basophils, T + B lymphocytes
���� IgE+, FcεεεεRI+, IL-4+cells in
bronchial epithelium
���� response to allergen skin test
���� eNO
Lung Ag Challenge
���� free IgE, IgE bound toFceRI, and FceRI expressionon mast cells, basophils,dendritic cells,monocytes
Omalizumab Down-Regulates Fc εεεεRI Expression on Dendritic Cells in SAR
Omalizumab Placebo
0
>100
0 7 2814Study day
25
50
75
42
0 7 2814 420
150300450
>600FcεεεεRIαααα (MFI)
0 7 2814Study day
42
0 7 2814 42
0
>100
25
50
75
0150300450
>600
pDC1
pDC2
*
*****
***
* ***
*
*p<0.05; **p<0.01; ***p<0.001 vs Day 0
FcεεεεRIαααα (MFI)
Prussin C, et al. J Allergy Clin Immunol 2003;112:1147-54.
Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation Effects Of Omalizumab On Airway Inflammation In Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic AsthmaticsIn Mild Atopic Asthmatics
� 5555----center, double blind , placebocenter, double blind , placebocenter, double blind , placebocenter, double blind , placebo----controlled, parallelcontrolled, parallelcontrolled, parallelcontrolled, parallel----group, 16group, 16group, 16group, 16----week study (n=44) :week study (n=44) :week study (n=44) :week study (n=44) :
•Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5Reduction in submucosal eos: 8.0 to 1.5
•10101010----fold reduction in IgE+cellsfold reduction in IgE+cellsfold reduction in IgE+cellsfold reduction in IgE+cells---- Decreases in FCDecreases in FCDecreases in FCDecreases in FCεεεεRI cellsRI cellsRI cellsRI cells
•Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and Decreases in B cells, and CD3+, CD4+, and CD8+ cells CD8+ cells CD8+ cells CD8+ cells ……………………
•implies that IgE plays an important role in implies that IgE plays an important role in implies that IgE plays an important role in implies that IgE plays an important role in airway inflammation in asthmaairway inflammation in asthmaairway inflammation in asthmaairway inflammation in asthma
R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004R Djukanovic, et al, AJRCCM,170:583,2004
Omalizumab Decreases Fc εεεεRI in Bronchial Biopsies
PrePre--OmalizumabOmalizumab PostPost --OmalizumabOmalizumab
Djukanović R, et al. Am J Respir Crit Care Med 2004;170-583-93.
Omalizumab Significantly Reduces Submucosal Eosinophils
Eos
inop
hils
(ce
lls/m
m2 )
Baseline Post-treatment0
20
60
8080
60
20
0
4040
Baseline Post-treatment
8.01.5
6.3 6.4
Placebo (n=14)Omalizumab (n=14)
p<0.001
p=0.81p=0.033
Djukanović R, et al. Am J Respir Crit Care Med 2004;170-583-93.
Clinical Effects Of Omalizumab:Clinical Effects Of Omalizumab:Pooled data from 7 trialsPooled data from 7 trials
� In patients on ICS alone, or in combination with ot her agents, addition of omalizumab:�Reduced number of exacerbations
�Reduced symptom scores
�Reduced need for inhaled corticosteroids
�Reduced use of rescue medication
� Improved asthma-related quality of life
� Consider using in patients with poor control despit e optimal care
11Busse W et al. Busse W et al. J Allergy CLin ImmunolJ Allergy CLin Immunol 2001;108:1842001;108:184 --90.90.22Soler M et al. Soler M et al. Eur Respir J Eur Respir J 2001;18:2542001;18:254 --61.61.33Humbert M, et al. Humbert M, et al. AllergyAllergy 2005;60:3092005;60:309 --16.16.
Effects Of Omalizumab On Exacerbations
G Rodrigo et al, Chest, 2010
Effects Of Omalizumab on Secondary Endpoints
G Rodrigo et al, Chest, 2010
Omalizumab effect was independent of:Omalizumab effect was independent of:
� Duration of treatment� Age� Severity of asthma
Omalizumab In Children 6 - 11
Lanier et al. JACI.2009;124:1210-6
Avg FP dose 515 mcg2/3 on LABA1/3 on LTRA
Effects Of Omalizumab In Elderly
All on high dose ICS & 50% on OCS
S Korn et al, Ann Allergy Asthma Immunol. 2010;105:313–319.
Steps of Therapy: Age Steps of Therapy: Age ≥≥12 Years12 Years
Steps of Therapy: Age Steps of Therapy: Age ≥≥12 Years12 Years
Interm ittentAsthm a
Persistent Asthm a: Daily M edicationConsult w ith asthma specialist if step 4 care or hi gher is required.
Consider consultation at s tep 3.
Step 1Preferred:
SABA PRN
Step 2Preferred:
Low-dose ICS
Alternative:
Cromolyn, LTRA,Nedocrom il, or Theophylline
Step 3Preferred:
Low-doseICS + LABA
OR
Medium-dose ICS
Alternative:
Low-dose ICS + either LTRA, Theophylline, or Zileuton
Step 5Preferred:
High-dose
ICS + LABA
AND
Consider
Omalizumab for
patients who have
allergies
Step 6Preferred:
High-dose
ICS + LABA + oral
corticosteroid
AND
Consider
Omalizumab for
patients who have
allergies
Step up if
needed
(first, check
adherence,
environmental
control, and
comorbid
conditions)
Step down if
possible
(and asthma is
well controlled
at least
3 months)
Step 4Preferred:
Medium-dose ICS
+ LABA
Alternative:
Medium-dose ICS
+ either LTRA,
Theophylline, or
Zileuton
Assess
control
Quick-Relief Medication for All Patients
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals
as needed. Short course of oral systemic corticosteroids may be needed.
• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step
up treatment.
Each step: Patient education, environmental control, and management of comorbidities.
Steps 2−4: Consider subcutaneous allergen imm unotherapy for patients who have allergic asthma (see notes).
Dosing Table:Dosing Table:0.016 mg/kg/IU/mL every 4 weeks0.016 mg/kg/IU/mL every 4 weeks
>> 100100--200200 450450
>> 200200--300300 450450 450450 450450 600600
>> 300300--400400 450450 450450 600600 600600
>> 400400--500500 600600 600600 750750 750750
>> 500500--600600 600600 750750
>> 600600--700700 750750
Body Weight (kg)
Mon
thly
Dos
ing
Biw
eekl
y D
osin
g
Omalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In AsthmaOmalizumab Onset Of Action In Asthma
Asthma trials suggest that 8 to 16 weeks of treatment might be a reasonable therapeutic trial:
� While the onset of response was measurable at 4 weeks, the proportion of responders continued to increase throughout the 16 week period:
4 wks: 61%8 wks: 78%12 wks: 87%
Factors Predictive of Response to Factors Predictive of Response to OmalizumabOmalizumab
Bousquet J, et al. Chest. 2004;125:1378-1386.
1.87*(0.88 – 3.99)°
N = 120
2.25(1.02 – 4.97)
N = 103
3.54(1.69 – 7.43)
N = 124
1.15(0.54 – 2.44)
N = 114
1.60(0.75 – 3.42)
N = 119
3.38(1.32 – 8.66)
N = 77
4.20
(1.69 – 10.45)
N = 85
BDP dose ≥≥≥≥ 800 µg/day
History of emergencyasthma treatment in past year
FEV1 ≤≤≤≤65% predicted
*Relative Rate(Confidence Interval)
Dose (mg/kg/IgE (IU/mL)) Dose (mg)
**
**p<0.002 vs placebo
Adequate IgE Suppression is NeededAdequate IgE Suppression is Neededto Demonstrate Clinical Responseto Demonstrate Clinical Response
25ng/mLtarget
Serum free IgE (ng/mL)
50mg150mg300mg
0
400
300
200
100
0.001 0.01 0.1
Placebo
0 50 150 300
Average nasal severity scores
1.1
1.0
0.9
0.8
0.7
Casale, JAMA “01
Factors Predictive Of Clinical Response
• Reasons for omalizumab being ineffective for some (~40%) patients are unknown.
• Improvements correlate with IgE reductions, BUT
free IgE levels in nonresponders are similar to those found in responders1
• Possible reasons:2
(1) Relationship between free IgE levels and FcεR1 expression
(2) Ratio of specific IgE to total IgE
(3) Intrinsic cellular sensitivity.
1. Slavin, et al. JACI . 2009;123:1072. MacGlashan. JACI 2009;23: 114
Do the Effects Of Omalizumab Continue After Treatment Is Stopped?
• Conflicting data, but may depend upon duration of treatment
• 2 different studies with 2 different answers:1. INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study2. Nopp et al, 2010 Allergy
28-week Omalizumab Treatment And 16-week Follow-up
N=476,Dark=Omal, Light=Pl
Slavin, et al. JACI . 2009;123:107
Effects Of Omalizumab On Asthma Control 3 Years After 6 Years Treatment
A Nopp et al, Allergy 2010
Omalizumab and Asthma Summary• Omalizumab is effective in children and adults
in reducing exacerbations and steroid requirements– Also positive effects on SABA use, QOL, Sxs
and PFTs (minor)• Omalizumab has anti-inflammatory effects• If not effective by 4-6 months, probably will not
be effective– Predictors of who will respond are unclear
• Whether omalizumab can be stopped with sustained clinical efficacy is unclear– May depend on duration of treatment
Other Potential Clinical Uses of Omalizumab In Asthma
• SAR and PAR +/- Asthma
• Non-allergic Asthma
•ABPA
• Adjuvant to Traditional Immunotherapy:
•Increased Efficacy As Add On in SAR
•Improved Safety As Pretreatment:
• 80% Decr In RIT Assoc Anaphylaxis in SAR
• 50% Decr In Cluster Assoc AEs in Asthma
Omalizumab Cluster IT
Placebo
Maintenance IT
Maintenance ITCluster IT
Screening
Period 1 Period 2 Period 3 Period 4
3 wk overlap
Omalizumab and Immunotherapy:Omalizumab and Immunotherapy:Study DesignStudy Design
150 Patients per arm, Randomized 1:1
Visit 0 Visit 1 Visit 5 Visit 11 Visit 14 Visit 19
-2wks 0 13wks 16 wks 17 wks 24 wks
Persistent perennial allergic asthmatics requiring ICS & FEV1 > 75%
26.2%
13.5%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
Placebo OmalizumabN=122 N=126
P= 0.017
N = 17N = 32
Proportion of Patients Who Experienced AProportion of Patients Who Experienced ASystemic Allergic Reaction: Primary EndpointSystemic Allergic Reaction: Primary Endpoint
M Massanari et al, JACI, 2010
6
0
24
2
7
26
2
0
5
10
15
20
25
30
Grade 1 (Skin) Grade 2 (GI) Grade 3(Resp)
Grade 4 (CV)
Num
ber
of P
atie
nts
Placebo (n=32) Omalizumab (n=17)
Severity of First Systemic Severity of First Systemic Allergic ReactionAllergic Reaction
M Massanari et al, JACI, 2010
Omalizumab and IT Conclusions
• Pretreatment with omalizumab:• Added Efficacy to SCIT•Added Safety to SCIT•Allowed more patients to reach maintenance
• 87 vs. 72% (p<0.01)
• Unanswered questions:•How long do you need to treat with both?•Can you stop the omalizumab after reaching maintenance IT?
Omalizumab Safety Issues
�Anaphylaxis�Cancer�Cardiovascular�Other?
Major Unanswered Question
� If Anti-IgE Prevents Anaphylaxis By Decreasing Circulating and Bound IgE…..
� And IgE is essential for development of anaphylaxis…… ..
How does it cause anaphylaxis?????- Incidence ~0.1 to 0.2%
ConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusions
� Since IgE plays an important role in a number of Since IgE plays an important role in a number of Since IgE plays an important role in a number of Since IgE plays an important role in a number of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of diseases, strategies aimed at blocking the effects of it will likely prove importantit will likely prove importantit will likely prove importantit will likely prove important…………........• Not just for asthma and rhinitisNot just for asthma and rhinitisNot just for asthma and rhinitisNot just for asthma and rhinitis
� Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic Omalizumab has many potential therapeutic applicationsapplicationsapplicationsapplications• On going safety issues need to be monitoredOn going safety issues need to be monitoredOn going safety issues need to be monitoredOn going safety issues need to be monitored
� Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should Small, easy to make and deliver antagonists should be pursued, especially those thatbe pursued, especially those thatbe pursued, especially those thatbe pursued, especially those that…………....• Induce toleranceInduce toleranceInduce toleranceInduce tolerance