Transcript Omalizumab Placebo

Anti-IgE in Asthma and Other Allergic
Diseases
Harold S. Nelson. MD
Professor of Medicine
National Jewish Health
And University of Colorado School
of Medicine.
Denver. Colorado, USA
Pivotal Trials: Study Design
BDP
Optimization
Placebo or
Omalizumab +
Stable BDP
Run-In
Phase
Stable-Steroid
Phase
4-6 Weeks
16 Weeks
Randomization
Placebo or
Omalizumab
+ BDP reduction
Placebo or
Omalizumab
 BDP
Steroid-Reduction Double-Blind
Phase
Extension Phase
12 Weeks
24 Weeks
Efficacy
28 Weeks Total
Safety
52 Weeks Total
Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261.
Baseline Asthma
Characteristics
008
009
OMAL
n = 268
Placebo
n = 257
OMAL
n = 274
Placebo
n = 272
Asthma, yr
21 (13)
23 (15)
20 (14)
19 (13)
IgE, IU/mL
172 (141)
186 (142)
223 (169)
206 (161)
BDP daily dose, µg
570 (149)
568 (148)
646 (199)
649 (222)
Rescue b2, puffs/day
5 (3)
5 (3)
4 (3)
5 (3)
Total asthma symptom
score, 0 to 9
4 (1)
4 (1)
4 (1)
4 (1)
68 (15)
68 (14)
70 (15)
70 (15)
2
4
4
7
10
14
12
10
Baseline characteristic†
FEV1, % of predicted
Hospitalized for asthma
past yr, %
ER visit for asthma
past yr, %
†Mean (SD) unless otherwise indicated.
Reduction in Asthma
Exacerbations
Stable steroid phase
16 wk
0.7
0.6
0.66
P=
.006†
0.54
0.5
0.4
0.3
0.8
P < .001†
0.28
0.28
0.2
0.1
0
Study 008
Study 009
Omalizumab
Mean exacerbations per patient
Mean exacerbations per patient
0.8
Steroid-reduction phase
12 wk
P < .001†
0.75
P = .003†
0.66
0.7
0.6
0.5
0.4
0.39
0.36
Study 008
Study 009
0.3
0.2
0.1
0
Placebo
†van Elteren test; protocol-defined analysis with imputation.
Proportion of patients
exacerbation free
Time to First Asthma
Exacerbation
009
008
1.0
1.0
0.75
0.75
0.50
P = .0067†
HR = 0.63
0.50
0.25
0.25
0
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
P = .0001†
HR = 0.51
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time since randomization
OMA
L
Placebo
Reduction in Inhaled Steroid Use
Studies 008 and 009 (Combined)
Xolair
Placebo
P < .001†
50
41.3
Patients, %
40
35.5
34.3
27.8
30
20
19.3
17.4
10.9
13.5
10
0
100%
50% - 99%
1% - 49%
BDP reduction from baseline at wk 28
BDP = Beclomethasone dipropionate.
†van Elteren test.
² 0%
Reduction in Albuterol Use
009
008
Puffs per day, n
5
5
4
4
NS
NS
3
NS
*
NS
NS NS
2
3
* * *
2
1
1
0
0
0
4
8
12
16
20
24
28
*
0
4
8
*
12
* * * * *
16
Time, wk
Time, wk
Xolair™
*P  .05, van Elteren test.
*
Placebo
20
24
*
*
28
Reduction of Symptoms
Asthma symptom scores
008
4.0
Nocturnal symptom scores
008
2.0
3.0
1.5
*
2.0
*
*
* * * * * * *
1.0
1.0
NS
0.5
*
0.0
0
4
8
4.0
3.0
12 16 20
Time, wk
009
24
28
*
0.0
0
4
8
* * * * * * *
12
16
Time, wk
2.0
20
24
28
009
1.5
*
2.0
*
1.0
*
* *
* * * * *
1.0
*
0.5
*
0.0
0
4
8
12 16 20
Time, wk
*P  .05, van Elteren test.
24
28
0.0
Omalizumab
0
4
Placebo
8
*
* *
* * * * *
12
16
Time, wk
20
24
28
Improvement in Pulmonary
Function
009
Mean FEV1 % predicted
008
75
75
*
70
*
*
**
***
**
65
60
60
0
4
8
12 16 20 24 28
Time since randomization, wk
Omalizumab
*P ≤ .05, ANCOVA.
*
70
65
-8 -4
NS
-8
-4
0
4
*
8
*
* *
* * *
*
12 16 20 24 28
Time since randomization, wk
Placebo
Omalizumab: Mechanisms of Action
1. Omalizumab binds to the IgE molecule preventing its
interaction with IgE receptors on inflammatory cells.
2. The fall in free-IgE leads to down regulation of FcεRI on
basophils, mast cells and plasmacytoid dendritic cells.
3. The release of pro-inflammatory cytokines from
basophils and mast cells is decreased.
4. The effect on pDCs may reduce allergen presentation to
T-cells.
4. There is a decrease in levels of blood, tissue and sputum
eosinophils.
S Holgate, et al. Allergy 2009;64:1728-36
Omalizumab in Patients with Severe
Persistent Asthma
 Data was pooled from 7 studies, with 4,308 subjects,
93% with severe persistent asthma.
 Mean baseline values:
ICS 1462 mcg BDP,
LABA use by 57%,
FEV1 70% predicted
 Exacerbations (90% treated with OCS)
Omalizumab 0.91/year Placebo 1.47/year
 Emergency Department Visits
0.026/y vs. 0.066/y
 Hospitalizations
0.03/y vs. 0.06/y
- 38%
p<.00001
- 61%
p = 0.013
- 50%
p = 0.04
J Bousquet, et al. Allergy 2005;60:302-8
There Are No Predictors of a Good
Response to Omalizumab
J Bousquet et al. Allergy 2005;60:302-8
Omalizumab in Children
• 627 children ages 6 to 11 years with
asthma not fully controlled on ≥ 200 mcg
FP/d plus history of ≥ 2 exacerbations or ≥
1 hospitalization in last year.
• Randomized 2:1 omalizumab: placebo for
52 weeks, steroid stable first 24 weeks.
• Exacerbation defined as doubling dose
ICS or oral CS ≥ 3 days.
B Lanier, ex al. J Allergy Clin Immunol
2009;124:1210-6
:
Omalizumab in Children:
Exacerbation Rate
24 WEEKS
52 WEEKS
Omalizumab
0.45
0.78
Placebo
0.64
1.36
% reduction / p value -31%/0.007
B Lanier, ex al. J Allergy Clin Immunol
2009;124:1210-6
-43%/0.001
Omalizumab Safety:
Anaphylaxis
• A joint task force of the AAAAI and
ACAAI reviewed all post-marketing
reports to the FDA from 1 June 2003 to
December 31 2005.
• 35 patients experienced 41 episodes of
anaphylaxis
• This represented 0.09% of patients
receiving omalizumab.
Omalizumab Safety:
Anaphylaxis
Timing
1-3rd Dose
≥ 4th Dose
Total
< 30 min
30-60 min
1-2 hours
2-12 hours
11
6
5
4
5
1
0
1
16
7
5
5
> 12 hours
Unknown
Total
3
3
32
0
2
9
3
5
41
L. Cox, ex al. J Allergy Clin Immunol 2007120:13737
Omalizumab Safety:
Recommendations for Administration
• Patient should sign informed consent.
• Patient should be instructed in administration
of auto-injected epinephrine and carry for 24
hours after each dose of omalizumab
• Patients should remain under observation for
2 hours after the first 3 administrations, then
30 minutes after each subsequent
administration.
L. Cox, ex al. J Allergy Clin Immunol 2007120:1373-7
Omalizumab:
Unapproved and Unproven Uses
• Seasonal & perennial allergic rhinitis
• Chronic urticaria:
- Autoimmune (JACI 2008;122:569-73)
- Non-autoimmune (JACI 2010;126:664-5)
- Delayed pressure, dermagraphism, cholinergic
• Food allergy (Allergy Asthma Proc 2010;31:76-83)
• Chronic sinusitis (JACI 2008;121:257-8)
• Atopic dermatitis (Allergy Asthma Proc
2008;29:530-7)
• Allergic bronchopulmonary Aspergillosis (Ped
Pulmonol 2009;44:516)
Omalizumab:
Unapproved and Unproven Uses
• Idiopathic anaphylaxis Ann Allergy Asthma Immunol
2009;102:257-8)
• Fire ant anaphylaxis (immunotherapy failure) (JACI
2010;126:664-5)
• Occupational latex sensitivity (JACI 2004;113:360-1)
• Systemic mastocytosis (JACI 2010;126:415-6)
• Systemic mastocytosis plus anaphylaxis to bee sting
(Allergy 2009;64:1384-5)
• Adjunct to hymenoptera immunotherapy (Allergy
2007;62:963-4).
• Insulin allergy (N Engl J Med 2009;360:1045-7)
Omalizumab as an Adjunct in
Allergen Immunotherapy
Omalizumab Pretreatment Decreases
Acute Reactions after Rush
Immunotherapy for ragweed-induced
Seasonal Allergic Rhinitis
TB Casale, et al J Allergy Clin Immunol 2006;117:134-40
123 adults with ragweed allergic rhinitis
 Pretreated with 9 weeks of omalizumab or placebo
1 day rush immunotherapy to top dose of 1.2 mcg
Amb a 1
 Followed by 12 weeks of combined omalizumab or placeb
and weekly immunotherapy with increase in dose to 12 mcg
Amb a 1.
Reduction of IgE by Pre-Treatment with
Omalizumab: Results
 Anaphylaxis risk vs. placebo during RIT:
IT alone
OR 12.1
Om plus IT
OR 2.1
 Anaphylaxis risk vs. placebo during weekly buildup:
IT alone
9.7%
Om plus IT
0%
TB Casale, et al. J. Allergy Clin Imm 20061117:134-40
Effect of Pretreatment with
Omalizumab on the Tolerability of
Specific Immunotherapy in Patients
with Persistent Symptomatic Asthma
Inadequately Controlled with Inhaled
Corticosteroids
Massanari M, Nelson H, Casale T, Busse W,
Kianifard F, Geba G, Zeldin R
Omalizumab as an Adjunct to
Immunotherapy: Study Design
 Subjects with at least moderate persistent
allergic asthma.
- Symptomatic on inhaled corticosteroids
- FEV1 ≥ 75% predicted
- Positive prick skin test to cat, dog or house
dust mite standardized extract.
 Excluded for severe asthma, oral
corticosteroid-requiring exacerbation within 3
months, ED visit or hospitalization within 6
months.
Xolair and Immunotherapy: Study Design
275 Patients, Randomized 1:1
Omalizumab
Cluster IT
Maintenance IT
Placebo
Cluster IT
Maintenance IT
Screening
3 wk overlap
Period 1
Visit 0
-2wks
Period 2
Visit 1
0
Period 3
Visit 5 Visit 11
13wks 16 wks
Period 4
Visit 14
17 wks
Visit 19
24 wks
Change in Average Total Asthma Symptom
Score Before Initiating Immunotherapy
Baseline Mean
Score
(Day -14 to Day -1)
1.15
Omalizumab
0.0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
N=124
1.17
Placebo
N=119
-0.47
-0.70
Change From Baseline to Visit 5 in Total
Average Asthma Symptom Score
(Average total symptom score Day 91 to Day 97)
Proportion of Patients Who Experienced a
Systemic Allergic Reaction
Percent of Patients with SARs
30%
25%
26.2%
P= 0.017
20%
15%
13.5%
10%
5%
N = 17
N = 32
0%
Omalizumab
Placebo
N=126
N=122
SARs in Patients According to Average Total Asthma
Symptom Scores* Pre Immunotherapy
Percent of Patients with SARs
35%
32.4%
30%
25%
20%
17.6%
16.7%
15%
8.8%
10%
5%
0%
0 (N=116)
Omalizumab
*Average total symptom score Day 91 to Day 97
> 0 (N=128)
Placebo
Severity of First Systemic
Allergic Reaction
Number of Patients
30
24
25
20
15
10
7
6
5
6
2
2
0
2
0
Grade 1 (Skin)
Grade 2 (GI)
Omalizumab
N=17
Grade 3
(Resp)
Placebo
N=32
Grade 4 (CV)
Proportion of Patients Who Experienced a
Systemic Allergic Reaction According to
Allergen Sensitivity
Percent of Patients with SARs
35%
31.9%
30%
24.0%
25%
20%
17.6%
15.2%
14.4%
13.3%
15%
10%
5%
N=16
N=25
N=11
N=15
N=14
N=29
0%
Cat
N=209
Dog
N=168
HDM
N=188
Omalizumab Placebo
15 g Fel d 1, 15 g Can d 1, 7 g Der p 1
Percent of Patients who Achieved
Target Maintenance IT Dose
p=0.004
100%
Percent of Patients
90%
87.3%
72.1%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Omalizumab (N=126)
Placebo (N=122)
Conclusions
 Pretreatment with omalizumab
significantly reduced systemic allergic
reactions from IT
 Pretreatment with omalizumab resulted in
a clinically meaningful shift in severity of
systemic allergic reactions from IT
 A significantly higher proportion of
omalizumab patients were able to reach
target maintenance dose of IT
 Omalizumab was well tolerated