1
Phase 2, Multicenter, Double-blind
Study of CNTO 148, a Human
Monoclonal anti-TNFα Antibody, in
Symptomatic Patients with Severe
Persistent Asthma
Sally Wenzel, MD
Director of Asthma and Allergic Diseases
University of Pittsburgh
for the T03 Investigators
September 16, 2007
16 Sep 2007 Wenzel 2
Conflict of Interest Disclosure
• Centocor Consultant
16 Sep 2007 Wenzel 3
Trial Organization
•Steering Committee •Independent Safety
Sally Wenzel, PI Monitoring Committee
Pascal Chanez, Co-PI Dirkje Postma, Chair
Peter Barnes William Calhoun
Eugene Bleeker Sebastian Johnston
Jean Bousquet David Salzburg
William Busse
Sven-Erik Dahlen •Data Management
Steven Holgate Centocor
Deborah Meyers
Klaus Rabe •Monitoring
Quintiles
•Pharmacogenomic Core lab
Wake Forest
16 Sep 2007 Wenzel 4
Severe Asthma,
Unmet Needs and TNF
• Severe asthma
Small percentage of asthma population, but
drives up to 50% of costs of disease
Poorly understood mechanisms
Likely heterogeneous
Refractory to current therapies
16 Sep 2007 Wenzel 5
Current Therapies of Little Help
10% 1 controller (n=338)
Ever intubated 11%
13%
2 controllers (n=1649)
Overnight hospitalization 6% 3 or more controllers (n=2679)
4%
past 3 mos 7%
Emergency room visit 20%
13%
Past 3 mos 17%
50%
Steroid burst past 3 mos 41%
52%
Unscheduled office visit 49%
41%
past 3 mos 47%
Scheduled office visit past 72%
71%
3 mos 80%
Missed at least 1 day of 21%
12%
work/school in past 2 wks 17%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
Patients (%)
16 Sep 2007 Wenzel 6
Severe Asthma Heterogeneity
• Long realized that “severe asthma”
used to define several different
“phenotypes”
• Now, attempts to define based on:
Frequent exacerbations/variable airflow vs
more “fixed airflow”
Presence or absence of “inflammation”
Allergic component (or not)
16 Sep 2007 Wenzel 7
TNF
Role in Human Asthma
• TNF increased in BAL fluid, airway
tissue cells (mast cells and
macrophages) and increased from
alveolar macrophages at time of late
asthmatic/allergic response
Ying 1991, Gosset 1991
• Released from macrophages following
IgE stimulation
Gosset 1992
16 Sep 2007 Wenzel 8
Effects of TNF in Asthma
• TNF increases smooth muscle
contractile responses in vivo and in vitro
No direct contractile activity
• Believed to be involved in neutrophil influx
LPS
IL-17?
• Co-operates with Th2 cytokines
16 Sep 2007 Wenzel 9
Airway Hyperreactivity
• One of hallmark features of asthma
Often associated with reversibility to beta agonists
But, poorly associated with airway obstruction
• May drive many of symptoms of asthma
• Thought to be related to BD
responsiveness, as well as peak flow
variability
16 Sep 2007 Wenzel 10
SARP: Relation of PC20 to BD
Responsiveness
• Severe Asthma
Research Program 1.6
PC20
(SARP, spons NHLBI)
mg/ml 1.4
>250 severe asthma P=0.01
1.2
subjects from US/UK
1
BD responsiveness
high despite severity 0.8
• Moore JACI 2007 0.6
Strong association of 0.4
bronchodilator 0.2
responsiveness with 0
increased BHR BD12%
• Defines group with more
atopy, higher HCU,
higher FeNO
16 Sep 2007 Wenzel 11
TNF and airway responsiveness
• Acute and single
inhalation of TNF
decreased
methacholine PC20
in majority of
subjects both at 24
and 48 hrs
• Similar results seen
in vitro in tracheal
strips treated with
TNF
Thomas, Thorax 2002,
16 Sep 2007 Wenzel 12
Panettieri 2000
Inhibiting TNF Through Soluble
Receptor Approach (Etanercept)
• Significant improvement
(3.5 doubling doses) in
PC20
Confirms open label results
• Suggests greater effect
on BHR than with ICS
• Seen in association with
reductions in TNF binding
to PBMCs
Berry NEJM 2006
16 Sep 2007 Wenzel 13
TNF and Airway Inflammation
• Inhalation of TNF
associated with
increases in both
neutrophils and
eosinophils (in
asthma)
Thomas Thorax 2002
16 Sep 2007 Wenzel 14
TNF and Mast Cells
• TNF modulation previously shown to
have modest/no effects on murine
allergic inflammation models Rudman 2000
• However, recent mast cell dependent
models appear to show improvement in
inflammation (Th2 and Th17), BHR
when TNF inhibited Nakae JACI 2007
• May explain decrease in histamine
observed in Berry entanercept study
16 Sep 2007 Wenzel 15
Th2 Cytokines and TNF
• TNF +IL-4 synergistically:
Activate and prolong eosinophil survival
Augment induction of ICAM-1 on epithelium
(Striz 1999), VCAM-1 on fibroblasts
Increase eotaxin production from fibroblasts
(Terada 2000)
16 Sep 2007 Wenzel 16
Eosinophil Survival Increases with
TNF + Th2 cytokines
4 days
Luttman W, Am J Resp Cell Mol Bio 1999
16 Sep 2007 Wenzel 17
Cooperative Effects of Rhinovirus and TNF on
Airway Epithelial Cell Chemokine Expression
• Co-stimulation of human bronchial epithelial cells and
primary mucociliary-differentiated tracheal epithelial
cells with rhinovirus and TNF induced synergistic
increases in IL-8 and epithelial neutrophil attractant-78
(CXCR-5) production
• RV39 infection induced phosphorylation of ERK and
transactivation of the IL-8 promoter AP-1 site, which
functions as a basal level enhancer, leading to
enhanced TNF responses
• Conclusion
“RV infection and TNF stimulation induce cooperative
increases in epithelial cell chemokine expression, providing a
cellular mechanism for RV-induced exacerbations of airways
disease”
Newcomb DC, et al. Am J Physiol Lung Cell Mol Physiol. 2007 Jul 13; [Epub ahead of print]
16 Sep 2007 Wenzel 18
Protocol C0524T03
A Phase 2, Multicenter, Randomized,
Double-blind, Placebo-controlled,
Parallel-group, Dose-ranging Study
Evaluating the Efficacy and Safety of
CNTO 148 Administered
Subcutaneously in Symptomatic
Subjects With Severe Persistent Asthma
012407_ Lo_T03-CNTO148 19
Objectives
• Primary:
To determine the efficacy of CNTO 148, measured by pulmonary
function and number of severe asthma exacerbations
• Secondary:
To assess the effect of CNTO 148 on asthma symptoms, rescue
medication use, mild asthma exacerbations, and QoL
To evaluate the maintenance of treatment effect of CNTO 148 during
a steroid taper phase measured by the number of asthma
exacerbations, pulmonary function parameters, asthma symptoms,
rescue medication use, and QoL
To assess the PK and PD of CNTO 148 treatment
To obtain safety information on CNTO 148
To determine the dose(s) of CNTO 148 to be evaluated in Phase 3
trials
16 Sep 2007 Wenzel 20
Major Inclusion Criteria
• Screening clinic FEV1 40% and 80% of predicted
(measured 4 hours post bronchodilator)
• Has evidence of at least one of the following in the 5
years prior to screening or during screening:
Reversible airway obstruction ( 12% change in FEV1
postbronchodilator)
Diurnal variation in PEFR ( 30% change)
Airway hyperresponsiveness
• > 2 OCS-treated asthma exacerbations in last year
• Continuous high dose ICS and LABA for > 3 months
before screening
16 Sep 2007 Wenzel 21
Study Design
Placebo (78 pts)
309 Pts with Severe CNTO 148 sc 50 mg q4w (77 pts)
Persistent Asthma R CNTO 148 sc 100 mg q4w (76 pts)
CNTO 148 sc 200 mg q4w (78 pts)
Screening/Run-in (50% higher dose at week 0 only
in each group as a loading dose)
Study drug
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52… 76
Stable Steroid Steroid Taper Safety
R Randomization Primary Endpoint
Follow Up
16 Sep 2007 Wenzel 22
Co-Primary Endpoints
• FEV1
Change from baseline to week 24 in clinic-measured, percent
predicted FEV1 comparing combined 100+200 mg group with
placebo
• Severe Asthma Exacerbation
Number of severe asthma exacerbations from baseline through
week 24, comparing combined 100+200 mg group with placebo
Worsening asthma requiring treatment with IV or oral
corticosteroid: an addition or increase in OCS dose of ≥ 20 mg/day
from baseline OCS dose
20-30% reduction considered clinically meaningful
79% power to detect a 35% difference in severe exacerbations
assuming 2 exacerbations / year in the placebo group
• Method of Imputation: Any subject who withdrew early from the
study had additional exacerbations imputed based on the worst
outcome of similar patients still in the study
16 Sep 2007 Wenzel 23
Major Secondary Endpoints
• Change from baseline to week 24 in:
Asthma Quality of Life Questionnaire (AQLQ) score
Domiciliary morning Peak Expiratory Flow Rate (PEFR)
Rescue medication (short acting b2 agonist) use
• Number of severe exacerbations between
week 24 and week 52 (corticosteroid taper
phase)
• For subjects receiving oral corticosteroid
(OCS) at baseline, change from baseline to
week 52 in dose of OCS
16 Sep 2007 Wenzel 24
Demographics
Placebo 50 mg 100 mg 200 mg Total
Subjects randomized 78 77 76 78 309
Sex (female) 54% 60% 51% 59% 56%
Race
White 85% 86% 91% 91% 88%
Black 15% 10% 9% 8% 11%
Asian 0% 0% 0% 1% 0%
Other 0% 4% 0% 0% 1%
Age (years)
Mean ± SD 49 ± 12 49 ± 11 49 ± 13 53 ± 12 50 ± 12
Range (23-77) (19-81) (21-78) (27-76) (19-81)
BMI (kg/m2)
Mean ± SD 31 ± 8 30 ± 7 30 ± 8 29 ± 7 30 ± 7
Range (16-55) (18-50) (18-54) (17-50) (17-54)
16 Sep 2007 Wenzel 25
Concomitant Medications:
Screening to Randomization
Placebo 50 mg 100 mg 200mg Total
Subjects randomized 78 77 76 78 309
LABA 100% 100% 100% 100% 100%
High Dose ICS 100% 100% 100% 100% 100%
OCS and
High Dose ISC 32% 33% 33% 31% 32%
Leukotriene modifier 32% 33% 33% 28% 33%
Theophylline 30% 16% 25% 23% 23%
Anticholinergics 21% 21% 12% 15% 17%
Anti-IgE 0% 0% 0% 0% 0%
16 Sep 2007 Wenzel 26
Medical History
• Groups well matched for smoking hx,
sinusitis, allergic rhinitis
• Only 30+% reported h/o positive skin
testing
• Anxiety and depression in 15-25%
• 32% on oral corticosteroids (OCS)
Median dose 12.5-15 mg per group
16 Sep 2007 Wenzel 27
Disease Characteristics at Baseline
Placebo 50 mg 100 mg 200 mg
FEV1 (% predicted) pre 60.9 + 11 59.6 + 11 58.9 + 12 59.8 + 11
(+ SD)
FEV1 (% predicted) 69.6 + 11 69.2 + 14 68.9 + 14 68.8 + 12
post (+ SD)
FEV1 reversibility 15.6 + 15 16.9 + 16 17.8 + 15 15.6 + 14
(+ SD)
ACQ (+ SD) 3.0 + 0.8 3.0 + 0.8 3.1 + 0.8 2.9 + 0.7
AQLQ (+ SD) 4.3 + 1.2 4.0 + 1.1 4.0 + 1.2 4.4 + 1.0
Rescue Med (puffs/day) 4.5 + 3.7 5.0 + 4.0 5.0 + 4.0 4.3 + 4.0
(+ SD)
16 Sep 2007 Wenzel 28
Safety Monitoring Committee
Evaluation
• Based on data at 24 weeks of study, SMC
recommended d/c additional administration
of study drug due to insufficient benefit:risk
profile in overall population
• SMC recommended additional follow up
• Follow up was carried out through 52 weeks
or mid July 2007 (whichever was longer) to
provide at least 1 year of data on all subjects
16 Sep 2007 Wenzel 29
Primary Analyses
16 Sep 2007 Wenzel 30
Co-Primary Endpoint: FEV1
Change from Baseline in Pre-bronchodilator Clinic-
measured FEV1 (% Predicted) with LOCF to Week 24
6
p = 0.357 p = 0.717 p = 0.945 p = 0.802
5
LSMean +/-SE
4
3
2
1
0
Placebo (n=78) 50 mg q4 wks (n=77)
100 mg q4 wks (n=76) 200 mg q4 wks (n=78)
Combined 100 mg & 200 mg (n=154)
Note: Last observation carried forward method was used to impute missing change from baseline values.
16 Sep 2007 Wenzel 31
Co-Primary Endpoint:
Number of Severe Exacerbations
Number of Severe Exacerbations per Subject from
Baseline through Week 24
p = 0.256 p = 0.649 p = 0.779 p = 0.718
30
Percent of
Subjects
20
10
0
(n=78) (n=77) (n=76) (n=78) (n=154)
Placebo 50 mg q4 wks 100 mg q4 200 mg q4 Combined
Treatment Group
# of severe exacerbations = 1 # of severe exacerbations = 2
# of severe exacerbations = 3 to 5 # of severe exacerbations = 6 or more
Note: Imputation using the worst case among similar subjects was applied for subjects who discontinued study participation early.
16 Sep 2007 Wenzel 32
Number of Severe Exacerbations
Total number of severe exacerbations
Through Week 24 (All subjects)
Number of severe exacerbations and imputations
80
70 p1=0.256
p1=0.256 p11=0.649
p =0.649 p =0.779
p11=0.779
p2=0.614 p2=0.246 p2=0.177
60
50
40
30
20
10
0
Placebo (n=78) 50 mg (n=77) 100 mg (n=76) 200 mg (n=78)
Observed
Exacerbations (observed) Added by imputation
Exacerbations with imputation
Both p values are based on CMH row mean score test; p1 is based on imputed data and p2 is based on observed data
16 Sep 2007 Wenzel 33
Severe Exacerbations (observed):
Subjects with >1 through Week 24
Baseline through Week 24
40
p = 1.000 p = 0.099 p = 0.374 p = 0.112
35
Percentage
30
25
20
15
10
5
0
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
P-values are based on Fisher’s Exact test
16 Sep 2007 Wenzel 34
Time to First Severe Exacerbation
Proportion Free from Severe Exacerbations (n=309)
Percent Subjects
100 p=0.08*
90
80
70
60
50
0 4 8 12 16 20 24
Time (Week)
Placebo 50 mg q4 wks
100 mg q4 wks 200 mg q4 wks
Combined 100 mg & 200 mg
*P-value compares Combined 100mg & 200 mg vs. Placebo
16 Sep 2007 Wenzel 35
Major Secondary Endpoints
AQLQ at Week 24
PEFR at Week 24
Rescue Medicine Use at Week 24
Steroid Taper Week 24-52
Severe Exacerbations Week 24-52
16 Sep 2007 Wenzel 36
Asthma Quality of Life Questionnaire
(AQLQ)
Change from Baseline in AQLQ Scores to Week 24
1.2
p = 0.946 p = 0.128 p = 0.742 p = 0.286
1
Mean +/-SE
0.8
0.6
0.4
0.2
0
Placebo (n=78) 50 mg q4 wks (n=77)
100 mg q4 wks (n=76) 200 mg q4 wks (n=78)
Combined 100 mg & 200 mg (n=154)
Note: Last observation carried forward method was used to impute missing change from baseline values.
16 Sep 2007 Wenzel 37
Overall AQLQ: Improvement by 0.5
Baseline through Week 24
80
p = 0.503 p = 0.082 p = 0.424 p = 0.124
70
Percentage
60
50
40
30
20
10
0
Placebo (n=76) 50 mg q 4wks (n=68)
100 mg q 4wks (n= 69) 200 mg q 4wks (n=73)
Combined 100 mg +200 mg (n=142)
P values using Pearson’s Chi square test
16 Sep 2007 Wenzel 38
Other Major Secondary Endpoints
• No changes in:
Peak Flow rates
Short acting beta agonist use
16 Sep 2007 Wenzel 39
Change in OCS Dose: 0-52 wks
Change in OCS Dose (Baseline to Week 52)
4
2 1.4
0
mg OCS
-2
-4
-6 -5.6
-5.7 -5.8 -5.7
-8
Placebo (n=25) 50mg q4 wks (n=25)
100mg q4 wks (n=25) 200mg q4 wks (n=24)
Combined 100mg & 200mg (n=49)
16 Sep 2007 Wenzel 40
However, marginally greater %
completely tapered off OCS
Percentage of Subjects Completely Tapered off OCS at
Week 52
30
p = 0.552 p = 0.123 p = 0.199 p = 0.122
25
Percentage
20
15
10
5
0
Placebo (n=25) 50 mg q 4wks (n=25)
100 mg q 4wks (n= 25) 200 mg q 4wks (n=24)
Combined 100 mg +200 mg (n=49)
16 Sep 2007 Wenzel 41
Number of Severe Exacerbations From Week 24
Through Week 52 (Subjects who did not discontinue
prior to Week 24)
Total number of severe exacerbations
Number of severe exacerbations and imputations
80
p1=0.341 p1=0.350 p1=0.382
70 p2=0.332 p2=0.423
p2=0.056
60
50
40
30
20
10
0
Placebo (n=77) 50 mg (n=68) 100 mg (n=71) 200 mg (n=74)
Observed
Exacerbations (observed) Added by imputation
Exacerbations with imputation
Both p values are based on CMH row mean score test; p1 is based on imputed data and p2 is based on observed data.
16 Sep 2007 Wenzel 42
Pre-specified Subgroup
Analysis:
Severe Exacerbations
16 Sep 2007 Wenzel 43
Pre-specified Subgroup Analysis:
Severe Exacerbations
• No differences in effect on severe
exacerbations by:
sex, race, weight, region of world studied, OCS
use
• Marginally better improvement in subjects
with:
age at onset 12 years (p=0.025)
FEV1 % predicted =12% Reversible >=12% Reversible >=12%
* p =12 (n=170)
Placebo 50 mg q 4wks
100 mg q 4wks 200 mg q 4wks
Combined 100 mg +200 mg
16 Sep 2007 Wenzel 57
AQLQ: Subgroup Analysis
AQLQ Overall Change from Baseline Through Week 24
1
* *
0.8
Mean
0.6
0.4
0.2
0
All Subjects (n=286) Reversible >=12% Reversible >=12% Reversible >=12%
* p =12 (n=170)
Placebo 50 mg q 4wks
100 mg q 4wks 200 mg q 4wks
Combined 100 mg +200 mg
16 Sep 2007 Wenzel 58
Benefit vs. Risk Over 6 Months:
Treatment of 100 Patients
Benefit Risk
70 70
Severe Exacerbations Excess Serious Excess
Extra Patients with Serious Infection or
Prevented Infections (pts) Malignancy (pts)
60 60
Malignacy per 100 patients treated
Prevented per 100 patients treated
Number of Severe Exacerbations
50 50
40 40
30 30
20 20
10 10
0 0 All Subj ects Rev ersible Rev ersible or Rev erible or All Subj ects Rev ersible Rev ersible or Rev erible or
All Subjects Reversible Reversible or Reverible or (n=309) (n=164) Sinusitis Sinusitis; (n=309) (n=164) Sinusitis Sinusitis;
(n=309) (n=164) Sinusitis Sinusitis; (n=240) onset>12 (n=240) onset>12
(n=240) onset>12 (n=170) (n=170)
(n=170)
50mg 100mg 200mg All
16 Sep 2007 Wenzel 59
Conclusions
• In a large scale study of anti-TNF in a wide
range of severe asthmatic subjects, no significant
improvement in either of 2 co-primary endpoints
Trends for reduction in severe exacerbations
• Safety profile similar to that observed with other
anti-TNF therapies, with trend for increased
infections and higher # of malignancies
Insufficient benefit:risk ratio caused DSMC to
recommend termination of dosing after week 24
16 Sep 2007 Wenzel 60
Conclusions (continued)
• Subgroup analyses
Subgroups may exist with better benefit:risk profile
• Possible increase in efficacy, mainly in prevention of severe
exacerbations
• 7 of 8 malignancies occurred in “non-responder”, less reversible
group
Clinically identifiable and meaningful subgroup of
patients with proven reversibility, chronic sinusitis and
later age at onset MAY have improvement in
exacerbations and AQLQ following anti-TNFRx
• Differences helped by worsening response in placebo group
• No effect on lung function
• 100 mg dose seems best choice for dose if further studies
undertaken
• Trend for better ability to completely taper off steroids, in small
numbers, across all subgroups
16 Sep 2007 Wenzel 61
Hypothetical Role of Anti-TNF
Therapy in Preventing Exacerbation
TNFlevel No exacerbation
No viral infection
FEV1 Exacerbation
TNF
activity
viral infection No Anti-TNFTherapy
FEV1 No exacerbation
TNF
activity
viral infection Anti-TNF Therapy
16 Sep 2007 Wenzel 62
Next Steps
• If further studies using anti-TNF are
undertaken in severe asthma, will need to
target responder population
• Additional analyses to help identify
subgroups of responders
Pharmacogenomics
Gene expression
Proteomics
CRP
IgE/RAST testing
16 Sep 2007 Wenzel 63
16 Sep 2007 Wenzel 64
Study Conduct
16 Sep 2007 Wenzel 65
Discontinuation of Study Agent
to Week 24
50 mg 100 mg 200 mg 100 & 200 mg
Placeboq4 Weeks q4 Weeks q4 WeeksCombined Total
Subjects randomized 78 77 76 78 154 309
Subjects who discontinued
study treatment 2 (2.6%)14 (18.2%)17 (22.4%)13 (16.7%)30 (19.5%)46
(14.9%)
Reason for discontinuation:
Adverse event 1 (1.3%) 6 (7.8%)10 (13.2%)8 (10.3%)18 (11.7%)25 (8.1%)
Unsatisfactory
therapeutic effect 0 (0.0%) 0 (0.0%) 2 (2.6%) 1 (1.3%) 3 (1.9%) 3 (1.0%)
Lost to follow-up 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (1.3%) 1 (0.6%) 2 (0.6%)
Death 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.3%) 1 (0.6%) 1 (0.3%)
Other 1 (1.3%) 7 (9.1%) 5 (6.6%) 2 (2.6%) 7 (4.5%) 15 (4.9%)
16 Sep 2007 Wenzel 66
Discontinuation from Study
to Week 24
50 mg 100 mg 200 mg 100 & 200 mg
Placebo q4 Weeks q4 Weeks q4 Weeks Combined Total
Subjects randomized 78 77 76 78 154 309
Subjects who discontinued
study participation 1 (1.3%) 9 (11.7%) 5 (6.6%) 4 (5.1%) 9 (5.8%) 19 (6.1%)
Reason for discontinuation:
Withdrawal of consent 1 (1.3%) 6 (7.8%) 5 (6.6%) 0 (0.0%) 5 (3.2%) 12 (3.9%)
Lost to follow 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (1.3%) 1 (0.6%) 2 (0.6%)
Death 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.3%) 1 (0.6%) 1 (0.3%)
Other 0 (0.0%) 2 (2.6%) 0 (0.0%) 2 (2.6%) 2 (1.3%) 4 (1.3%)
16 Sep 2007 Wenzel 67
Discontinuation of Study Agent to
Week 52
50 mg 100 mg 200 mg 100 & 200 mg
Placebo q4 Weeks q4 Weeks q4 Weeks Combined Total
Subjects randomized 78 77 76 78 154 309
Subjects who discontinued
study treatment 37% 53% 53% 55% 54% 50%
Reason for discontinuation:
Adverse event 5% 18% 18% 14% 16% 14%
Unsatisfactory
therapeutic effect 1% 0% 3% 5% 4% 2%
Lost to follow-up 0% 3% 1% 1% 1% 1%
Death 0% 0% 0% 1% 1% 0%
Other: sponsor directive 28% 20% 21% 27% 24% 24%
Other 3% 13% 9% 6% 8% 8%
16 Sep 2007 Wenzel 68
Discontinuation from Study
to Week 76
50 mg 100 mg 200 mg 100 & 200 mg
Placebo q4 Weeks q4 Weeks q4 Weeks Combined Total
Subjects randomized 78 77 76 78 154 309
Subjects who discontinued
study participation 34 (44%) 45 (58%) 42 (55%) 46 (59%) 88 (57%) 167 (54%)
Reason for discontinuation:
Withdrawal of consent 4 (5%) 11 (14%) 10 (13%) 6 (8%) 16 (10%) 31 (10%)
Lost to follow 0 (0%) 3 (4%) 3 (4%) 4 (5%) 7 (5%) 10 (3%)
Death 0 (0%) 0 (0%) 0 (0%) 1 (1%) 1 (1%) 1 (0.3%)
Other: (sponsor directive) 27 (35%) 21 (27%) 19 (25%) 22 (28%) 41 (27%) 89 (29%)
Other 3 (4%) 10 (13%) 10 (13%) 13 (17%) 23 (15%) 36 (12%)
16 Sep 2007 Wenzel 69
Medical History
100 mg and 200 mg
Placebo 50 mg q4 100 mg q4 200 mg q4 Combined Total
Subjects randomized 78 77 76 78 154 309
Allergic rhinitis 46 (59.0%) 47 (61.0%) 46 (60.5%) 51 (65.4%) 97 (63.0%) 190 (61.5%)
Sinusitis 39 (50.0%) 37 (48.1%) 42 (55.3%) 37 (47.4%) 79 (51.3%) 155 (50.2%)
GERD 28 (35.9%) 28 (36.4%) 28 (36.8%) 29 (37.2%) 57 (37.0%) 113 (36.6%)
Hypertension requiring medical therapy 27 (34.6%) 28 (36.4%) 16 (21.1%) 22 (28.2%) 38 (24.7%) 93 (30.1%)
Atopy 27 (34.6%) 17 (22.1%) 23 (30.3%) 26 (33.3%) 49 (31.8%) 93 (30.1%)
History of smoking 19 (24.4%) 20 (26.0%) 26 (34.2%) 16 (20.5%) 42 (27.3%) 81 (26.2%)
Depression 12 (15.4%) 14 (18.2%) 19 (25.0%) 9 (11.5%) 28 (18.2%) 54 (17.5%)
Aspirin or NSAID intolerance or sensitivity 11 (14.1%) 14 (18.2%) 15 (19.7%) 14 (17.9%) 29 (18.8%) 54 (17.5%)
Migraine 11 (14.1%) 14 (18.2%) 12 (15.8%) 10 (12.8%) 22 (14.3%) 47 (15.2%)
Oral candidiasis 14 (17.9%) 5 (6.5%) 11 (14.5%) 14 (17.9%) 25 (16.2%) 44 (14.2%)
Osteoporosis 11 (14.1%) 13 (16.9%) 5 (6.6%) 15 (19.2%) 20 (13.0%) 44 (14.2%)
Anxiety disorder 8 (10.3%) 12 (15.6%) 11 (14.5%) 6 (7.7%) 17 (11.0%) 37 (12.0%)
Diabetes mellitus 13 (16.7%) 10 (13.0%) 3 (3.9%) 10 (12.8%) 13 (8.4%) 36 (11.7%)
Sleep apnea 5 (6.4%) 8 (10.4%) 2 (2.6%) 6 (7.7%) 8 (5.2%) 21 (6.8%)
Peripheral vascular disease 6 (7.7%) 6 (7.8%) 2 (2.6%) 3 (3.8%) 5 (3.2%) 17 (5.5%)
Ischemic heart disease 2 (2.6%) 7 (9.1%) 2 (2.6%) 3 (3.8%) 5 (3.2%) 14 (4.5%
Vocal cord dysfunction 3 (3.8%) 4 (5.2%) 2 (2.6%) 2 (2.6%) 4 (2.6%) 11 (3.6%)
Cushing's syndrome 2 (2.6%) 4 (5.2%) 2 (2.6%) 2 (2.6%) 4 (2.6%) 10 (3.2%)
Myocardial infarction 1 (1.3%) 2 (2.6%) 0 (0.0%) 1 (1.3%) 1 (0.6%) 4 (1.3%)
Churg Strauss syndrome 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
16 Sep 2007 Wenzel 70
# of Exacerbations for Subjects that
Withdrew Through Week 24
Last Observed Imputed Last Observed Imputed
visit visit
Week 0 0 7 Week 12 0 1
Week 0 0 7 Week 16 0 1
Week 4 0 3 Week 16 0 1
Week 4 0 3 Week 16 0 1
Week 4 0 3 Week 16 1 3
Week 4 0 3 Week 16 1 3
Week 4 0 3 Week 16 1 3
Week 4 0 3 Week 20 0 1
Week 8 0 3 Week 20 0 1
Week 8 0 3
16 Sep 2007 Wenzel 71
Effect of Imputation Method on
Primary Endpoint
Number of severe exacerbations (observed + additional due to
imputation)
25.0%
Percent of subjects
20.0%
15.0%
10.0%
5.0%
0.0%
1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7
Placebo 50 mg 100 mg 200 mg
Number of severe exacerbations after imputation
Observed Added 1 Added 2 Added 3 Added 7
16 Sep 2007 Wenzel 72
Number of Severe Exacerbations
Through Week 24 (All subjects)
Total number of severe exacerbations
Number of severe exacerbations and imputations
60
50
40
30
20
10
0
Placebo 50 mg 100 mg 200 mg Placebo 50 mg 100 mg 200 mg
(n=78) (n=77) (n=76) (n=78) (n=78) (n=77) (n=76) (n=78)
Added by INNOVATE imputation
Added by protocol-defined imputation
Observed
16 Sep 2007 Wenzel 73
Number of Severe Exacerbations From Week 24
Through Week 52 (Subjects who did not discontinue
prior to Week 24)
Total number of severe exacerbations
Number of severe exacerbations and imputations
70
60
50
40
30
20
10
0
Placebo 50 mg 100 mg 200 mg Placebo 50 mg 100 mg 200 mg
(n=77) (n=68) (n=71) (n=74) (n=77) (n=68) (n=71) (n=74)
Added by INNOVATE imputation
Added by protocol-defined imputation
Observed
16 Sep 2007 Wenzel 74
Efficacy
16 Sep 2007 Wenzel 75
Change in % Predicted FEV1
Through Week 24
9
Clinic-Measured FEV1
Change from Baseline
in Prebronchodilator
7
(Mean +/- SE)
5
3
1
-1
-3
-5
0 4 8 12 16 20 24
Week
Placebo 50 mg q4 wks
100 mg q4 wks 200 mg q4 wks
Combined 100 mg & 200 mg
16 Sep 2007 Wenzel 76
Change in % Predicted FEV1
Through Week 76
16 Sep 2007 Wenzel 77
AQLQ Symptom Domain: Improvement
by 0.5
Baseline through Week 24
80
70 p = 0.531 p = 0.043 p = 0.132 p = 0.030
Percentage
60
50
40
30
20
10
0
Placebo (n=76) 50 mg q 4wks (n=68)
100 mg q 4wks (n= 69) 200 mg q 4wks (n=73)
Combined 100 mg +200 mg (n=142)
16 Sep 2007 Wenzel 78
Severe Exacerbations:
Observed Data
Annual Rate
1.4
Number/Subject/Year
1.2
1
0.8
0.6
0.4
0.2
0
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
16 Sep 2007 Wenzel 79
Mild Exacerbations:
Observed Data
Mean Number of Mild Exacerbations through Week 24
3
p = 0.040 p = 0.760 p = 0.078 p = 0.228
2.5
2
Mean
1.5
1
0.5
0
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
16 Sep 2007 Wenzel 80
Mild Exacerbations:
Observed Data
One or More Mild Exacerbations through Week 24
100
p = 0.046 p = 0.860 p = 0.391 p = 0.550
80
Percentage
60
40
20
0
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
16 Sep 2007 Wenzel 81
Duration of Exacerbations:
Observed Data
Median Duration in Days of Exacerbation
25
p=0.656 p=0.698
p=0.286 p=0.604 p=0.484 p=0.872
20 p=0.247 p=0.670
Median
15
10
5
0
Mild Severe
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
16 Sep 2007 Wenzel 82
Severe Exacerbations:
Observed Data
Mean through Week 24 (including potential untreated
exacerbations)
1.4
1.2 p = 0.311 p = 0.129 p = 0.037 p = 0.026
Mean (+/- SD)
1
0.8
0.6
0.4
0.2
0
Placebo (n=78) 50 mg q 4wks (n=77)
100 mg q 4wks (n= 76) 200 mg q 4wks (n=78)
Combined 100 mg +200 mg (n=154)
16 Sep 2007 Wenzel 83
Time to First Severe Asthma
Exacerbation
HR 0.24 HR 0.99
P=0.004 P=0.97
Asthma Exacerbations
Percent of Subjects
100
Free from Severe
90
80
70
p=0.08 HR 0.63
60 P=0.083
50
0 4 8 12 16 20 24
Time (Week)
Placebo 50 mg q4 wks
100 mg q4 wks 200 mg q4 wks
Combined 100 mg & 200 mg
P-value compares Combined 100mg & 200 mg vs. Placebo
16 Sep 2007 Wenzel 84
Time to First Severe Exacerbation
(All Subjects)
Proportion Free from Severe Exacerbations (n=309)
Percent Subjects
100
90
80
70
60 p=0.08
50
0 4 8 12 16 20 24
Time (Week)
Placebo 50 mg q4 wks
100 mg q4 wks 200 mg q4 wks
Combined 100 mg & 200 mg
P-value compares Combined 100mg & 200 mg vs. Placebo
16 Sep 2007 Wenzel 85
Severe Exacerbations:
Week 24 – Week 52
Number of Severe Exacerbations per Subject from
Week 24 through Week 52
p = 0.341 p = 0.350 p = 0.382 p = 0.273
30
Percent of
Subjects
20
10
0
(n=77) (n=68) (n=71) (n=74) (n=145)
Placebo 50 mg q4 wks 100 mg q4 200 mg q4 Combined
Treatment Group
# of severe exacerbations = 1 # of severe exacerbations = 2
# of severe exacerbations = 3 # of severe exacerbations = 4
Note: Imputation using the worst case among similar subjects was applied for subjects who discontinued study participation early.
16 Sep 2007 Wenzel 86
Time to First Severe Asthma
Exacerbation through Week 52
16 Sep 2007 Wenzel 87
Asthma-related Hospitalization
through Week 24
CNTO 148
50 mg 100 mg 200 mg 100 & 200 mg
Placebo q4 Weeks q4 Weeks q4 Weeks Combined
Subjects randomized 78 77 76 78 154
Number of hospitalizations:
0 75 (96.2%) 71 (92.2%) 70 (92.1%) 75 (96.2%) 145 (94.2%)
1 2 (2.6%) 5 (6.5%) 6 (7.9%) 3 (3.8%) 9 (5.8%)
2 0 (0.0%) 1 (1.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
3-5 1 (1.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
012407_ Lo_T03-CNTO148 88
Subgroup Analyses
16 Sep 2007 Wenzel 89
Subgroup Analysis:
Gender, Age, Race, Wt
16 Sep 2007 Wenzel 90
Subgroup Analysis:
OCS, Age of Onset, FEV1
16 Sep 2007 Wenzel 91
Subgroup Analysis:
Region
16 Sep 2007 Wenzel 92
Subgroup Analysis:
Prior Hospitalizations or ER Visits
16 Sep 2007 Wenzel 93
Subgroup Analysis:
Hospitalization or ER visit in Last Yr
16 Sep 2007 Wenzel 94
Subgroup Analysis: Hx of Sinusitis,
Reversibility 12%
16 Sep 2007 Wenzel 95
1 or More Severe Exacerbations:
Subgroups
Gender
50
p = 0.288 p = 0.464 p = 0.551
40
Percentage
30
20
10
0
All Male Female
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 96
1 or More Severe Exacerbations:
Subgroups
Weight
50
p = 0.288 p = 0.498 p = 0.399
40
Percentage
30
20
10
0
All = median
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 97
1 or More Severe Exacerbations:
Subgroups
OCS Use
50
p = 0.288 p = 0.799 p = 0.397
40
Percentage
30
20
10
0
All OCS No OCS
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 98
1 or More Severe Exacerbations:
Subgroups
Region
50
p = 0.288 p = 0.547 p = 0.372 p = 0.660
Percentage
40
30
20
10
0
All Eastern Western North America
Europe Europe
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 99
1 or More Severe Exacerbations:
Subgroups
Age
50
p = 0.288 p = 1.000 p = 0.129
40
Percentage
30
20
10
0
All = median
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 100
1 or More Severe Exacerbations:
Subgroups
Race
70
p = 0.288 p = 0.736 p = 0.431
60
Percentage
50
40
30
20
10
0
All White Non-White
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 101
1 or More Severe Exacerbations:
Subgroups
Age at Onset of Asthma
50
p = 0.288 p = 0.445 p = 0.086
40
Percentage
30
20
10
0
All = Age 12
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 102
1 or More Severe Exacerbations:
Subgroups
Baseline FEV1
50
p = 0.288 p = 0.171 p = 1.000
40
Percentage
30
20
10
0
All = median
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 103
1 or More Severe Exacerbations:
Subgroups
Hospitalizaitons in Prior Year
60
p = 0.288 p = 0.722 p = 0.355
50
Percentage
40
30
20
10
0
All No Hospitalizations >=1 Hospitalization
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 104
1 or More Severe Exacerbations:
Subgroups
ER Visits in Prior Year
60
p = 0.288 p = 1.000 p = 0.326
50
Percentage
40
30
20
10
0
All No ER Visits >=1 ER Visit
Placebo (n=78) Combined 100 mg +200 mg (n=154)
Note: Subgroup analysis uses imputed exacerbations
16 Sep 2007 Wenzel 105
Reversible Subgroup
16 Sep 2007 Wenzel 106
Odds of Being Free of Severe Exacerbation
by % Reversibility at Baseline
16 Sep 2007 Wenzel 107
AQLQ
Mean change from baseline to Week 24 in AQLQ (LOCF)
1.2
12% Reversible
1 All subjects
0.8
Mean
0.6
0.4
0.2
0
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 108
0.5 points improvement in AQLQ
Proportion of subjects with > 0.5 points improvement in
AQLQ (observed)
100
12% Reversible
All subjects
80
Percent
60
40
20
0
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 109
Rescue Medication Use
Mean change from baseline to Week 24 in rescue med use
(LOCF)
-0.1
-0.3
-0.5
Mean
-0.7
-0.9
12% Reversible
-1.1 All subjects
-1.3
-1.5
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 110
Morning PEFR
Mean change from baseline to Week 24 in domiciliary
morning PEFR (LOCF)
25
12% Reversible
All subjects
20
Mean
15
10
5
0
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 111
FEV1
Mean change from baseline to Week 24 in % predicted FEV1
(LOCF)
10
12% Reversible
8 All subjects
Mean
6
4
2
0
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 112
Rate of Severe Exacerbations from
Week 24 through Week 52
Severe Exacerbations (Mean) from Week 24 through Week 52 for subjects
who did not discontinue prior to Week 24
1.8
1.6
1.4
1.2 *
Mean
1
0.8
0.6
0.4
0.2
0
Imputed Observed Observed and Observed and
* p =12% (n=150) >=12% or sinusitis >=12 or sinusitis
* p =12
(n=158)
Placebo 50 mg q 4wks
100 mg q 4wks 200 mg q 4wks
Combined 100 mg +200 mg
16 Sep 2007 Wenzel 116
Rate of Severe Exacerbations
Severe Exacerbations (Mean) through Week 24
1.8
1.6 12% Reversible
1.4 All subjects
1.2
Mean
1
0.8
0.6
0.4
0.2
0
Imputed Observed Observed Observed Imputed Observed Observed Observed
and D/C and and D/C and
Untreated Untreated
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 117
AQLQ: Subgroup Analysis
AQLQ Overall Change from Baseline Through Week 24
1
* * * *
Mean (+/- SD)
0.8
0.6
0.4
0.2
0
All Subjects (n=286) >=12% (n=147) >=12% or sinusitis >=12 or sinusitis
* p =12
(n=156)
Placebo 50 mg q 4wks
100 mg q 4wks 200 mg q 4wks
Combined 50mg + 100mg Combined 100 mg +200 mg
All CNTO 148
16 Sep 2007 Wenzel 118
Steroid Taper: Subgroup Analysis
Completely Tapered Off Oral Corticosteroids
40%
% Subjects
30%
20%
10%
0%
All Subjects (n=99) >=12% (n=58) >=12% or sinusitis >=12 or sinusitis
(n=82) and onset >=12
(n=59)
Placebo 50 mg q 4wks 100 mg q 4wks 200 mg q 4wks
16 Sep 2007 Wenzel 119 31
Benefit Over 6 Months:
Treatment of 100 Patients
Number of Severe Exacerbations Prevented
per 100 patients treated
Prevented per 100 patients treated
60
Number of Severe Exacerbations
50
40
30
20
10
0
All Subjects (n=309) Reversible (n=164) Reversible or Sinusitis Reverible or Sinusitis;
(n=240) onset>12 (n=170)
50mg 100mg 200mg All
16 Sep 2007 Wenzel 120
Safety
16 Sep 2007 Wenzel 121
Supplemental Information On
Subjects with Malignancy
Subject Study Drug Age/ # Doses Malignancy Comments
Group Gender Prior
to Dx
1424- 200 mg 77/M 2 basal cell Basal cell carcinoma on scalp. Patient has a history of basal cell
004 carcinoma carcinomas on face and head.
0501- 200 mg 67/M 3 renal cell 1 day after last infusion (20Jul05) developed pain upper abdomen,
007 carcinoma hypotension, swollen lymph node. Hospitalized on 08Aug05 for
(with mets: evaluation. CT on 09Aug05 revealed 2 masses in parenchyma of right
liver, bone, kidney. Renal punch biopsy on 12-Aug-05 confirmed adenocarcinoma.
lung, lymph Metastases of liver, bones, and lungs documented in Feb06 and Mar06.
node)
1002- 50 mg 64/F 5 breast History of a tumor in right breast (surgically excised in 1994). According to
016 carcinoma the patient, no neoplastic cells were found during histopathological
examination and no other treatment was given Diagnosed with
“carcinoma praecipuae tubullare invasium” 4 weeks after 5th dose. Patient
had radical mastectomy and lymphadenectomy
1441- 100 mg 78/F 5 metastatic History of smoking (distant past) and nasal polyps. Presented with an
013 melanoma extremely fast growing nasal polyp. Polyp was resected, (27Sep06)
resulting in diagnosis of sinonasal melanoma. Tumor was strongly
positive for S100, HMB-45, and melanin A. PET scan revealed
metastases to right hilum and both lungs.
1001- 200 mg 50/F 6 cervical Cytology pre-study “of concern” Developed uterine bleeding ~ 2 weeks
002 carcinoma before last dose
0705- 100 mg 59/F 9 B-cell Patient experienced enlargement of left inguinal lymph node and swelling
016 lymphoma of left leg approx. 2 months prior to diagnosis of follicular lymphoma,
grade IIIA (confirmed by cytology). Treatment with chemotherapy started
0303- 200 mg 71/F 14 colon cancer Colonoscopy with polypectomy performed as diagnostic and therapeutic
003 stage 0 procedures. Non-invasive, non-penetrating basal membrane
adenocarcinoma; 2nd colonoscopy 3 mo later was clean, without any
clinical signs/symptoms
1400- 200 mg 64/M 14 basal cell Patient had procedure to remove basal cell from head ~2mo after last
015
16 Sep 2007 Wenzel 122 carcinoma dose
Serious Adverse Events through
Week 24
50 mg q4 Weeks 100 mg q4 Weeks 200 mg q4 Weeks Combined
Subjects treated 78 75 78 78 231
Avg duration of follow-up (weeks) 24.1 22.8 23.5 23.5 23.3
Avg exposure (weeks) 20.0 18.1 18.3 18.7 18.4
Subjects with 1 or more serious
adverse events 6 (7.7%) 11 (14.7%) 14 (17.9%) 13 (16.7%) 38 (16.5%)
System-organ class/preferred term
Respiratory, thoracic and
mediastinal disorders 3 (3.8%) 6 (8.0%) 6 (7.7%) 3 (3.8%) 15 (6.5%)
Asthma 3 (3.8%) 6 (8.0%) 4 (5.1%) 3 (3.8%) 13 (5.6%)
Diffuse panbronchiolitis 0 (0.0%) 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (0.4%)
Pneumonitis 0 (0.0%) 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (0.4%)
Respiratory failure 0 (0.0%) 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (0.4%)
Infections and infestations 0 (0.0%) 3 (4.0%) 5 (6.4%) 5 (6.4%) 13 (5.6%)
Pneumonia 0 (0.0%) 2 (2.7%) 4 (5.1%) 2 (2.6%) 8 (3.5%)
Cellulitis 0 (0.0%) 1 (1.3%) 1 (1.3%) 2 (2.6%) 4 (1.7%)
Sepsis 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (2.6%) 2 (0.9%)
Bacteraemia 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.3%) 1 (0.4%)
Bursitis infective 0 (0.0%) 1 (1.3%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
Choriomeningitis lymphocytic 0 (0.0%) 0 (0.0%) 1 (1.3%) 0 (0.0%) 1 (0.4%)
Escherichia bacteraemia 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.3%) 1 (0.4%)
Septic shock 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.3%) 1 (0.4%)
Staphylococcal bacteraemia 0 (0.0%) 1 (1.3%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
16 Sep 2007 Wenzel 123
Serious Adverse Events through
Week 24 (2)
16 Sep 2007 Wenzel 124
SAE infections in subgroup
( 12% reversible)
All Subjects
12% reversible Placebo 50 mg 100 mg 200 mg Combined
Infections and infestations 0 (0.0%) 1 (2.5%) 2 (4.3%) 3 (7.3%) 6 (4.7%)
Pneumonia 0 (0.0%) 1 (2.5%) 1 (2.1%) 0 (0.0%) 2 (1.6%)
Cellulitis 0 (0.0%) 0 (0.0%) 1 (2.1%) 2 (4.9%) 3 (2.3%)
Sepsis 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (4.9%) 2 (1.6%)
Bacteraemia 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.4%) 1 (0.8%)
Escherichia bacteraemia 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.4%) 1 (0.8%)
Septic shock 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (2.4%) 1 (0.8%)
32
16 Sep 2007 Wenzel 125
Benefit vs. Risk Over 6 Months:
Treatment of 100 Patients
60
Severe Exacerbations Excess Pts with Excess Pts with
Completely Prevented Serious Infection Malignancy
Subjects per 100 treated
50
40
30
20
10
0
ll
ll
ll
in
in
in
12
12
12
ev
ev
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/S
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R
R
R
ev
ev
ev
in
in
in
/S
/S
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R
R
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ev
ev
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50mg 100mg 200mg All
16 Sep 2007 Wenzel 126
INNOVATE vs T03
16 Sep 2007 Wenzel 127
T03 vs. INNOVATE:
Comparison of Populations
T03 INNOVATE
• N=309 • N=419 (in PITT population)
• Mean Age 50.1 (range 19-81) • Mean Age 43.4 (range 12-79)
• Female 56% • Female 67%
• Race: • Race
White 88% White 78%
Black 11% Black 7%
Other 1% Other 15%
• Weight 86 kg • Weight 80 kg
• FEV1 (mean) 59.8% • FEV1 (mean) 61.3%
predicted predicted
• Morning PEF 296 L/min • Morning PEF 305 L/min
• Rescue Meds(puffs/day) 4.7 • Rescue Meds(puffs/day) 6.1
• AQLQ 4.2 • AQLQ 3.9
• Duration of asthma 23.7 • Duration of asthma (yr) 22.9
• Leukotriene modifier (%) 33.0 • Leukotriene modifier (%) 34.9
• OCS at baseline (%) 32.0 • OCS at baseline (%) 21.7
• Asthma ER visit in last year 30.4% • Asthma ER visit in last 14 mo 55.9%
• Asthma Hosp. in last year
16 Sep 2007 Wenzel 128
20.4% • Asthma Hosp. in last 14 mo 38.7%
T03 vs. INNOVATE:
Results
T03 INNOVATE
• Discontinued treatment •Discontinued treatment
2.6% placebo vs 19.0% golimumab 12.2% placebo vs 9.3% omalizumab
• Co-Primary endpoint: number of •Primary Endpoint: Hazard ratio for reduction
severe exacerbations in clinical significant exacerbations
ITT primary analysis (with imputation) no
significant reduction (mean 0.5 vs 0.5 per 24 ITT primary analysis HR 0.806 (p=0.153)
weeks p=0.636) Post hoc modified ITT (Adjusted for slight imbalance in #
Post hoc observed HR 0.63 (p=0.083) exacerbations in prior yr
• HR 0.738 (CI 0.552-0.998, p = 0.043)
• placebo 0.91 vs. omalizumab 0.68
• AQLQ (0.5 – point improvement) •AQLQ (0.5 – point improvement)
Placebo 47.7% golimumab 60.6% P=0.124 Placebo 47.8% omalizumab 60.8% P=0.008
• FEV1 (% predicted improvement) •FEV1 (% predicted improvement)
0.47% improvement (P=0.802)
2.8% improvement (P=0.043)
• Rescue medication use
0.12 puffs less/day (P=NS) •Rescue medication use
0.5 puffs less/day (P=NS)
• Injection site erythema
Placebo 0.0% vs golimumab 4.3% •Injection site reactions
Placebo 1.7% vs omalizumab 4.9%
• SAE (1:3 randomization)
infections 1 placebo vs. 19 active •SAE (drug related) 1:1 randomization
malignancy 0 placebo vs. 6 active One patient with pruritis, rash, petechiae
16 Sep 2007 Wenzel 129