Transcript SB 207499 (Ariflo , cilomilast) GlaxoSmithKline New Drug Application 21-573

SB 207499 (Ariflo®, cilomilast)
GlaxoSmithKline
New Drug Application 21-573
Pulmonary - Allergy Drugs
Advisory Committee Meeting
Holiday Inn
Gaithersburg, Maryland
5 September, 2003
Pulmonary and Allergy Drug Products Advisory Committee Meeting
September 5, 2003
The Drug & Development Program
• SB 207499 (phosphodiesterase IV inhibitor)
– new molecular entity
– first drug in its class
– twice daily oral dosing
• Indication: “…maintenance of lung function (FEV1)
in patients with Chronic Obstructive Pulmonary
Disease (COPD) who are poorly responsive to
albuterol.”
• Multi-national development program
– Europe, Australia, Japan, New Zealand, North
America, South Africa
PADAC
Sept. 5, 2003
2
Presenters
• Preclinical Pharmacology-Toxicology
– Virgil Whitehurst, Ph.D.
• Dose-Finding
– Sandra Suarez, Ph.D
• Statistics
– James Gebert, Ph.D.
• Efficacy & Safety
– Raymond Anthracite, M.D.
PADAC
Sept. 5, 2003
3
Preclinical Considerations
Virgil Whitehurst, Ph.D.
Pharmacologist
Pulmonary and Allergy Drug Products Advisory Committee Meeting
September 5, 2003
Characterization of
Toxicological Profile




Identify target organs of toxicity
Identify the no-observed-adverse-effectlevel (NOAEL) in animals
Determine severity, reversibility and
monitorability of the toxicity
Determine the margin of safety, a ratio
based on exposure (e.g., AUC) comparison
between animal (NOAEL in the sensitive
species) and human
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Sept. 5, 2003
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Toxic Effects of
Cilomilast in Animals





PADAC
Sept. 5, 2003
Arteritis (multi-organs), including
the mesentery
Testicular Degeneration
Adrenal Cortex Hypertrophy
Myocardial Necrosis
GI Disturbances
6
Arteritis
 Arteritis
appears to be a class effect of PDE4 inhibitors (rolipram and others). Other
PDE inhibitors, such as theophylline, also
induce arteritis.
 Arteritis
is irreversible in animals.
 Arteritis
induced by cilomilast occurs in
animals at an AUC that is only a fraction of
the expected human AUC.
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Sept. 5, 2003
7
Cilomilast Induced Arteritis
Effect
AUC
AUC
Margin
of
Species Dose
(mcg.h NOAEL (mcg.h
(mg/kg)
/mL)
(mg/kg) /mL) Safety**
≥ 30 *
≥ 12
20
4
0.2 x
Mouse
200
424
100
157
7x
Monkey
_
_
10***
88
4x
Rat
* deaths occurred @ 40 mg/kg; ** based on human AUC of 22
mcg.h/ml; *** Highest dose tested
PADAC
Sept. 5, 2003
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Summary – Cilomilast (1)
 Cilomilast
induced arteritis and death
in rats.
 The severity of the toxicity in rats
increases over a narrow range of
exposure.
 Human exposure at the proposed
clinical dose is higher than the toxic
dose in the rat.
PADAC
Sept. 5, 2003
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Summary – Cilomilast (2)
 Therefore,
the data provide no
margin of safety for arteritis
compared to the proposed clinical
dose regimen
 Arteritis is a significant safety
concern
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Sept. 5, 2003
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PADAC
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NDA 21-573
Ariflo Immediate Release Tablets
Study 032: Dose-Response
CLINICAL PHARMACOLOGY AND
BIOPHARMACEUTICS REVIEW
Sandra Suarez-Sharp, Ph.D.
Pulmonary and Allergy Drug Products Advisory Committee Meeting
September 5, 2003
Study 032: Multiple Administration of Oral Cilomilast (5,
10 and 15mg Twice Daily) for 6 Weeks to Patients with
COPD
Mean (SEM) change from baseline in trough
pre-bronchodilator FEV1 by week and treatment group
N
*
*
*
*
*
Dose baseline
0
106
5
109
10
102
15
107
Week 6
91
95
85
90
*
* p<0.02
PADAC
Sept. 5, 2003
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Cilomilast Trough Concentration as a
Function of Dose and Visit
Cilomilast trough concentration
(ng/mL)
WEEK 1
WEEK 2
WEEK 4
WEEK 6
3000
2000
1000
0
0
5
10 15
5
10 15
5 10 15
5 10 15
Dose (mg)
PADAC
Sept. 5, 2003
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Baseline FEV1 as a Function of Dose
4
Baseline FEV1 (L)
Baseline FEV1 (L)
Dose (mg) Mean (SD)
3
2
1
Median
0
1.38 (0.53)
1.28
5
1.32 (0.39)
1.25
10
1.41 (0.49)
1.32
15
1.35 (0.45)
1.26
0
0
5
10 15
Dose (mg)
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Sept. 5, 2003
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Change from baseline in FEV1 (L)
Change from Baseline in FEV1 after
Baseline Adjustment
0 mg
0.2
5 mg
10 mg
0.15
15 mg
0.1
0.05
0
1
2
4
6
-0.05
Week
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Sept. 5, 2003
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Change from Baseline in FEV1-Cilomilast Trough
Concentration Relationship
Change from baseline in FEV1 (L)
0
WEEK 4
1000 2000 3000
WEEK 6
2.0
1.2
0.4
-0.4
WEEK 1
WEEK 2
-1.2
2.0
1.2
0.4
-0.4
-1.2
0
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Sept. 5, 2003
1000 2000 3000
Cilomilast trough concentration (ng/mL)
17
Adverse Experiences (GIT) Occurring in more than 5%
of Patients in Any Treatment Group (% of Patients)
Abd Pain
Diarrhea
Nausea
Vomiting
0 5 10 15
0 5 10 15
0 5 10 15
0 5 10 15
Percentage AE
12
10
8
6
4
2
0
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Sept. 5, 2003
Dose (mg)
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Cilomilast trough concentration (ng/mL)
Cilomilast Trough Concentration in Patients Experiencing
GIT Side Effects vs. No AEs
NAUSEA
ABDOMINAL PAIN
D: 0 5 10 15
0
5 10 15
2000
VOMITING
0
5 10 15
NO AEs
5
10
4567
4567
15
1500
1000
500
0
3 34
45673 34
45673 34
45673 34
4567
Visit
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Sept. 5, 2003
3 646
4563 646
4563 646
4563 646
456
Visit
356
356
356
Visit
356
4567
Visit
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CONCLUSIONS

Dose-response relationship was not fully
addressed by the sponsor. Data from Study 032
is not robust enough and 10 mg dose was not
tested in Phase III clinical trials.

The lack of concentration-response relationship
may be due to:



large degree of variability in the Cilomilast plasma trough
concentrations (CV>60%)
Unbalanced data
A higher incidence of side effects (such as
nausea, abdominal pain, diarrhea) was
observed with increasing doses of Cilomilast.
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Sept. 5, 2003
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CONCLUSIONS, cont.

Plasma concentrations increased proportionally
to dose, however no clear correlation between
trough concentrations of Cilomilast and some
adverse events (AEs) was observed, most likely
due to:


the variability of the data
No correlation between Cilomilast trough concentrations and
side effects.
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Sept. 5, 2003
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ACKNOWLEDGEMENTS
He Sun, Ph.D.
 Emmanuel O. Fadiran, Ph.D.
 Henry Malinowski, Ph.D.

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PADAC
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®
Ariflo
Glaxo Smith Kline
NDA 21573
Pulmonary and Allergy Drugs
Advisory Committee Meeting
Gaithersburg, Maryland
September 5, 2003
Statistical Reviewer: James Gebert
Pulmonary and Allergy Drug Products Advisory Committee Meeting
September 5, 2003
Topics
Hochberg Procedure
 Repeated Measures Analyses
 Endpoint Analyses
 Sample Size Discussion
 Sponsor’s Delta

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Hochberg Procedure







Modified Bonferroni procedure
Both endpoints significant if both p-values <0.05.
One endpoint significant if p<0.025.
Statistical significance not clinical significance
95 % confidence limits on treatment difference no
longer appropriate
May be inappropriate in regulatory setting because
of risk benefit considerations. Both may need to be
significant.
What if different endpoints significant in two different
studies? How do you write label?
PADAC
Sept. 5, 2003
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Repeated Measures Analyses





Compares treatments over 24 weeks of
treatment
No imputation of missing visit data
Underweighs dropouts
Overweighs earlier visits
Needs more assumptions (must specify
correlation structure of visits)
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Endpoint Analyses
Little or no weight to earlier visits
 All patients including dropouts given equal
weight
 No imputation of missing visit data
 Equivalent to last visit analysis after doing
LOCF
 Usually larger delta but larger variability

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Sample Size








Chosen to have 90% power
3 of 4 studies used 2:1 weighting
Alpha level was chosen to be 0.025 for both
endpoints
Delta=120 ml for FEV1
Delta=4 for SGRQ Total Score
May give statistical significance not clinical
significance
Large sample size can show significance even if
true delta is smaller than assumed delta
Large sample size gives better estimate of true
delta
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Why Significance with Smaller
Delta?


90 % Power
Choice of 0.025 Significance Level
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PADAC
Sept. 5, 2003
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Ariflo Immediate Release Tablets
NDA 21-573
Clinical Considerations
Raymond Anthracite, M.D.
Medical Officer
Pulmonary and Allergy Drugs Advisory Committee Meeting
Gaithersburg, Maryland
September 5, 2003
Pulmonary and Allergy Drug Products Advisory Committee Meeting
September 5, 2003
Background
• 4 Pre-Clinical Toxicities
– Mesenteric Arteritis
• the most serious animal toxicity
• found in 2 species
– Remaining 3 will not be addressed
• Dose Selection – we agree that the dose selected
was appropriate for development
• Statistics – we agree with appropriateness of the
analyses chosen
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Sept. 5, 2003
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Efficacy & Safety Outline
• EFFICACY
– 4 Pivotal Trials
• Co-Primary Endpoints
– Trough FEV1
– SGRQ
• Secondary Endpoints
• SAFETY
– AEs, SAEs, AE Withdrawals & Deaths
– Emphasis On:
• Gastro-Intestinal AEs (GIAEs)
• Adequacy Of Evaluation For Mesenteric
Arteritis
PADAC
Sept. 5, 2003
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Phase II - III Clinical Trials
• Asthma Studies – 4 (n=1069)
• COPD Studies – 12 (n=5162+)
– adequate & well-controlled (pivotal) – 4
(n=2883)
– long-term, uncontrolled safety – 2
(n=1069+)
– supportive – 6 (n=1210)
• mechanism of action – 3 (n=280)
• dose finding – 2 (n=648)
• cardiology safety – 1 (n=282)
PADAC
Sept. 5, 2003
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Phase III Pivotal Efficacy Trials
• multi-national, multi-center, randomized, doubleblind, placebo-controlled, parallel-group
• 4-week single-blind placebo run-in period
• 24-week double-blind treatment period
• COPD patients 40-80 years of age (COPD criteria of
ATS & ERS)
• current and/or former smoking history > 10 packyears
PADAC
Sept. 5, 2003
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Phase III Pivotal Efficacy Trials (cont.)
• pre-albuterol FEV1/FVC < 0.70 at screening
• post-albuterol FEV1:
– 30 - 70% of predicted normal, inclusive
• “poorly responsive to albuterol” = “fixed airway
obstruction” = post-albuterol FEV1:
– < 15% increase over baseline, OR
– < 200 mL increase over baseline
PADAC
Sept. 5, 2003
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Phase III Pivotal Efficacy Trials (cont.)
Similarities & Differences
• 4 had the same co-primary efficacy endpoints and
statistical analysis (039, 042, 091, 156)
– FEV1 & SGRQ difference between treatments in
mean change from baseline, each at p < 0.025
• 3 had the same randomization strategy (2:1, SB
207499 to PBO) & all 5 secondary efficacy
endpoints (039, 042, 091)
– 1:1 randomization (156)
– COPD Symptom Score moved from diary to visit
and excluded “breathlessness” (156)
– 6-Minute Walk demoted to tertiary endpoint (156)
PADAC
Sept. 5, 2003
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Phase III Pivotal Efficacy Trials (cont.)
Similarities & Differences
• Albuterol or salbutamol responsiveness:
– 180 mcg by MDI with spacer (039, 156)
– 400 (360) mcg by MDI with spacer (042, 091)
• Pharmacokinetic sampling (039, 091, 156)
• 2-week, double-blind run-out (091)
– SB 207499 patients re-randomized (1:1) to
placebo or SB 207499
– placebo patients continued taking placebo
PADAC
Sept. 5, 2003
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Demographics & Disposition Of Phase III
Pivotal COPD Trials (039, 042, 091, 156)
Demographic
Characteristics
Placebo
(N = 1091)
SB 207499
(N = 1792)
784 (71.9)
307 (28.1)
1274 (71.1)
518 (28.9)
1047 (96.0)
28 (2.6)
1718 (95.9)
45 (2.5)
64.2 (8.8)
64.3 (8.6)
49.99 (11.74)
49.69 (11.80)
Reversibility (%) Mean (SD)
6.72 (7.83)
6.52 (7.95)
Smoking History (pack-years)
Mean (SD)
52.5 (29.9)
51.1 (28.5)
Completed Study
827 (75.8)
1265 (70.6)
Sex:
Male (%)
Female (%)
Race: Caucasian (%)
Black (%)
Age:
Mean (SD)
FEV1 (% pred) Mean (SD)
PADAC
Sept. 5, 2003
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Study 039
FEV1 (L) By Week
1.35
1.15
0.95
0.75
0.55
0.35
0.15
-0.1
-0.3
PBO
SB
Baseline
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Mean
Change
1.43
1.33
1.4
1.36
1.38
1.34
1.37
1.34
1.37
1.35
1.38
1.36
1.39
1.37
1.38
1.36
-0.03
0.01
PADAC
Sept. 5, 2003
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Study 042
FEV1 (L) By Week
1.35
1.15
0.95
0.75
0.55
0.35
0.15
-0.1
-0.3
PBO
SB
Baseline
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Mean
Change
1.35
1.37
1.34
1.39
1.35
1.4
1.34
1.41
1.34
1.42
1.35
1.43
1.35
1.42
1.35
1.42
0
0.03
PADAC
Sept. 5, 2003
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Study 091
FEV1 (L) By Week
1.35
1.15
0.95
0.75
0.55
0.35
0.15
-0.1
-0.3
PBO
SB
Baseline
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Mean
Change
1.45
1.46
1.41
1.45
1.43
1.45
1.42
1.48
1.41
1.46
1.41
1.47
1.38
1.47
1.4
1.45
-0.03
0
PADAC
Sept. 5, 2003
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ISE – MEAN TROUGH FEV1 (L) AT WEEK 24
AND AFTER 2-WEEK RUN-OUT
Study 091
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
P/P
SB/SB
SB/P
PADAC
Sept. 5, 2003
Week 24
Run-Out
1.39
1.46
1.44
1.38
1.45
1.43
44
Study 156
FEV1 (L) By Week
1.35
1.15
0.95
0.75
0.55
0.35
0.15
-0.1
-0.3
PBO
SB
Baseline
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
Mean
Change
1.39
1.35
1.38
1.37
1.37
1.37
1.37
1.37
1.37
1.37
1.37
1.39
1.36
1.38
1.35
1.37
-0.02
0.01
PADAC
Sept. 5, 2003
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ISE – Trough FEV1, Mean Change From
Baseline, Difference Between Treatments &
Statistical Significance
039
(N = 585)
042
(N = 659)
091
(N = 665)
156
(N = 741)
BL1
MC2
BL
MC
BL
MC
BL
MC
Placebo
1.42
-0.03
1.36
-0.00
1.44
-0.03
1.38
-0.02
SB 207499
1.34
0.01
1.38
0.03
1.45
0.00
1.36
0.01
Treatment
Difference3
0.04
0.03
0.03
0.02
Stat. Signif.
Yes
No
No
Yes
1 = BaseLine
2 = Mean Change (from baseline)
3 = Difference between treatments in MC adjusted for center and week.
PADAC
Sept. 5, 2003
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Study 039
Total SGRQ By Week (0-100 scale)
50
40
30
20
10
0
-10
PBO
SB
PADAC
Sept. 5, 2003
Baseline
Wk 12
Wk 24
Mean Change
44.6
45
44.8
41.4
44.5
40.4
0.4
-3.7
47
Study 042
Total SGRQ By Week (0-100 scale)
50
40
30
20
10
0
-10
PBO
SB
PADAC
Sept. 5, 2003
Baseline
Wk 12
Wk 24
Mean Change
46
43.9
41.5
39.7
40.7
39.5
-4.9
-4.2
48
Study 091
Total SGRQ By Week (0-100 scale)
50
40
30
20
10
0
-10
PBO
SB
PADAC
Sept. 5, 2003
Baseline
Wk 12
Wk 24
Mean Change
41.5
42.1
39.3
39.6
41.4
41.2
-2.3
-2.7
49
Study 156
Total SGRQ By Week (0-100 scale)
50
40
30
20
10
0
-10
PBO
SB
PADAC
Sept. 5, 2003
Baseline
Wk 12
Wk 24
Mean Change
43.5
43.8
42
41.5
40.7
40.6
-1.3
-3.2
50
ISE – Total SGRQ At Baseline, Mean Change
From Baseline, Difference Between
Treatments, Statistical Significance & MID4
039
(N = 491)
042
(N = 565)
091
(N = 566)
156
(N = 641)
Treatment
BL1
MC2
BL
MC
BL
MC
BL
MC
Placebo
44.8
0.4
45.9
-4.9
42.1
-2.3
43.2
-1.3
SB 207499
45.1
-3.7
43.8
-4.2
42.7
-2.7
44.4
-3.2
Difference3
-4.1
0.7
-0.4
-1.9
Stat. Signif.
Yes
No
No
Yes
MID4
Yes
No
No
No
1 = BaseLine
2 = Mean Change (from baseline)
3 = Difference adjusted for country and week.
4 = Minimum Important Difference (> 4.0)
PADAC
Sept. 5, 2003
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Secondary Efficacy Endpoints
(mean change from baseline)
• Trough FVC (L)
• Post-exercise (6-Minute Walk) breathlessness by
modified Borg Scale (11-point, 0-10 scale)
• Summary Diary COPD symptom score (11-point, 010 scale)
• 6-minute walk (meters)
• Percent of patients COPD exacerbation-free
through 24 weeks (% of patients in treatment group)
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Sept. 5, 2003
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Modified Borg Breathlessness Scale
0
nothing at all
1
very, very slight (just noticeable)
2
very slight
3
moderate
4
somewhat severe
5
severe
6
7
very severe
8
9
very, very severe (almost maximal)
10
maximal
PADAC
Sept. 5, 2003
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ISE – Post-Exercise Breathlessness, Mean
Change From Baseline In Pivotal Efficacy
Trials
Modified Borg Scale (0-10 units)
4.5
039
4
091
042
156
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
-1
Baseline
Mean
Change
Baseline
Mean
Change
Baseline
Mean
Change
Baseline
Mean
Change
PBO
3.4
0.07
3.54
-0.16
3.8
0
3.22
0.05
SB
3.37
-0.17
3.73
-0.36
3.69
-0.16
3.37
-0.1
PADAC
Sept. 5, 2003
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ISE – Efficacy Trials Summary
• FEV1
– 24-week trials
– 25-30% drop outs
– placebo decline in 3 trials occurred over first few
weeks & did not occur at all in the 4th
– 2 of 4 pivotal trials statistically significant
• SGRQ
– 1 of 4 pivotal trials statistically significant & Minimally
Importantly Different
• Secondary Endpoints
– 1 of 5 endpoints show some support for SB 207499
PADAC
Sept. 5, 2003
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ISE – Efficacy Trials Summary (cont.)
Has SB 207499 shown a magnitude and
consistency of efficacy that is sufficient to
approve SB 207499 for the indication,
“…maintenance of lung function (FEV1)…?”
PADAC
Sept. 5, 2003
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Integrated Safety Outline
• Includes:
– Asthma & COPD Controlled Trials
– COPD Controlled Trials
– COPD Uncontrolled Long-Term Extensions
(LTEs) for safety
• AEs, SAEs, AE Withdrawals & Deaths
• Emphasis On:
– Gastro-Intestinal AEs (GIAEs)
– Adequacy Of Evaluation For Mesenteric Arteritis
PADAC
Sept. 5, 2003
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ISS - Screening Demographics: Asthma &
COPD Patients In All Controlled Studies
Characteristic
Placebo
n = 1802
SB 15mg
n = 2475
Total SB
n = 3350
Gender: male N (%)
1229 (68) 1720 (70) 2259 (67)
Race: Caucasian N (%)
1734 (96) 2373 (96) 3220 (96)
Age (yrs): Mean (SD)
61 (12)
62 (11)
59 (13)
Smoke (pack-years): Mean (SD)
50 (30)
50 (29)
48 (29)
FEV1 % pred. (L): Mean (SD)
53 (13)
52 (13)
53 (13)
PADAC
Sept. 5, 2003
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ISS – Disposition: Asthma & COPD Patients
In All Controlled Studies
Reason For Withdrawal
Placebo SB 15mg1 Tot SB1
n = 1802 n = 2475 n = 3350
Total Withdrawn
343 (19)
640 (26)
781 (23)
adverse event
169 (9)
403 (16)
463 (14)
COPD exacerbation2
51 (3)
50 (2)
53 (2)
not COPD exacerbation
118 (7)
353 (14)
410 (12)
29 (2)
342 (14)
364 (11)
protocol deviation
55 (3)
64 (3)
98 (3)
lost to follow-up
38 (2)
45 (2)
60 (2)
other
64 (4)
105 (4)
135 (4)
Gastrointestinal3
1
2 does not include asthma patients
twice daily
3 nausea, abdominal pain, diarrhea, vomiting & dyspepsia
PADAC
Sept. 5, 2003
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ISS – N (%) Of Adverse Events (Where % In 15
mg Twice Daily SB 2074999 > PBO): All
Controlled Asthma & COPD Trials
Adverse
Event
0 mg
(n=1802)
2.5 mg
(n=72)
5 mg
(n=366)
10 mg
(n=437)
15 mg
(n=2475)
76 (4)
2 (3)
17 (5)
3 (8)
361 (15)
DIARRHEA
110 (6)
4 (6)
11 (3)
15 (3)
325 (13)
ABD PAIN
97 (5)
1 (1)
4 (1)
16 (4)
256 (10)
headache
109 (6)
7 (10)
24 (7)
32 (7)
198 (8)
DYSPEPSIA
38 (2)
0
8 (2)
7 (2)
167 (7)
VOMITING
22 (1)
1 (1)
5 (1)
11 (3)
133 (5)
NAUSEA
PADAC
Sept. 5, 2003
60
ISS – Deaths In All Controlled Asthma & COPD
Trials
PLACEBO
SB 207499
Run-In:
72yM suicide
Double-Blind:
75yF MI
Double-Blind:
63yM MI
73YM MI
71yF MI
67yM AAA
70yM CVA
72yM cerebral aneurysm
Post-Therapy:
74yM CHF
75yM CHF
58yM CHF
57yF MI
77yM aneurysm
Post-Therapy:
63yM MI
79yM Resp Fail
80yM CHF
74yF MI
PADAC
Sept. 5, 2003
61
ISS – N (%) Of SAEs Where % In SB 15 mg >
PBO: All Controlled Asthma & COPD Trials
Serious
AE
0 mg1
(n=1802)
2.5 mg1
(n=72)
5 mg1
(n=366)
10 mg1
(n=437)
15 mg1
(n=2475)
TOTAL
110 (6)
1 (1)
7 (2)
8 (2)
127 (5)
CV disorder
1 (<1)
0
0
0
6 (<1)
aneurysm
2 (<1)
0
0
0
5 (<1)
abdominal pain
0
0
0
0
4 (<1)
vasc. disorder
1 (<1)
0
0
0
4 (<1)
urinary retent.
0
0
0
0
3 (<1)
alcohol intol.
0
0
0
0
2 (<1)
myalgia
0
0
0
0
2 (<1)
PADAC
Sept. 5, 2003
62
ISS – N (%) Of W/Ds Due To AEs Where % In
Twice Daily SB 15 mg > PBO: All Controlled
Asthma & COPD Trials
Serious
AE
0 mg
(n=1802)
2.5 mg
(n=72)
5 mg
(n=366)
10 mg
(n=437)
15 mg
(n=2475)
TOTAL
161 (9)
3 (4)
25 (7)
31 (7)
388 (16)
8 (<1)
0
0
8 (2)
114 (5)
ABD. PAIN
9 (1)
0
2 (1)
3 (1)
89 (4)
DIARRHEA
7 (<1)
0
1 (<1)
4 (1)
82 (3)
VOMITING
3 (<1)
0
0
3 (1)
32 (1)
DYSPEPSIA
2 (<1)
0
0
1 (<1)
25 (1)
dizziness
2 (<1)
0
0
2 (1)
21 (1)
headache
2 (<1)
0
0
1 (<1)
19 (1)
NAUSEA
PADAC
Sept. 5, 2003
63
ISS – Development Of “GIAEs Of Concern”
• Pre-Clinical Arteritis
– mostly mesenteric
– seen in two species
– no safety margin between animals & humans
• Early in development, GSK had tried to identify
biomarkers for arteritis, unsuccessfully
PADAC
Sept. 5, 2003
64
ISS – Development Of “GIAEs Of Concern”
• GIAEs
– thought to be centrally mediated for PDE inhibitors
– also, may reflect mesenteric arteritis with SB 207499
– were severe enough to cause premature patient
termination from clinical studies
– account for majority of the early terminators in SB
207499 groups
• Continued drug development required a plan for
evaluating patients for arteritis
PADAC
Sept. 5, 2003
65
ISS –Development Of “GIAEs Of Concern”
• Prospective Evaluation
– single out cases with GIAEs for thorough evaluation
– search for a pre-fatal and possibly monitorable
manifestation (fecal blood loss)
– establish a database of colonoscopies from which
human safety could be inferred
• Justification
– colonoscopy becoming standard of care for adenocarcinoma surveillance in asymptomatic adults > 50
– certainly, symptomatic individuals in the same age
range with GI blood loss would be candidates for the
same procedure
PADAC
Sept. 5, 2003
66
ISS –Development Of “GIAEs Of Concern”
•
•
•
•
All Pivotal Controlled Studies (039, 042, 091, 156)
Both Uncontrolled Studies (040, 041)
Cardiac Safety Study (168)
Mechanism-Of-Action Studies (076, 110, 111)
• “GIAE Of Concern” Defined As:
– GI symptoms that cause patient concern, e.g.
• bloody or black stools
• pain, cramps, diarrhea, vomiting
– AND/OR… interfere with patient’s daytime activities
or sleep
PADAC
Sept. 5, 2003
67
ISS – Protocol-Specified Initial
Evaluation Of “GIAEs Of Concern”
WITHIN 24 HOURS, A PHYSICIAN EVALUATION WILL
INCLUDE EXAMINATION AND...
• Fecal Occult Blood (FOB) to signal need for further
clinical evaluation
– patient to use previously provided FOB test, OR…
– digital rectal exam with FOB testing on exam
• Orthostatic Vital Signs to signal acute volume
depletion from blood loss or fluid third-spacing
PADAC
Sept. 5, 2003
68
ISS – Protocol-Specified Follow-Up Evaluation
Of “GIAEs Of Concern”
• Pivotal Studies 039, 156, Cardiac Safety Study 168,
Mechanism of Action 110, 111 and LTE Study 041 required
DAILY monitoring by…
– clinical examination
– FOB
– Orthostatic VS
– …until resolution or definitive diagnosis
• Pivotal Study 156, Cardiac Safety study 168 LTEs 040 and
041 were amended to require a complete colonoscopy
within 2 weeks of…
• melena
• FOB-positive stools
PADAC
Sept. 5, 2003
69
ISS – GIAEs Of Concern In All Phase III
Controlled COPD Trials
GI Adverse Event
Of Concern
Placebo
(N = 1326)
n (%)
Total
56 (4)
SB 207499 15 mg
(N = 2119)
n (%)
264 (13)
abdominal pain
30 (2)
119 (6)
diarrhea
23 (2)
108 (5)
nausea
8 (1)
90 (4)
vomiting
6 (1)
60 (3)
dyspepsia
4 (<1)
34 (2)
melena
9 (1)
21 (1)
flatulence
2 (<1)
18 (1)
GE reflux
0
10 (1)
PADAC
Sept. 5, 2003
70
ISS – Implementation Of Planned FOB
Monitoring Of GIAEs Of Concern And FollowUp In All Phase III Controlled COPD Trials
Implementation Of Planned
Monitoring
FOB any time after GIAEOC
FOB-positive test
FOB test within 14 days
FOB-positive test
GIAEOC+(FOB+)+CScope
PADAC
Sept. 5, 2003
Placebo
(N = 56)
n (%)
46 (82)
SB 207499 15 mg
(N = 264)
n (%)
237 (90)
6 (11)
31 (55)
18 (7)
154 (58)
6 (11)
2 (4)
15 (6)
4 (2)
71
ISS – Colonoscopies In Patients With A
GIAEOC And Positive FOB From All Phase III
Controlled COPD Trials
• Placebo-Treated:
– 156.457.14400 – diverticulae, polyps, IH
– 168.625.18447 – diverticulae, polyps
• SB 207499-Treated:
– 156.490.16423 – diverticulae
– 156.505.15358 – vilotubular adenomas
– 156.509.22706 – diverticulae, polyps, IH
– 168.648.18699 – diverticulae, IH
PADAC
Sept. 5, 2003
72
ISS - N (%) Of COPD Patients With On-Therapy
FOB Results In Phase III Controlled COPD
Trials
Double-Blind Period
Treatment
Placebo
SB 207499
Patients
Tested
Baseline
Negative
n (%)*
Positive
n (%)*
955
negative
939 (98.3)
16 (1.7)
3
positive
3 (100)
0
12
missing
12 (100)
0
1488
negative
1455 (97.8)
33 (2.2)
6
positive
5 (83.3)
1 (16.7)
10
missing
10 (100)
0
* Percentages are calculated on the row totals for each treatment
PADAC
Sept. 5, 2003
73
ISS – Baseline FOB-Negative Phase III COPD
Patients Who Became Positive During
Treatment In Phase III Controlled COPD Trials
Set/Subset
Placebo
SB 207499
Total Patients
16
33
# FOB-positive stool samples
31
67
# patients with > 1 GIAE of concern
7
15
# patients receiving colonoscopy
2*
3*
* The results of these examinations were previously presented.
PADAC
Sept. 5, 2003
74
Demographics & Disposition In Uncontrolled
Trials (040, 041)
Prior Treatment
Demographic
Characteristics
Placebo
(N = 383)
SB 207499
(N = 695)
305 (79.6)
78 (20.4)
534 (76.8)
161 (23.2)
Race: Caucasian (%)
Black (%)
374 (97.7)
2 (0.5)
670 (96.4)
12 (1.7)
Age:
64.0 (8.9)
63.4 (9.0)
49.94 (11.69)
49.43 (11.83)
48.4 (25.9)
50.3 (28.0)
Sex:
Male (%)
Female (%)
Mean (SD)
FEV1 (% pred) Mean (SD)
Smoking History (pack-years)
Mean (SD)
PADAC
Sept. 5, 2003
75
ISS – Dispositions In Uncontrolled Trials
Prior Treatment
Reason For Withdrawal
Placebo
n = 383
SB 15mg
n = 695
Tot SB
n = 1078
Total Withdrawn
177 (46)
263 (38)
440 (41)
adverse event
93 (24)
104 (15)
197 (18)
6 (2)
11 (2)
17 (2)
87 (23)
93 (13)
180 (17)
74 (19)
27 (4)
111 (10)
protocol deviation
8 (2)
6 (1)
14 (1)
lost to follow-up
5 (1)
11 (2)
16 (2)
71 (19)
142 (20)
213 (20)
COPD exacerbation1
not COPD exacerbation
Gastrointestinal2
other
1
does not include asthma patients
2 nausea, abdominal pain, diarrhea, vomiting & dyspepsia
PADAC
Sept. 5, 2003
76
ISS – Treatment Exposure In Uncontrolled
Trials, Including Controlled Feeder Studies
Exposed
(days)
SB 207499
n = 1078
> 90
1003
>180
973
>360
865
>540
774
PADAC
Sept. 5, 2003
77
ISS – N (%) Of Patients With AEs in Uncontrolled
Trials
Adverse Event
Total SB 207499
n = 1078
Total
1009 (94)
chronic obstructive airways disease
653 (61)
upper respiratory tract infection
187 (17)
DIARRHEA
175 (16)
ABDOMINAL PAIN
173 (16)
injury
142 (13)
NAUSEA
140 (13)
headache
120 (11)
back pain
117 (11)
DYSPEPSIA
114 (11)
PADAC
Sept. 5, 2003
78
ISS – On-Therapy Deaths In Uncontrolled
Trials
66yM COPD
59yM CHF
56yM bronchopneumonia
74yM hanging
77yM heart failure
75yM MI
70yM probable MI
68yM MI
68yM ischemic colitis
PADAC
Sept. 5, 2003
79
ISS – Post-Therapy Deaths In Uncontrolled
Trials
66yF COPD
66yM pneumonia
69yM respiratory insufficiency
84yM COPD
73yM cardiac arrest
76yM circulatory failure
71yM cardiac arrest
71yM neoplasm NOS
PADAC
Sept. 5, 2003
63yM cardiac arrest
69yM cardiac arrest
56yM sudden death
51yF malignant neoplasm
75yM pneumonia
74yM MI
74yM cardiac arrest
73yM COPD
80
ISS – N (%) Of Patients With SAEs In
Uncontrolled Trials
SAEs
Total
n = 1078
Total
273 (25)
chronic obstructive pulmonary disease
85 (8)
pneumonia
34 (3)
injury
20 (2)
chest pain
13 (1)
angina pectoris
10 (1)
pulmonary carcinoma
10 (1)
myocardial infarction
9 (1)
neoplasm
9 (1)
PADAC
Sept. 5, 2003
81
ISS – N (%) Of Patients Withdrawing Due To
AEs From Uncontrolled Trials
AE Causing Withdrawal
Total
n = 1078
Total
177 (16)
ABDOMINAL PAIN
36 (3)
NAUSEA
26 (2)
DIARRHEA
23 (2)
chronic obstructive pulmonary disease
17 (2)
VOMITING
12 (1)
lung cancer
9 (1)
headache
5 (1)
myocardial infarction
5 (1)
PADAC
Sept. 5, 2003
82
ISS – GIAEs Of Concern In Uncontrolled
COPD Trials
GIAE Of Concern
Total (N = 1078)
n (%)
Total
141 (13)
abdominal pain
65 (6)
diarrhea
47 (4)
nausea
30 (3)
vomiting
18 (2)
dyspepsia
10 (1)
melena
10 (1)
gastritis
6 (1)
constipation
4 (<1)
PADAC
Sept. 5, 2003
83
ISS – Implementation Of Planned FOB
Monitoring Of GIAEs Of Concern And FollowUp In Uncontrolled COPD Trials
Implementation Of Planned
Monitoring
FOB any time after GIAEOC
Total (N = 141)
n (%)
128 (91)
FOB-positive test
FOB test within 14 days
9 (6)
68 (48)
FOB-positive test
8 (6)
GIAEOC+(FOB+)+CScope
4 (3)
PADAC
Sept. 5, 2003
84
ISS – Colonoscopies From Patients In
Uncontrolled Studies 040 & 041
• On-Treatment:
– 040.148.9866 – polyps
– 040.226.7371 – diverticulae
– 041.020.05598 – hemorrhoids
– 041.038.05057 – hemorrhoids
• Post-Treatment:
– 041.064.06001 – normal
PADAC
Sept. 5, 2003
85
ISS - Conclusion
• GIAEs
– …were a feature of treatment with SB 207499
– …were of sufficient severity to cause most of the
withdrawals in patients treated with SB 207499
• GIAEs Of Concern (GIAEOC)
– only 50-60% of patients with GIAEOC were tested
for FOB within 2 weeks
– FOB+ patients with GIAEOC were not all
evaluated for ischemic colitis by colonoscopy
PADAC
Sept. 5, 2003
86
ISS – Conclusion (cont.)
• Database of colonoscopy patients with GIAEOC and
FOB+
– SB 207499 - Treated
• Controlled Trials:
– 4 patients
• Uncontrolled Trials (includes 1 post-therapy
patient):
– 5 patients
– Placebo – Treated
• 2 patients
PADAC
Sept. 5, 2003
87
Overall Summary
• Efficacy (FEV1)
– 24-week trials with 25-30% drop outs
– where a placebo decline was seen, it
occurred over first few weeks
– 2 of 4 pivotal trials statistically significant
– support for efficacy of SB 207499 from:
• 1 of 4 trials of the co-primary endpoint
• 1 of 5 secondary endpoints
PADAC
Sept. 5, 2003
88
Overall Summary (cont.)
• Safety
– preclinical findings of mesenteric arteritis
– prominent dose-related GI AEs and
withdrawals due to them
– limited safety database of colonoscopies
in FOB+ patients with GIAEOCs
• Controlled & Uncontrolled SB 207499
–9 patients
• Placebo Patients
–2 patients
PADAC
Sept. 5, 2003
89
Advisory Committee Questions
1. Has cilomilast, at a dose of 15 mg twice daily, shown a
magnitude and consistency of efficacy that is sufficient to
support approval for the maintenance of lung function (FEV1)
in patients with COPD?
2. Is the safety database, aside from the concern about
vasculitis, for cilomilast for the maintenance of lung function
(FEV1) in patients with COPD sufficient to support approval?
3. Do you feel that the concern about mesenteric arteritis has
been adequately studied to be dismissed as a safety concern
in humans?
4. Do the efficacy and safety data provide substantial and
convincing evidence that support the approval of cilomilast at
a dose of 15 mg twice daily for the maintenance of lung
function (FEV1) in patients with COPD?
PADAC
Sept. 5, 2003
90
PADAC
Sept. 5, 2003
91
Advisory Committee Questions
1. Has cilomilast, at a dose of 15 mg twice
daily, shown a magnitude and consistency
of efficacy that is sufficient to support
approval for the maintenance of lung
function (FEV1) in patients with COPD?
a. If not, what further efficacy data should
be obtained?
PADAC
Sept. 5, 2003
92
Advisory Committee Questions
2. Is the safety database for cilomilast, aside
from the concern about vasculitis, for the
maintenance of lung function (FEV1) in
patients with COPD sufficient to support
approval?
a. If not, what further safety data should be
obtained?
PADAC
Sept. 5, 2003
93
Advisory Committee Questions
3. Do you feel that the concern about
mesenteric arteritis has been adequately
studied to be dismissed as a safety
concern in humans?
a. If not, what further data should be
obtained?
PADAC
Sept. 5, 2003
94
Advisory Committee Questions
4. Do the efficacy and safety data provide
substantial and convincing evidence that
support the approval of cilomilast at a dose
of 15 mg twice daily for the maintenance of
lung function (FEV1) in patients with
COPD?
PADAC
Sept. 5, 2003
95
PADAC
Sept. 5, 2003
96