Transcript Inhaled Cyclosporine (CyIS) Clinical Evidence of Efficacy and Safety Chiron | BioPharmaceuticals

CE-1
Inhaled Cyclosporine (CyIS)
Clinical Evidence of Efficacy and Safety
Sarah Noonberg, MD, PhD
Chiron | BioPharmaceuticals
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Animal Trials of CyIS at UPMC
Nontransplanted canine model
– High pulmonary concentrations
– No change in pulmonary function/arteriolar-alveolar
gradient
– No histologic abnormalities
• Ref: Burckart GJ, et al. J Clin Pharmacol. 1989;29:860
Canine transplant model
– Dose-dependent decrease in allograft rejection
• Ref: Dowling RD, et al. Surgery. 1990;108:198
Rodent transplant model
– Dose-dependent decrease in proinflammatory
cytokine production
– Decreased allograft rejection
• Ref: Mitruka SN, et al. J Thorac Cardiovasc Surg. 1998;115:28
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Open-Label Trials of CyIS at UPMC
Patients with chronic rejection:
– Improvement in chronic rejection histology
– Stabilization of pulmonary function
– Improvement in survival
•
Refs: Iacono AT, et al. Am J Respir Crit Care Med. 1996; 153:1451
Iacono AT, et al. Eur Respir J. 2004 23:384
Patients with refractory acute rejection:
– Improvement in acute rejection histology
– Reduction in proinflammatory cytokines
– Dose-dependent improvement in pulmonary function
– Improvement in survival
•
Refs: Keenan RJ, et al. J Thoracic Cardiovasc Surg. 1997;113:335
Iacono AT, et al. Transplantation. 1997;64:263
Iacono AT, et al. Am J Respir Crit Care Med. 1997;155:1690
Results of these trials led to unregulated compounding and use
of CyIS in lung transplant recipients with chronic rejection
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The Prophylaxis Trial: ACS001
Pivotal prospective clinical trial: 1997 through 2003
Randomized, double-blind, placebo-controlled trial to test
the efficacy of CyIS in preventing allograft rejection and
improving outcomes
Pilot phase initiated in 1997
– 10 patients on open-label CyIS
– Designed to test safety and tolerability
Randomized phase initiated in 1998
– 58 patients randomized, 56 treated with either
CyIS or placebo
Study endpoints:
– Primary endpoint: rate of acute rejection (AR)
– Secondary endpoints: survival, rate of chronic rejection,
and pulmonary function
Inclusion/Exclusion Criteria—
Study ACS001
Chiron Briefing Document Figure 4.1-1
Inclusion criteria:
Single- or double-lung
transplant recipients
18 years or older
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Exclusion criteria:
Active fungal or bacterial
pneumonia or anastomotic
infections prior to initiation
of appropriate treatment
Untreated bronchial
stenosis > 80%
Failure to wean from
mechanical ventilation
Women of childbearing
potential unwilling to use
appropriate birth control
and avoid pregnancy
All patients met study inclusion/exclusion criteria
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ACS001 Trial Design
Calcineurin inhibitors
Standard-ofcare systemic
immunotherapy
Anti-metabolites
Corticosteroids
Dose escalation
(10 days)
Study drug
Active or placebo
Transplant
Days 7 - 42
2 years intended treatment with
300 mg or MTD CyIS, 3 neb.s q wk
Entered into trial
No patients lost
to follow-up
Follow up for efficacy
First randomized
patient enrolled
16 NOV 98
Study end date
21 AUG 03
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Randomization
Developed by the Deptartment of Statistics at
University of Pittsburgh
Randomization stratified by
– CMV donor/recipient mismatch
(donor+/recipient- versus other)
• ISHLT registry data demonstrate CMV mismatch
is a significant risk factor for death within 1
year (relative risk = 1.32, P ≤ .0001)
– Enrollment period (7-21 versus 22-42 days posttransplant surgery)
ICH guidelines caution that it is impractical to stratify
by more than 2 factors
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Summary of Demographics—ACS001
Placebo
n = 30
Recipient age (years)
Median
Sex, n (%)
Male
18 (60)
16 (62)
Race, n (%)
Caucasian
28 (93)
24 (92)
Weight (kg)
Median
61.0
69.4
Height (cm)
Median
166.5
173.0
CMV match/mismatch
stratum, n (%)
Match
23 (77)
21 (81)
7 (23)
5 (19)
Baseline/maintenance
immunosuppression, n (%)
Imuran
30 (100)
22 (85)
Tacrolimus
30 (100)
26 (100)
Corticosteroid
30 (100)
26 (100)
Mycophenolate mofetil
5 (17)
5 (19)
Cyclosporine
1 (3)
1 (4)
37
36
Smoking (pack years)
AR 2+ prior to dosing, n (%)
Ischemic time (mean min)
Mismatch
Mean (all diagnoses)
55
CyIS random
n = 26
13 (43)
265.5
55
8 (31)
283.6
ISHLT: Predictive Value of Primary
Diagnosis and Transplant Type
100
IPF (N = 2,119)
75
Survival (%)
Survival (%)
100
COPD (N = 4,955)
75
50
50
25
25
0
0
0
1
2
3
4
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5
Bilateral/double
lung (N = 6,686)
Single lung
(N = 8,581)
0
1
2
3
4
Time (years)
Time (years)
ACS001
COPD: 35% CyIS vs 63% Placebo
IPF: 23% CyIS vs 3% Placebo
Would favor Placebo
ACS001
DLT: 42% CyIS vs 20% Placebo
SLT: 58% CyIS vs 80% Placebo
Would favor CyIS
Ref: ISHLT 2004
5
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Comparable Treatment Duration
63% (Placebo) and 69% (CyIS) completed ≥ 1 year of therapy;
43% (Placebo) and 50% (CyIS) completed the planned 2 years of therapy;
21/22 months median duration of dosing (Placebo/CyIS)
No patients were lost to follow-up
Patients, n (%)
Primary reason for drug discontinuation
Placebo
n = 30
CyIS random
n = 26
Completed 2-year dosing schedule
13 (43)
13 (50)
Adverse event
10 (33)
4 (15 )
0
6 (23)
Withdrawal of consent
Unsatisfactory therapeutic response
2 (7)
1 (4)
Protocol deviation/violation
5 (17)
2 (8)
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Summary of Results From ACS001
Efficacy
– Significant improvement in overall survival
duration
– Significant improvement in chronic rejection-free
survival
– No effect on acute rejection
Safety
– No increase in renal toxicity
– No increase in infections, neoplasms, or other
systemic toxicities
– Significant increase in mild/moderate respiratory
tract irritation and bronchospasm
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CyIS Extends Survival
The statistically significant survival effect was
observed in
An unadjusted analysis (log-rank P = .007)
– Relative risk (CyIS/placebo) = 0.213
Chiron Briefing Document Figure 1.3.2-1
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Estimated Survival Duration
1.0
0.9
0.8
Survival
0.7
0.6
Relative risk = 0.213
Log-rank P = .007
0.5
0.4
0.3
CyIS
Placebo
0.2
0.1
0.0
N at risk
Placebo
CyIS
0
6
12
18
24
30
36
Time (months)
42
48
54
60
30
26
27
26
25
25
24
25
21
22
10
12
7
6
3
0
0
0
16
18
11
13
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CyIS Extends Survival
The statistically significant survival effect was
observed in
An unadjusted analysis (log-rank P = .007)
– Relative risk (CyIS/Placebo) = 0.213
Analyses adjusting for known risk factors individually
– Relative risk (CyIS/Placebo) = 0.15 to 0.25
Relative Risk Unchanged After Adjusting
for Donor/Recipient Characteristics
Unadjusted analysis
Single LT
Prior grade 2+ AR
D+/R– mismatch
Non-emphysema diagnosis
Enrollment period
PRA > 10%
Recipient diabetes
Obesity
Recipient > 65 years
Donor > 35 years
Either D/R is male
Sex mismatch
ICU stay > 4 days
ICU stay > 10 days
Donor inotropic support
0.0 0.2 0.4 0.6 0.8 1.0 1.2
Relative risk
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CyIS Extends Survival
The statistically significant survival effect was
observed in
An unadjusted analysis (log-rank P = .007)
– Relative risk (CyIS/Placebo) = 0.213
Analyses adjusting for known risk factors individually
– Mean relative risk (CyIS/Placebo) = 0.15 to 0.25
Analyses adjusting for the key known risk factors
simultaneously in multivariable models (P < .032)
– Relative risk (CyIS/Placebo) = 0.227 to 0.238
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Baseline Donor/Recipient Characteristics
Imbalances potentially
favoring CyIS cohort
• Single-lung transplant
(80% placebo vs 58% CyIS)
• Grade 2+ AR prior to
dosing (43% placebo vs
31% CyIS)
Balanced baseline
characteristics
• CMV D+/R– mismatch
(23% placebo vs 19% CyIS)
• Enrollment period 2 (22-42
days) (43% placebo vs 42%
CyIS)
• Sex mismatch
(33% placebo vs 27% CyIS)
• Female donor/female recipient
(27% placebo vs 31% CyIS)
• Donor age > 35 years
(60% placebo vs 62% CyIS)
• Recipient age > 35 years
(87% placebo vs 88% CyIS)
• Prior grade 1+ AR prior to
dosing (57% placebo vs
54% CyIS)
• Donor lung bacterial
colonization (40% placebo vs
35% CyIS)
• Donor history of diabetes
(0% placebo vs 0% CyIS)
Imbalances potentially
favoring placebo cohort
• Primary diagnosis other
than emphysema
(37% placebo vs 65% CyIS)
• Primary diagnosis of IPF
(3% placebo vs 23% CyIS)
• Donor weight > 70 kg
(63% placebo vs 50% CyIS)
• Panel reactive antibodies
> 10% (0% placebo vs
8% CyIS)
• Recipient diagnosis of
diabetes mellitus
(3% placebo vs 12% CyIS)
• Recipient diagnosis of
obesity (10% placebo vs
19% CyIS)
Chiron Briefing Document Table 4.3.2.1-1
Relative Risk Unchanged When Controlling
for Baseline Characteristics Simultaneously
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95% CI for relative risk
(CyIS / Placebo)
Survival duration
 Unadjusted analysis
P = .007
Covariates in model in addition to treatment group
 Single LT, prior grade 2+ AR
P = .026
 Single LT, prior grade 2+ AR, CMV mismatch
P = .030
 Single LT, prior grade 2+ AR, CMV mismatch,
primary diagnosis (emphysema or other)
P = .032
 Single LT, prior grade 2+ AR, CMV mismatch,
primary diagnosis, enrollment period
P = .032
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Summary of Sensitivity Analyses
Around the Survival Endpoint
Chiron Briefing Document Table 4.3.1.1-1
Sample size
CE-19
Placebo
CyIS
Relative risk
(CyIS/Placebo)
Analysis on full data set
30
26
0.213
.007
Include patients randomized but not dosed
30
28
0.200
.005
Survival relative to date of first dose
30
26
0.216
.008
Patients (n = 3) who died within the first
3 months removed from analysis
27
26
0.265
.029
Patients (n = 14) who did not receive at least
80% of maximum dose study drug (adjusting
for death) removed from analysis
24
18
0.243
.048
Patients (n = 15) who developed pneumonia
within 1 month of initiation of study
medication removed from analysis
20
21
0.250
.058
Patients (n = 5) who were in the ICU more
than 14 days removed from analysis
26
25
0.275
.036
Sensitivity analysis
Log-rank
P value
Survival Advantage Persists 10 months
Poststudy
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1.0
Biases introduced
after study close:
0.9
Survival probability
0.8
 Study unblinding
0.7
 Patients off drug for
10 months to 3.5
years
0.6
0.5
0.4
0.3
 2 placebo patients
cross over to openlabel CyIS
Relative risk = 0.310
0.2
Placebo
CyIS
0.1
Log-rank P = .017
 Expect effects to
trend toward the null
0.0
0
6
12 18 24 30 36 42 48 54 60 66
N at Risk
Time (months)
Placebo
30
27 25
24 23 21 17
11
10
7
3
0
CyIS
26
26 25
25 23 23 20
15
13
10
4
0
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Placebo Survival Is Representative
ACS001 subject data matched with non-UPMC subject data
provided by United Network for Organ Sharing (UNOS)
– Lung transplants occurring 1998 through 2001
(ACS001 enrollment period)
– Subjects matched by
• Transplant type
• Age (18-40, 41-50, 51-60, 61+ years)
• Sex
• CMV D+/R- match or mismatch
• Primary diagnosis
• Early acute rejection
– Matching also excluded early postoperative deaths
from UNOS cohort
Chiron Briefing Document Figure 4.3.1.2-2
Placebo Survival Similar to
Matched UNOS Controls
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1.0
0.9
Survival probability
0.8
0.7
0.6
0.5
0.4
0.3
ACS001 placebo
Matched UNOS controls
0.2
0.1
0.0
0
N at risk
Placebo
30
UNOS
1038
6
12
18
27
942
25
866
24
815
24
30
36
Time (months)
23
21
18
761
705
561
42
48
54
60
17
476
14
339
8
249
8
161
Chiron Briefing Document Figure 4.3.1.2-3
CyIS Survival Significantly Longer vs
Matched UNOS Controls
CE-23
1.0
0.9
Survival probability
0.8
0.7
0.6
0.5
0.4
0.3
Relative risk
(CyIS/UNOS) = 0.252
CyIS
Matched UNOS controls
0.2
0.1
P =.019
0.0
0
N at risk
CyIS
26
UNOS
1058
6
12
18
24
30
36
Time (months)
26
951
25
876
25
810
22
679
18
538
13
430
42
48
54
60
12
311
6
220
0
132
0
63
Prevention of Chronic Rejection
Leads to Improved Survival
Chiron Briefing Document Figure 1.3.2-1
1.0
PNA/AR PNA/AR
Sepsis
PNA/AR/CR
PNA/PE
CR/AR
PNA/AR/PE
PNA/RF
Sepsis
CR/PNA
0.9
0.8
Survival
0.7
0.6
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CyIS
Placebo
Sepsis/CR
PE/CR
Sepsis/pHTN
CR
CR/PNA
CR/AR
0.5
CHF/CR
0.4
CR = Chronic rejection
PNA = Pneumonia
AR = Acute rejection
PE = Pulmonary embolism
RF = Renal failure
pHTN = Pulmonary hypertension
CHF = Congestive heart failure
0.3
No unexpected deaths
0.2
Infection most prominent early
0.1
CR most prominent after 18 months
0.0
0
6
12
18
24
30
36
Time (months)
42
48
54
60
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CyIS Prevented Chronic Rejection
Chronic rejection measured
– Histologically through transbronchial
biopsy (OB)
– Clinically through an unexplained 20%+
sustained decrease in FEV1 (BOS)
CyIS resulted in a 72% decrease in the risk of
chronic rejection or death (log-rank P = .001)
– Relative risk (CyIS/placebo) = 0.279
[95% CI = 0.124, 0.630]
– Consistent results when adjusting for
prognostic factors
Chiron Briefing Document Figure 4.3. 2-1
Chronic rejection-free survival probability
Kaplan-Meier Estimate of
Chronic Rejection-Free Survival
CE-26
1.0
0.9
0.8
0.7
Relative risk = 0.279
[95% CI: 0.124, 0.630]
Log-rank P = .001
0.6
0.5
0.4
0.3
CyIS
Placebo
0.2
0.1
0.0
N at risk
Placebo
CyIS
0
6
12
18
24
30
36
Time (months)
30
26
24
26
19
24
14
21
12
16
6
12
5
11
42
48
54
60
4
9
3
5
1
0
0
0
Relative Risk of Chronic Rejection or
Death Is Robust
Unadjusted analysis
Single LT
Prior grade 2+ AR
D+/R- mismatch
Non-emphysema diagnosis
Enrollment period
PRA > 10%
Recipient diabetes
Obesity
Recipient > 65 years
Donor > 35 years
Either D/R is male
Sex mismatch
ICU stay > 4 days
ICU stay > 10 days
Donor inotropic support
0.0 0.2 0.4 0.6 0.8 1.0 1.2
Relative risk
CE-27
Chiron Briefing Document Table 4.3.2.1-1
Relative Risk Unchanged When Controlling
for Baseline Characteristics Simultaneously
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95% CI for relative risk
(CyIS / Placebo)
Chronic rejection-free survival
 Unadjusted analysis
P = .001
Covariates in model in addition to treatment group
 Single LT, prior grade 2+ AR
P = .007
 Single LT, prior grade 2+ AR, CMV mismatch
P = .007
 Single LT, prior grade 2+ AR, CMV mismatch,
primary diagnosis (emphysema vs. other)
P = .008
 Single LT, prior grade 2+ AR, CMV mismatch,
primary diagnosis, enrollment period
P = .007
0.0
0.2
0.4
0.6
0.8
1.0
1.2
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CyIS Prevents Chronic Rejection
The effect on chronic rejection is not driven
solely by mortality
Analysis of chronic rejection (deaths censored):
– Biased against CyIS due to larger number of
Placebo deaths (informative censoring)
– Yet statistically significant (P = .015) in
favor of CyIS
Chronic rejection occurred among
– 15 (50%) of Placebo patients
– 7 (27%) of CyIS patients
Chiron Briefing Document Figure 4.3.2-3
Kaplan-Meier Estimates of Time to
Chronic Rejection—Deaths Censored
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OB-free and BOS-free probability
1.0
0.9
0.8
0.7
0.6
Log-rank P = .015
0.5
0.4
0.3
CyIS
Placebo
0.2
0.1
0.0
N at risk
Placebo
CyIS
0
6
12
18
24
30
36
Time (months)
30
26
24
26
19
24
14
21
12
16
6
12
5
11
42
48
54
60
4
9
3
5
1
0
0
0
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Acute Rejection
71% of patients in both groups had at least 1 episode of
documented grade 2+ AR prior to study termination
Number of AR episodes
after start of dosing
Placebo
0
1
2
9
11
6
7
9
5
3
4
Total
3
1
36
4
1
35
CyIS
Estimate of ratio of ARs (CyIS/placebo) = 1.09, P = .73
CyIS Results in Low Systemic
Cyclosporine Levels
Chiron Briefing Document Table 3.2.3-1
CyIS
Dose
Population
300 mg
Recent lung
transplant
CE-32
Mean peak
Mean
blood
blood
Mean
concentration concentration AUC0-24h
(ng/mL)
at 24h (ng/mL) (ng·hr/mL)
206
< 30b
1034
Neoral® 597 mg/da Recent
renal
transplant
1802
361
8772
Neoral
1555
268
7187
458 mg/da Recent liver
transplant
Given orally as divided doses 12 hours apart.
b Approximation: range was 9 to 48 ng/mL measured 24 hours postdose.
a
CE-33
Sources of Data for Safety Evaluation
Animal studies
– Findings for CyIS and PG (placebo) minimal in animals and
consistent with findings in ACS001 and ACS002
ACS001: randomized, placebo controlled trial
– N = 30 Placebo vs N = 26/36 CyIS (randomized/+pilot)
ACS002: open-label, noncomparative trials
– N = 70 patients in patients with refractory acute or
chronic rejection
– Only transplants in 1995 or later included to create a cohort
with comparable immunosuppressant use
ISS: combination of ACS001 and ACS002
– N = 102 unique patients treated with CyIS
CE-34
Summary of Clinical Safety Data
Review of AE data in ACS001 revealed CyIS was safe
– No increased risk of nephrotoxicity, neurotoxicity,
infections, malignancies, or other known toxicities
of systemic cyclosporine
– CyIS was not associated with any new systemic
toxicities
– CyIS was associated with respiratory tract irritation
and bronchospasm
Review of AE data in ACS002 and ISS confirmed safety
findings of ACS001
Review of SAE data in ACS001, ACS002, and ISS
revealed no new safety signals
Respiratory Adverse Events
Study ACS001
CE-35
Patients, %
Any respiratory, thoracic or
mediastinal disorder
Cough
Dyspnea exacerbated
Dyspnea
Lung consolidation
Pharyngitis
Pleural effusion
Postnasal drip
Pulmonary hemosiderosis
Wheezing
Placebo
n = 30
All CyIS
n = 36
97
100
27
13
60
13
17
50
37
63
20
50
31
53
31
39
47
28
64
33
Respiratory tract irritation and bronchospasm were generally
mild/moderate, occurred early, and diminished with time and did
not progress to more serious respiratory complications
CE-36
Single Center Study Design
Study ACS001 was conducted at a single center
– No other studies/registries analyses have ever
shown a survival benefit comparable with that
CyIS patients
– Placebo data are comparable with UNOS data
– Single-center trials provide better estimates of
treatment effect than multicenter trials of the
same size
– Chiron is committed to a multicenter
postapproval trial to further evaluate the
generalizability of the efficacy and
safety of CyIS
CE-37
Sample Size
The sample size of N = 56 for efficacy and
N = 102 for safety is small
– The lung transplant population is small
– Despite the size, the survival data (P = .007)
and chronic rejection data (P = .001) are
highly statistically significant
– The safety of cyclosporine is well documented
and the safety profile of CyIS is extremely
favorable
– Chiron is committed to creating a larger
efficacy and safety database through a
postapproval trial
CE-38
Randomization and CRF Assembly
The randomization code was susceptible to
unblinding and CRF assembly was retrospective
– Actions of study team suggest they were unaware
of individual treatment assignments
• Randomization was sequential with
consent date
• 3 CyIS patients and 2 Placebo patients were
withdrawn from the study to receive
open-label CyIS
– Pathologists were not exposed to patient numbers
– Retrospective CRF assembly cannot bias
assessments of death, presence of OB on a
histopathology report, or > 20% decline in FEV1
CE-39
Treatment Groups
Treatment groups were not balanced on each and
every baseline characteristic
– The goal of randomization is not to eliminate
imbalances but to randomly distribute
imbalances between treatment groups
– Treatment groups are comparable
• For the 16 characteristics supported by
evidence in the literature, 8 balanced,
2 favor CyIS, 6 and favor placebo
– Statistical models can adjust for clinically
relevant imbalances
– Imbalances did not explain efficacy of CyIS
CE-40
Acute vs Chronic Rejection
The study did not meet its primary endpoint of
decreased rate of acute rejection
– Reflects evolving understanding of acute versus
chronic rejection
– Lack of effect on acute rejection is consistent with
low systemic exposure
– Study design does not impact the assessment of
survival or chronic rejection
– Survival and chronic rejection were prospectively
defined secondary endpoints
– The survival and chronic rejection data are
clinically important, statistically significant, and
scientifically sound
Differences of Opinion in
Statistical Analysis
Covariates in a statistical model should be chosen
based on association with clinical outcome rather
than on imbalance
– ICU time posttransplant > 10 days
– Donor inotropic support
Survival data should not be excluded from patients
whose donor use of an inotrope is unknown
Primary data set for analysis should be based on
study end date
Patients with OB need to be included in a chronic
rejection analysis
Deaths should not be censored in an analysis of
chronic rejection
CE-41
CE-42
Summary of Clinical Data
In the lung transplant population with no approved drugs,
very few randomized clinical trials, and dismal prognosis…
CyIS was associated with a 79% decrease in risk of death
CyIS was associated with a 72% decrease in the risk of
chronic rejection or death
CyIS efficacy results are robust
ACS001 Placebo population is representative
CyIS was not associated with any systemic toxicity
CyIS was associated with local respiratory tract irritation
and bronchospasm
Chiron Briefing Document Figure 1.3.2-1
CE-43
Estimated Survival Duration
1.0
0.9
0.8
Survival
0.7
0.6
Relative risk = 0.213
P = .007
0.5
0.4
0.3
CyIS
Placebo
0.2
0.1
0.0
N at risk
Placebo
CyIS
0
6
12
18
24
30
36
Time (months)
42
48
54
60
30
26
27
26
25
25
24
25
21
22
10
12
7
6
3
0
0
0
16
18
11
13