Transcript Slide 1

Prostate Cancer Epidemiology:
Estimated 2010
Total Active Disease: 773,000
Stages I-III: 508,000
Metastatic (M+):
183,000
Castrate Sensitive*:
80,000
Castrate Resistant*:
103,000
US Census,
SEER 2007,
NODBIMPAC
Market
Research
Symptomatic
M+ CRPC
Asymptomatic
M+ CRPC
*Estimated based on physician reported percentages among 200
community oncologists and urologists.(2005).
Life After Traditional
Androgen Deprivation Failure
• Other Hormonal Therapy
• Chemo Therapy
• Immunotherapy
Rationale For Immunotherapy
• Cancer
• Cellular dysfunction
• Resistance to or escape from host defenses
• Active immunotherapy
• Suitable target antigen
• Effective presentation of antigen
• Mobilization of immune cascade
Antigen Presenting Cells
(APCs)
 Dendritic cells (DCs) are antigen-presenting
cells that process and present MHC-peptide
complexes to activate a T-lymphocyte
response
T-cell
CD154
CD11/CD18
CD8
TCR CD4
CD28
Peptide
CD40
CD54
MHC class I
MHC class II
Dendritic cell
CD80
CD86
CTLA4
sipuleucel-T (Provenge®)
sipuleucel-T is an autologous active cellular
immunotherapy that activates the immune
system against prostate cancer
Sipuleucel-T: Patient-Specific Therapy
Day 1
Leukapheresis
Apheresis Center
Day 2-3
sipuleucel-T is
manufactured
Dendreon
Day 3-4
Patient is infused
Doctor’s Office
COMPLETE COURSE OF THERAPY:
Weeks 0, 2, 4
Percent without Progression
Primary Endpoint (Trial 9901)
Time to Disease Progression Study 1
100
sipuleucel-T (n=82)
placebo (n=45)
75
p = 0.052 (log rank)
HR = 1.45 [95% CI: 0.99, 2.11]
50
25
0
0
8
16 24 32 40 48 56 64 72 80
Weeks
Secondary Endpoint - Survival
Clinically Significant and Statistically
Persuasive Overall Survival Benefit
100
sipuleucel-T (n=82)
placebo (n=45)
75
p = 0.010 (log rank)
HR = 1.71 [95% CI: 1.13, 2.58]
50
Median benefit
4.5 months
34%
25
11%
0
0
6
12
18
24
30
36
Vote of FDA Expert Panel
 17 – 0 for safety
 13 – 4 for substantial evidence of efficacy
 FDA Requires More Data
(<2% Event)
Randomized Phase 3 IMPACT Trial
(IMmunotherapy Prostate AdenoCarcinoma Treatment)
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=512)
Primary endpoint:
Secondary endpoint:
Sipuleucel-T
Q 2 weeks x 3
2:1
Placebo
Q 2 weeks x 3
P
R
O
G
R
E
S
S
I
O
N
Treated at
Physician
discretion
Treated at
Physician
discretion
and/or Salvage
Protocol
Overall Survival
Time to Objective Disease Progression
S
U
R
V
I
V
A
L
Eligibility Criteria
 Metastatic castrate resistant prostate cancer
 Life expectancy of at least 6 months
 Serum PSA ≥ 5.0 ng/mL
 Castrate level of testosterone (< 50 ng/dL)
achieved via medical or surgical castration
 Adequate hematologic, renal, and liver
function
 Negative serology for HIV 1 & 2, HTLV-1, and
Hepatitis B & C
Patient Demographics and Baseline
Characteristics
Age, median yrs (range)
Race, white (%)
ECOG status, 0 (%)
Gleason Score ≤ 7 (%)
Sipuleucel-T
(N = 341)
72 (49 – 91)
89.4
82.1
75.4
Placebo
(N = 171)
70 (40 – 89)
91.2
81.3
75.4
Disease localization
Bone only (%)
Soft tissue only (%)
Bone & soft tissue (%)
>10 bone mets (%)
50.7
7.0
41.9
42.8
43.3
8.2
48.5
42.7
Bisphosphonate use
Prior docetaxel (%)
48.1
15.5
48.0
12.3
Baseline Median Laboratory Values
Sipuleucel-T
(N = 341)
Placebo
(N = 171)
Serum PSA, ng/mL
51.7
47.2
Serum PAP, U/L
2.7
3.2
Alk. Phosphatase, U/L
99.0
109.0
Hemoglobin, g/dL
12.9
12.7
LDH, U/L
194.0
193.0
6.2
6.0
WBC, 103/µL
IMPACT Overall Survival: Primary Endpoint
Intent-to-Treat Population
P = 0.032 (Cox model)
HR = 0.775 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
Percent Survival
100
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
75
50
25
Placebo (n = 171)
Median Survival: 21.7 Mos.
0
0
6
12
18
24
30
36
42
48
Survival (Months)
54
60
66
Overall Survival Summary
Survival Percentiles (months)
N
75%
50%
25%
Sipuleucel-T
341
15.1
25.8
41.3
Placebo
171
11.0
21.7
35.6
4.1 mos
Sipuleucel-T
Placebo
% Survival (K-M estimates
24 Mos.
36 Mos.
48 Mos.
52.1
31.7
20.5
41.2
23.0
8.7%
16.0
Survival Consistency Between Population
Subsets
Favors sipuleucel-T
Bisphosphonate Use: Yes
No
Primary Gleason Grade:  4
3
No. Bone Metastases: > 10
 10
Disease Localization: Single
Bone + Soft Tissue
ECOG Performance Status: 1
0
Age: Above Median
Below Median
PSA: Above Median
Below Median
LDH: Above Median
Below Median
Alkaline Phos: Above Median
Below Median
Hemoglobin: Above Median
Below Median
0.0
0.5
1.0
1.5
Hazard Ratio (95% Confidence Interval)
Survival Results Confirmed by Multiple
Sensitivity Analyses
Favors sipuleucel-T
0.775
P = 0.032
0.766
P = 0.023
0.763
P = 0.036
0.772
P = 0.036
Primary Model (Adj. for PSA, LDH)
Unadjusted/Log Rank
Adjusted for Docetaxel Use
PCa-Specific Survival
0.0
0.5
1.0
Hazard Ratio (95% Confidence Interval)
1.5
Most Common Adverse Events (≥ 5%)
Higher Rate in Sipuleucel-T (p ≤ 0.05)
Sipuleucel-T
N = 338
%
54.1
Placebo
N = 168
%
12.5
Pyrexia
29.3
13.7
Headache
16.0
4.8
Influenza-like illness
9.8
3.6
Hypertension
7.4
3.0
Hyperhidrosis
5.3
0.6
Preferred Term
Chills
Serious Adverse Events*
Safety Population
SAE Preferred Term
Any SAE
Pyrexia
Cerebrovascular accident
Pulmonary embolism
Spinal cord compression
Nausea
Atrial fibrillation
Dehydration
Cardiac failure congestive
Pneumonia
Hematuria
Deep vein thrombosis
Renal failure acute
*Occurring in ≥ 4 patients.
Sipuleucel-T
N=338
%
24.0
1.8
1.8
1.2
1.2
0.9
0.9
0.9
0.6
0.6
0.6
0.3
0.3
Placebo
N=168
%
23.8
0.6
1.8
0.0
1.2
1.2
0.6
0.6
1.2
1.2
1.2
1.8
2.4
Consistency Across Phase 3 Studies
D9901*
D9902A*
IMPACT **
Integrated**
(N = 127)
(N = 98)
(N = 512)
0.586
0.786
0.775
(N=737)
0.735
p = 0.010
p = 0.331
p = 0.032
p < 0.001
4.5
3.3
4.1
3.9
sipuleucel-T
34%
32%
32%
33%
placebo
11%
21%
23%
20%
Hazard Ratio
p-value
Median Survival Benefit
(months)
36-Month survival (%)
*Unadjusted Cox model & log rank
**Cox model adjusted for PSA and LDH
Summary
 First active immunotherapy to demonstrate
improvement in overall survival for cancer
 Highly favorable benefit to risk profile
 Short duration of therapy
 Potential to create new paradigm in treatment
of metastatic, castrate resistant prostate
cancer
Time to Objective Disease Progression
 Secondary endpoint
 Result
– Independent radiologic review
– HR=0.951 (95% CI: 0.77,1.17); P=0.628 (log rank)
 Consistent with other trials in advanced
prostate cancer
 Difficult endpoint to measure reliably and
doesn’t correlate with overall survival
PSA-TRICom Randomized Phase II Study
Asymptomatic or
Minimally
Symptomatic
Metastatic
Castrate
Resistant
Prostate Cancer
(N=125)
PROSTVAC-VF
Tricom + GM
2:1
Empty Vector +
placebo
P
R
O
G
R
E
S
S
I
O
N
Treated at
physician
discretion
Treated at
physician
discretion
and/or Salvage
Protocol
Primary endpoint:
Progression Free Survival
Secondary endpoint:
Overall Survival
S
U
R
V
I
V
A
L
PSA-TRICom Progression-Free Survival
Hazard Ratio = 0.88 (95% CI 0.57 to 1.38)
P = 0.60 (stratified logrank)
100
80
60
40
20
N
Control
40
PROSTVAC 82
0
0
1
Events Median
30
3.7
58
3.8
2
3
Months
4
5
6
25
PSA-TRICom Overall Survival
Hazard Ratio = 0.56 (95% CI 0.37 to 0.85)
P = 0.006 (stratified logrank)
100
N
Control
40
PROSTVAC 82
Deaths Median
37
16.6
65
25.1
80
60
40
20
0
0
12
24
36
Months
48
60
26
Background-The Development of
PROSTVAC-VF-Tricom
 Vaccinia
– Potent immunological priming agent
– Derived from wild-type Wyeth strain (used in millions of
immunizations)
 Fowlpox
– Minimally/non-cross-reactive with vaccinia

Enables boosting
 Slightly altered PSA transgene
 Tricom
– Lymphocyte function-associated antigen LFA-3 (CD58)
– Intercellular adhesion molecule ICAM-1 (CD54)
– Costimulatory molecule for the T-cell receptor B7.1
(CD80)
27
PROSTVAC-PSA-Tricom
Vaccinia-PSA-Tricom
Fowlpox-PSA-Tricom
Prime
Boosts
28
Conclusions
 Poxviral-based immunotherapy is feasible and safe
 Primary endpoint of prolonged PFS was not met
 Secondary endpoint of prolonged median OS
– 8.5 month difference in OS, HR 0.56 (95% CI 0.37-0.85) with
p=0.0061
 Baseline characteristics of patients in both arms
similar
 Need to validate these findings in large Phase III study
with survival endpoint