Alain Rolland Presents TransVax Phase 2 Trial Results at the World Vaccine Congress in Lyon, France.

1. TransVax™ Phase 2 Trial Results
T V ™ Ph T i lR lt
A Therapeutic DNA Vaccine to Control
Cytomegalovirus in Hematopoietic Cell
Transplant Recipients
Alain Rolland, Pharm.D., Ph.D.
Executive Vice P id t P d t D
E ti Vi President, Product Development
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October 5, 2010 - World Vaccine Congress - Lyon

2. Why Cytomegalovirus (CMV) Vaccine?
 Persistent, latent herpes virus
 Infects 50-85% of US adults by age 40
 Significant health threat for immunocompromised
 Initial high risk target populations (North America/Europe)
 Hematopoietic stem cell transplant (HCT) patients (~60,000/yr)
 Solid organ transplant (SOT) patients (~60,000/yr)
 No approved vaccine available
 Biolog of protection from rec rrence is well understood
Biology recurrence ell nderstood
 Current antiviral treatments can provide benefits but
p
present significant risks
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3. Unmet Need for HCT Vaccine
 Reactivation in ~60% of CMV+ recipients within 6 months
after transplant; if untreated, can cause pneumonitis,
hepatitis, gastroenteritis, retinitis, leukopenia, encephalitis
p ,g , , p , p
 Most centers give preemptive antiviral therapy after virus is detected
 ~5% develop CMV disease despite therapy
 G
Ganciclovir and other antivirals h
i l i d th ti i l have li it ti
limitations
 Bone marrow toxicity, fever, nausea, vomiting, diarrhea, tremor
 Hospitalization required, expensive
 DNA vaccine offers opportunity to control CMV reactivation
 Stimulates both cellular and humoral immunity
 No infectious components – safe in imm nocompromised patients
infectio s immunocompromised

4. TransVax™ CMV Vaccine
Product Description
 Intramuscular injection
 Two plasmids: gB + pp65 (5 mg/mL dose)
 CRL1005 poloxamer (7.5 mg/mL)
+ benzalkonium chloride (BAK; 0.11 mg/mL)
( g )
 Stable at -30°C for >3 years
 Tested in Phase 1* and Phase 2 trials
 F
Favorable safety profile
bl f t fil
 Induces T-cell and antibody responses
 Commercially practical
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 Convenient single-vial packaging
 Established manufacturing capacity sufficient
for worldwide HCT need
 U.S. Orphan drug status for HCT and SOT
*Wloch et al., J Inf Dis 2008

5. Plasmid Selection Kan
HCMV pro
p
Intron A
VCL-6368
6135 bps
ori
hCMV pp65
mRBG
Construct Rationale Details
pp65 (VCL-6368) Immunodominant CTL 435-438
target in infected
g (
(kinase domain deleted)
)
individuals AD169 strain-derived,
Codon-optimized
gB (VCL 6365)
(VCL-6365) Major target of a.a. 1-713
a a 1 713
neutralizing antibody Secreted
AD169 strain-derived,
Codon-optimized

6. Poloxamer CRL1005 Delivery System
Hydrophobic core
POP
~1.5 m
 CRL1005
 Nonionic block copolymer
Hydrophilic corona
 POP 12 kDa (y=205) and POE 5% (x=8) + BAK POE
 Maximum DNA d
M i dose, 5 mg/mL
/ L
 Forms nanoparticles with DNA > 10°C +
 Selected based on balanced and improved +DNA
cellular and humoral immune responses
A.F. Micro
300 nm
Hartikka et al., J Gene Med 2008

7. CMV in Hematopoietic Cell Transplant
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Hypotheses and Assumptions
 Reactivation in ~60% of CMV+ recipients within 6 months
after transplant
 Meyers et al., 1986; Junghanss et al., 2002, 2003
y , ; g , ,
 DNA vaccination should increase CMV-specific immune
responses
 S li k et al., 2005; Hartikka et al., 2008 Wl h et al., 2008
Selinsky t l 2005 H tikk t l 2008; Wloch t l
 Increased cellular immune responses should reduce viremia
 Cwynarski et al., 2001; Aubert et al., 2001, Hakki et al., 2003
 Reduced viremia should decrease antiviral use and CMV
disease
 Emery et al., 2000
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8. TransVax™ Phase 2 HCT Trial
 Randomized double blind placebo controlled
Randomized, double-blind, placebo-controlled
 18-65 yo CMV+ HCT recipients with leukemia or lymphoma
 6/6 or 5/6 HLA allele match
 Stratified by site donor CMV status, HLA match
site, status
 Randomized 1:1 for active vs. placebo vaccination
 Endpoint-defining study
 Multicenter (16 enrolling sites)
 Endpoints
 Safety
 Immunogenicity
 Viral load
 CMV antiviral therapy
i i l h

9. TransVax™ Phase 2 HCT Trial
Recipient Immunization Regimen
Hematopoietic Cell Transplant (HCT Study)
HCT Recipient
CMV+ only
Pretransplant,
Pretransplant R
1, 3, and 6 mo Immunosuppressed
HCT Donor
CMV+ or CMV- HCT
D Transplant
T l t
Related or unrelated
80 subjects enrolled 1:1 TransVax™ to placebo

10. Recipients Key Inclusion Criteria
 18 t 65 years of age
to f
 CMV-seropositive
 Planned 6/6 or 5/6 classic HLA allele-matched transplant
 Minimal to no T-cell depletion of graft
 For the treatment of hematologic cancers including
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 Acute lymphoblastic leukemia in 1st or 2nd remission
 Acute myelogenous leukemia in 1st or 2nd remission
 Chronic myelogenous leukemia in first chronic or accelerated
phase, or in second chronic phase
 Hodgkin’s and non-Hodgkin’s lymphoma
 M l d
Myelodysplastic syndrome
l ti d

11. Recipients Key Exclusion Criteria
 Poor-risk subject, as defined by any one of the following
 Chronic myelogenous leukemia in blast crisis
 Acute myeloid leukemia beyond second remission
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 Multiple myeloma
 Aplastic anemia
 Pl
Planned prophylactic th
d h l ti therapy with CMV i
ith immunoglobulin
l b li
and/or antivirals
 Complete T-cell depletion of graft and/or use of
alemtuzumab (C (Campath-1H))

12. Demographic and Baseline Characteristics
TransVaxTM Placebo
Intent to Treat (ITT) Population
I t t t T t (ITT) P l ti (N=42) (N=38)
Gender Female 22 (52%) 15 (39%)
Male 20 (48%) 23 (61%)
Race Caucasian 39 (93%) 35 (92%)
African American 3 (7%) 3 (8%)
Age Mean (years) 49.2 49.1
Donor CMV Status* Positive 20 (48%) 21 (55%)
Negative 22 (52%) 17 (45%)
HLA Allele Matching* 6/6 38 (90%) 36 (95%)
5/6 4 (10%) 2 (5%)
Relatedness to Donor Related 23 (55%) 17 (45%)
Unrelated 19 (45%) 21 (55%)
Conditioning Regimen Myeloablative 31 (74%) 27 (71%)
Partially myeloablative 11 (26%) 11 (29%)
* Groups were stratified by site, donor CMV status, and HLA match.
Unaudited data

13. Safety Findings
 No safety concerns
 DSMB reviewed first 20 patients through Day 56
 C ti
Continued review of SAE and safety reports for
d i f SAEs d f t t f
remainder of study
 SAEs
 One report of angioedema after second
dose, possibly related to metoclopramide or study
drug
 No other study discontinuations due to related AEs
 No difference between groups in SAEs

14. Safety Observations
TransVax™ Placebo
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Adverse Events (ITT population)
(N=42) (N=38)
Subjects with at least one AE 42 (100%)
42 (100%) 38 (100%)
38 (100%)
Subjects with related AEs 16 (38%) 17 (45%)
Subjects with at least one SAE 33 (79%) 29 (76%)
Subjects with related SAEs 2* (5%) 1° (3%)
Subjects discontinued due to AE 5 (12%) 5 (13%)
Subject discontinued due to related AEs 1 (2%) 0 (0%)
Subjects who died during the study 8 (19%) 12 (32%)
* Includes angioedema (1hr) and subarachnoid hemorrhage from a known aneurysm (3mo) after receiving the investigational product.
° CMV colitis 6mo after last dose.
Unaudited data

15. T-cell
T cell Responses to pp65 for 1 Year
Median pp65 IFN  ELISPOT Response
Median pp65 IFN‐ ELISPOT Response
4500
4000
3500
3000
SFU/106 PBMC
p=0.003*
2500 TransVax™
2000 Placebo
1500
1000
500
0
‐10 65 140 215 290 365
Days
N=20-31 for Placebo
N=26-33 for TransVax™
*p-value is from a repeated measurement ANOVA using log10 transformed data from day 56-365.

16. T-cell
T cell Responses to gB for 1 Year
g 
Median gB IFN‐ ELISPOT Response
p
400
350
300
SFU/106 PBMC
250
p=0.075*
TransVax™
200
0
Placebo
150
100
50
0
‐10
10 65 140 215 290 365
Days
N=20-33 for Placebo
N=26-33 for TransVax™
*p-value is from a repeated measurement ANOVA using log10 transformed data from day 56-365.

17. Antibody Responses to gB for 1 Year
Geometric Mean gB Antibody (90% CI)
500000
p=0.009
*
body (EU/mL)
)
50000 Vaccine
gB Antib
Placebo
Pl b
5000
‐10 65 140 215 290 365
Days
N=26-38 for TransVaxTM, N=20-34 for Placebo
*Trend (0.05<p<0.10); Wilcoxon rank-sum test used for individual datapoints
Overall p-value=0.119 based on repeated measurement ANOVA using log10 transformed data from day 56 to 365

18. Viral Load and Antiviral Approach
 Viral load monitored by both local and central lab assays
 Weekly (wk 3-13), Biweekly (wk 14-28), Monthly (wk 29-52)
 Decision to administer antiviral treatments based on
local labs and site-specific treatment algorithms
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 PCR or antigenemia assays
 Typical treatment is ganciclovir or valganciclovir
 Phase 2 viral load data for all sites based on
standardized assay at central Mayo Clinic lab
 Roche LightCycler PCR assay (LOD: 500 copies/mL)

19. Viral Load and Treatment Endpoints
TransVax™ Placebo %
Per Protocol Population (to 1 yr)
Pop lation r) p al e
p-value
(N=40) (N=34) Change
*Occurrence of CMV reactivation (≥ 500 copies/mL) 13 (32%) 21 (62%) -48% 0.008a
Time to initial CMV reactivation (days) Median >365 109.5 NA 0.003b
Number of CMV reactivation episodes 0 27 (68%) 13 (38%)
1 8 (20%) 14 (41%)
2 4 (10%) 3 (9%) NA 0.017c
3 1 (3%)
( ) 3 (9%)
( )
≥4 0 1 (3%)
Duration of viremia (days) Mean 10.6 (0-68) 19.5 (0-181) -46% 0.069c
Normalized (as a % of time on study) Mean 4.9 (0-63) 7.7 (0-49) -36% 0.042c
*Occurrence of initiating CMV-specific antiviral therapy 19 (48%) 21 (62%) -23% 0.145a
Cumulative CMV-specific antiviral therapy (days) Mean 30.2 (0-315) 39.8 (0-212) -24% 0.266c
CMV-associated disease (GI and/or pneumonia) 3 (8%) 4 (12%) -33% 0.696d
*Note that viral load endpoints were obtained from the central lab, whereas local lab results and site-specific
algorithms were primarily used for treatment decisions.
p-value was computed by aCMH test stratified by site, blog rank test, cWilcoxon rank sum, or dFisher’s exact test.
Unaudited data

20. Time to Initial Viral Reactivation
≥ 500 copies/mL
Median
109 days
↑ ↑ ↑ ↑ p=0.003
Note: p-value is from a log-rank test with stratification by site.
Plotted circles represent censored data. Viral load determined by a central lab PCR assay.

21. Prevalence of CMV Episodes
p=0.036*
↑ ↑ ↑ ↑
Reflects multiple occurrences, time to onset, and interevent correlations
*p-value based on time to CMV viremia episodes by Andersen-Gill analysis with sandwich variance estimate.

22. Treatment Endpoint Subset Analysis
 Per Protocol population apparently included 7 subjects who were
never CMV infected, despite positive antibody titers at screening
 Steadily decreasing CMV-specific antibody titers that below LOD
 No CMV-specific T cells at entry
 No viral load at any time
 Presumed cause is prior transfusion with CMV+ blood products
TransVax™ Placebo % p‐
Protocol subset (PP ‐ 7 subjects) (N=38) (N=29) Change value
Occurrence of CMV reactivation (≥ 500 copies/mL) 13 (34%) 21 (72%) ‐53% 0.002*
Duration of viremia (d )
i f i i (days) Mean 11.2 (0‐68)
( ) 22.8 (0‐181)
( ) ‐51%
% 0.026§
(as a % of time on study) Mean 5.2 (0‐63) 9.0 (0‐49) ‐42% 0.013§
Occurrence of initiating CMV‐specific antiviral therapy 19 (50%) 21 (72%) ‐30% 0.035*
Duration of antiviral therapy (days) Mean 32.0 (7‐323) 46.7 (26‐212) ‐31% 0.105§
(as a % of time on study) Mean 11.5 (0‐88) 17.7 (0‐71) ‐35% 0.074§
p-value was computed by *CMH test stratified by site, and §Wilcoxon rank sum test
Unaudited data

23. TransVax™ Phase 2 HCT Trial
Summary of Findings
 TransVax™ improved cellular responses to pp65 and gB vs. placebo
 TransVax™ enhanced the level of gB antibodies at later time points
and these were sustained at one year
 Viral load endpoints significantly favored TransVax™ vs. placebo
 Decreased occurrence of CMV reactivation (detectable viremia by Mayo PCR)
 Decreased recurrence of CMV reactivation and duration of viremia
 Delayed time to CMV viremia episodes
 Antiviral treatment endpoints were improved, but not significantly for
the
th per protocol population
t l l ti
 Local labs and algorithms may have influenced clinical decisions
 Group sizes were underpowered with 74 subjects (~66% power)
 DNA vaccination appeared to be well tolerated in HCT subjects

24. Clinical Impact
 Fi t CMV vaccine showing evidence of protection i a
First i h i id f t ti in
double-blind Phase 2 HCT trial
 Si ifi
Significant d l and reduction i number of viral episodes
t delay d d ti in b f i l i d
 Lowers risks and expense associated with antiviral therapy
 May lower risk of CMV disease during immune reconstitution
 Supports use of viral load for a major Phase 3 endpoint
 TransVax™ appears to be safe and well tolerated in
immuno-compromised
immuno compromised patients
 Immune response in immunocompromised population
bodes well for CMV prophylaxis in healthy women

25. Summary of CMV Opportunity
 Vical is well positioned for broad CMV markets
 Scientific, clinical and regulatory expertise
 Comprehensive IP coverage
 Established manufacturing capacity
 TransVax™ therapeutic vaccine for transplants
 Established proof of concept in Phase 2 HCT trial
 Orphan drug status for HCT and SOT
 Market potential: $300M - $500M
 CyMVectin™ prophylactic vaccine
 Phase 1 IND allowed
 Next big vaccine market: similar to Gardasil® / Cervarix®
 Open to commercial partnerships for all major markets

26. Acknowledgements
The PIs, staff, and subjects at the 16 study centers
RF Betts, MD University of Rochester Medical Center
M Boeckh, MD Fred Hutchinson Cancer Research Center
I Braunschweig, MD Montefiore Medical Center
PH Chandrasekar, MD Barbara Ann Karmanos Cancer Institute; Harper University Hospital
A Freifeld MD
Freifeld, The Nebraska Medical Center
R Herzig, MD James Graham Brown Cancer Center
M Kharfan-Dabaja, MD H. Lee Moffitt Cancer Center
AA Langston, MD Emory University Hospital; Winship Cancer Institute
P McCarthy, MD
y, Roswell Park Cancer Institute
J McGuirk, DO University of Kansas Cancer Center
R Nakamura, MD City of Hope Medical Center
G Papanicolaou, MD Memorial Sloan-Kettering Cancer Center
SD Rowley, MD The Cancer Center at Hackensack University Medical Center
E Vance, MD Baylor University Medical Center
MB Wilck, MD Brigham and Women’s Hospital, Dana Farber Cancer Institute
AM Yeager, MD Arizona Cancer Center; University Medical Center
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