T V ™ Ph 2 T i l R ltTransVax™ Phase 2 Trial Results A Therapeutic DNA Vaccine to Control Cytomegalovirus in Hematopoietic Cell Transplant Recipients

Alain Rolland, Pharm.D., Ph.D.E ti Vi P id t P d t D l tExecutive Vice President, Product Development

October 5, 2010 - World Vaccine Congress - Lyon

Why Cytomegalovirus (CMV) Vaccine?Why Cytomegalovirus (CMV) Vaccine?

Persistent, latent herpes virus Infects 50-85% of US adults by age 40 Significant health threat for immunocompromised 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 availableBiolog of protection from rec rrence is ell nderstood Biology of protection from recurrence is well understood

Current antiviral treatments can provide benefits but present significant risksp g

Unmet Need for HCT VaccineUnmet Need for HCT Vaccine

Reactivation in ~60% of CMV+ recipients within 6 months after transplant; if untreated, can cause pneumonitis, hepatitis, gastroenteritis, retinitis, leukopenia, encephalitisp , g , , p , p Most centers give preemptive antiviral therapy after virus is detected ~5% develop CMV disease despite therapy

G i l i d th ti i l h li it ti Ganciclovir and other antivirals have 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 infectio s components safe in imm nocompromised patients No infectious components – safe in immunocompromised patients

TransVax™ CMV VaccineProduct 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 trialsF bl f t fil Favorable safety profile

Induces T-cell and antibody responses

Commercially practicaly p Convenient single-vial packaging Established manufacturing capacity sufficient

for worldwide HCT needfor worldwide HCT need

U.S. Orphan drug status for HCT and SOT*Wloch et al., J Inf Dis 2008

Plasmid Selection HCMV proPlasmid Selection6135 bps

p

Intron AKan

ori

VCL-6368

hCMV pp65

mRBG

ori

Construct Rationale Details

pp65 (VCL-6368) Immunodominant CTLtarget in infected

435-438 (kinase domain deleted)g

individuals( )AD169 strain-derived, Codon-optimized

gB (VCL 6365) Major target of a a 1 713gB (VCL-6365) Major target of neutralizing antibody

a.a. 1-713SecretedAD169 strain-derived,Codon-optimized

Poloxamer CRL1005 Delivery SystemPoloxamer CRL1005 Delivery SystemHydrophobic core

POPPOP

CRL1005

~1.5 m

CRL1005 Nonionic block copolymer POP 12 kDa (y=205) and POE 5% (x=8)

M i DNA d 5 / L+ BAK

Hydrophilic coronaPOE

Maximum DNA dose, 5 mg/mL Forms nanoparticles with DNA > 10°C Selected based on balanced and improved

+

+DNA

cellular and humoral immune responses300 nm

Hartikka et al., J Gene Med 2008

A.F. Micro

CMV in Hematopoietic Cell Transplant Hematopoietic Cell Transplant p pp pHypotheses and Assumptions

Reactivation in ~60% of CMV+ recipients within 6 months after transplant

Meyers et al., 1986; Junghanss et al., 2002, 2003y , ; g , ,

DNA vaccination should increase CMV-specific immune responses

S li k t l 2005 H tikk t l 2008 Wl h t l 2008 Selinsky et al., 2005; Hartikka et al., 2008; Wloch et al., 2008

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., 2000y ,

TransVax™ Phase 2 HCT TrialTransVax™ 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 matchStratified by site, donor CMV status, HLA match Randomized 1:1 for active vs. placebo vaccination

Endpoint-defining study

Multicenter (16 enrolling sites)

Endpoints Safety Immunogenicity Viral load

CMV i i l h CMV antiviral therapy

TransVax™ Phase 2 HCT TrialRecipient Immunization RegimenHematopoietic Cell Transplant (HCT Study)

HCT RecipientCMV+ only

R

Hematopoietic Cell Transplant (HCT Study)

Pretransplant

HCT DonorCMV+ or CMV-

Immunosuppressed

HCTT l t

R

D

Pretransplant, 1, 3, and 6 mo

Related or unrelated TransplantD

80 subjects enrolled 1:1 TransVax™ to placebo

Recipients Key Inclusion CriteriaRecipients Key Inclusion Criteria

18 t 65 f 18 to 65 years of age CMV-seropositive Planned 6/6 or 5/6 classic HLA allele-matched transplant 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 includingg g

Acute lymphoblastic leukemia in 1st or 2nd remission Acute myelogenous leukemia in 1st or 2nd remission Chronic myelogenous leukemia in first chronic or accelerated Chronic myelogenous leukemia in first chronic or accelerated

phase, or in second chronic phase Hodgkin’s and non-Hodgkin’s lymphoma

M l d l ti d Myelodysplastic syndrome

Recipients Key Exclusion CriteriaRecipients 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 remissiony y Multiple myeloma Aplastic anemia

Pl d h l ti th ith CMV i l b li Planned prophylactic therapy with CMV immunoglobulin and/or antivirals

Complete T-cell depletion of graft and/or use of (C )alemtuzumab (Campath-1H)

Demographic and Baseline CharacteristicsDemographic and Baseline Characteristics

I t t t T t (ITT) P l tiTransVaxTM Placebo

Intent to Treat (ITT) Population (N=42) (N=38)

Gender FemaleMale

22 (52%)20 (48%)

15 (39%)23 (61%)

Race CaucasianAfrican American

39 (93%)3 (7%)

35 (92%)3 (8%)

Age Mean (years) 49.2 49.1

Donor CMV Status* PositiveNegative

20 (48%)22 (52%)

21 (55%)17 (45%)

HLA Allele Matching* 6/6 38 (90%) 36 (95%)5/6 4 (10%) 2 (5%)

Relatedness to Donor RelatedUnrelated

23 (55%)19 (45%)

17 (45%)21 (55%)

Conditioning Regimen MyeloablativePartially myeloablative

31 (74%)11 (26%)

27 (71%)11 (29%)

* Groups were stratified by site, donor CMV status, and HLA match.Unaudited data

Safety FindingsSafety Findings

No safety concerns DSMB reviewed first 20 patients through Day 56

C ti d i f SAE d f t t f Continued review of SAEs and safety reports for remainder of study

SAEs 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 No difference between groups in SAEs

Safety Observations

l b

Safety Observations

Adverse Events (ITT population)TransVax™(N=42)

Placebo(N=38)

Subjects with at least one AE 42 (100%) 38 (100%)Subjects with at least one AE 42 (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

T cell Responses to pp65 for 1 Year

Median pp65 IFN‐ ELISPOT Response

T-cell Responses to pp65 for 1 Year

3500

4000

4500

Median pp65 IFN ELISPOT Response

2500

3000

3500

PBMC

TransVax™p=0.003*

1000

1500

2000

SFU/106 Placebo

0

500

‐10 65 140 215 290 365Days

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.

T cell Responses to gB for 1 YearT-cell Responses to gB for 1 Year

Median gB IFN‐ ELISPOT Response

300

350

400g p

200

250

300

06PB

MC

TransVax™p=0.075*

100

150

SFU/10

Placebo

0

50

‐10 65 140 215 290 36510 65 140 215 290 365Days

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.

Antibody Responses to gB for 1 YearGeometric Mean gB Antibody (90% CI)

Antibody Responses to gB for 1 Year

500000

)

p=0.009

*

50000

body

 (EU/m

L)

Vaccine

Pl b

gB Antib Placebo

5000

‐10 65 140 215 290 365

DaysDays

N=26-38 for TransVaxTM, N=20-34 for Placebo *Trend (0.05<p<0.10); Wilcoxon rank-sum test used for individual datapointsOverall p-value=0.119 based on repeated measurement ANOVA using log10 transformed data from day 56 to 365

Viral Load and Antiviral ApproachViral 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 algorithmsp g 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)

Viral Load and Treatment EndpointsViral Load and Treatment Endpoints

Per Protocol Pop lation (to 1 r) TransVax™ Placebo % p al ePer Protocol Population (to 1 yr) (N=40) (N=34) Change p-value

*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 0 123

27 (68%)8 (20%)4 (10%)1 (3%)

13 (38%)14 (41%)3 (9%)3 (9%)

NA 0.017c

≥4( )0

( )1 (3%)

Duration of viremia (days) MeanNormalized (as a % of time on study) Mean

10.6 (0-68)4.9 (0-63)

19.5 (0-181)7.7 (0-49)

-46%-36%

0.069c

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

Unaudited data

*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.

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.

Prevalence of CMV EpisodesPrevalence 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.

Treatment Endpoint Subset AnalysisTreatment Endpoint Subset Analysis

Per Protocol population apparently included 7 subjects who werePer 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

Protocol subset (PP ‐ 7 subjects) TransVax™(N=38)

Placebo(N=29)

% Change

p‐value

Occurrence of CMV reactivation (≥ 500 copies/mL) 13 (34%) 21 (72%) ‐53% 0.002*

i f i i (d ) ( ) ( ) % §Duration of viremia (days) Mean(as a % of time on study) Mean

11.2 (0‐68)5.2 (0‐63)

22.8 (0‐181)9.0 (0‐49)

‐51%‐42%

0.026§

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

TransVax™ Phase 2 HCT TrialSummary 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 yearand 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 Decreased recurrence of CMV reactivation and duration of viremia Delayed time to CMV viremia episodes

Antiviral treatment endpoints were improved, but not significantly for th t l l tithe per protocol population 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

Clinical ImpactClinical Impact

Fi t CMV i h i id f t ti i First CMV vaccine showing evidence of protection in a double-blind Phase 2 HCT trial

Si ifi t d l d d ti i b f i l i d Significant delay and reduction in number of viral episodes 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 Supports use of viral load for a major Phase 3 endpoint

TransVax™ appears to be safe and well tolerated in immuno compromised patientsimmuno-compromised patients

Immune response in immunocompromised population bodes well for CMV prophylaxis in healthy womenbodes well for CMV prophylaxis in healthy women

Summary of CMV OpportunitySummary of CMV Opportunity

Vical is well positioned for broad CMV markets 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 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®Next big vaccine market: similar to Gardasil / Cervarix

Open to commercial partnerships for all major markets

AcknowledgementsAcknowledgements

The PIs, staff, and subjects at the 16 study centersRF Betts, MD University of Rochester Medical Center

M Boeckh, MD Fred Hutchinson Cancer Research CenterI Braunschweig, MD Montefiore Medical Center

PH Chandrasekar, MD Barbara Ann Karmanos Cancer Institute; Harper University HospitalA Freifeld MD The Nebraska Medical CenterA Freifeld, MD The Nebraska Medical CenterR 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 Roswell Park Cancer Institutey,J McGuirk, DO University of Kansas Cancer Center

R Nakamura, MD City of Hope Medical CenterG Papanicolaou, MD Memorial Sloan-Kettering Cancer Center

SD Rowley, MD The Cancer Center at Hackensack University Medical Center

Copyright 2010, Vical Incorporated. All Rights Reserved

E Vance, MD Baylor University Medical CenterMB Wilck, MD Brigham and Women’s Hospital, Dana Farber Cancer Institute

AM Yeager, MD Arizona Cancer Center; University Medical Center