transvax phase 2 trial results
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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