TransVax™ Phase 2 Trial ResultsT V ™ Ph T i lR ltA Therapeutic DNA Vaccine to ControlCytomegalovirus in Hematopoietic CellTransplant RecipientsAlain Rolland, Pharm.D., Ph.D.Executive Vice P id t P d t DE ti Vi President, Product Development l tOctober 5, 2010 - World Vaccine Congress - Lyon
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 g
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
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 trials F Favorable safety profile bl f t fil Induces T-cell and antibody responses Commercially practical yp 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
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
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
CMV in Hematopoietic Cell Transplant p pHypotheses 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 y ,
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
TransVax™ Phase 2 HCT TrialRecipient Immunization RegimenHematopoietic 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 tRelated or unrelated 80 subjects enrolled 1:1 TransVax™ to placebo
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 g 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 phase, or in second chronic phase Hodgkin’s and non-Hodgkin’s lymphoma M l d Myelodysplastic syndrome l ti d
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 y y 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))
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
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
Safety Observations TransVax™ Placebo l bAdverse 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
T-cellT cell Responses to pp65 for 1 Year Median pp65 IFN ELISPOT Response Median pp65 IFN‐ ELISPOT Response 4500 4000 3500 3000SFU/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.
T-cell T cell Responses to gB for 1 Year g Median gB IFN‐ ELISPOT Response p 400 350 300SFU/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.
Antibody Responses to gB for 1 Year Geometric Mean gB Antibody (90% CI) 500000 p=0.009 * body (EU/mL) ) 50000 VaccinegB 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
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 p 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 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% 0.008aTime to initial CMV reactivation (days) Median >365 109.5 NA 0.003bNumber 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% 0.145aCumulative CMV-specific antiviral therapy (days) Mean 30.2 (0-315) 39.8 (0-212) -24% 0.266cCMV-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
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 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 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 valueOccurrence 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
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 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
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
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
AcknowledgementsThe 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 Copyright 2010, Vical Incorporated. All Rights Reserved