TransVax Phase 2 Trial Results
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TransVax Phase 2 Trial Results

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

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

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    TransVax Phase 2 Trial Results TransVax Phase 2 Trial Results Presentation Transcript

    • 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