Takeda’s Dengue Vaccine Candidate · Dengue Fact Sheet, Australian Government Department of...
Transcript of Takeda’s Dengue Vaccine Candidate · Dengue Fact Sheet, Australian Government Department of...
Joanne McCoubrie, PhD
Senior Medical Advisor Takeda Pharmaceuticals
Takeda’s Dengue Vaccine Candidate
• This presentation is solely for the purpose of responding to inquiries
about our vaccine candidates
• Nothing in this presentation is intended to, nor should be construed as
an offer to sell or to promote our vaccine candidates
• These candidates are under investigation and the information contained
herein is current only as of the date of this presentation
• New and additional information will be obtained through the investigation
process, potentially making the information in this presentation not
current
2
Disclaimer
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
Dengue virus: Background and structure
• Dengue is a flavivirus1
• There are more than 70 different
flaviviruses, including tick-borne
encephalitis virus, yellow fever
virus, Japanese encephalitis virus & Zika
virus1
• Many of these are arthropod-borne and
transmitted by either mosquitoes or ticks1
• There are four closely related dengue virus
serotypes: DENV-1, DENV-2, DENV-3
and DENV-42
• Each virus can cause infection and the
full spectrum of dengue disease symptoms2
5
C: capsid; E: envelope protein; M: membrane protein; prM: precursor-membrane; sE: soluble forms of E; TM: transmembrane
* Image reproduced from reference 1 with permission from Elsevier
1. Heinz, et al. Vaccine 2012;30:4301–6
2. Gubler, et al. Emerg Infect Dis 1995;1:55–7
Schematic model of a flavivirus particle
(both immature and mature stages)1*
Dengue vector: Aedes mosquitoes
Aedes aegypti
• Primary vector for the dengue virus1
• Lives in urban habitats and breeds in
man-made containers1
• Eggs can survive drying for long periods of
time, allowing distribution to new locations1
• The females bite people and are
daytime feeders1
Aedes albopictus
• Secondary vector in Asia, has
spread to Africa, North America and
Europe, in part due to the international
trade in used tires1
• Eggs can survive drying for long periods1
• Highly adaptive – can survive in cooler
temperate regions of Europe1
6
1. http://www.who.int/denguecontrol/mosquito/en/. Accessed 27/06/2016
2. https://commons.wikimedia.org/wiki/File:Aedes_aegypti_CDC-Gathany.jpg. Accessed 23/06/2016
3. https://commons.wikimedia.org/wiki/File:Aedes_Albopictus.jpg.Accessed 23/06/2016
Ae. aegypti mosquito2 Ae. albopictus mosquito3
Dengue disease: Clinical presentation
Dengue fever1
• Severe, flu-like illness
• Should be suspected when
high fever (40°C/104°F) is accompanied
by two of the following symptoms: severe
headache, pain behind the eyes, muscle
and joint pains, nausea, vomiting, swollen
glands or rash
• Symptoms usually last for 2–7 days,
after incubation period of 4–10 days
after bite from infected mosquito
Severe dengue1
• A small proportion of patients progress to
severe disease
• Warning signs include: severe abdominal
pain, persistent vomiting, rapid breathing,
bleeding gums, fatigue, restlessness and
blood in vomit
• Above signs occur 3–7 days after the first
symptoms, in conjunction with a decrease
in temperature (below 38°C/100°F)
• Marks start of 24- to 48-hour critical
period - may lead to shock and death
7
After D. Vaughn
1. www.who.int/mediacentre/factsheets/fs117/en/. Accessed 27/06/2016
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
More than 2,000 cases of dengue were confirmed in Australia in 2016.1
Dengue in Australia
9 1. Australian Government Department of Health.
Outbreaks of dengue occur each year in
North Queensland and there is the risk of
local spread in areas where Aedes aegypti is
present.
Aedes aegypti is currently limited to parts of
Northern, Central and Southwest
Queensland.
The Aedes albopictus mosquito only occurs
in the Torres Strait Islands.1
In most parts of Australia, there is no risk of
dengue being spread by mosquitoes
because most areas of Australia do not have
the Aedes aegypti or Aedes
albopictus mosquitoes
Dengue outbreaks in Australia
10 1. Dengue Fact Sheet, Australian Government Department of Health.
Map adapted from Figure 2, Queensland Dengue Management Plan 2015-2020. The State of Queensland (Queensland Health. V1 21Sept2016.
Impact of international travel on geographic expansion
of dengue
• Marked increase in dengue since 1980s associated with increasing
international travel1
1.Kilpatrick, et al. Lancet 2012;380:1946–55 11
The global aviation network1*
Lines show direct links between airports
Color indicates passenger capacity in people per day:
Red – thousands
Yellow – hundreds
Blue – tens
Dengue fever distribution
12 https://wwwnc.cdc.gov/travel/images/map3-2-dengue-eastern-hemisphere-large.jpg
https://wwwnc.cdc.gov/travel/images/map3-1-dengue-western-hemisphere-large.jpg
Most common destinations for returned travellers with
dengue 2007–2011
1. Leder, et al. Ann Intern Med 2013;158:456–68
Data collected from
GeoSentinel sites:
• N. America – 21 sites
• Europe – 17 sites
• Australasia - 10 sites
• Latin America – 3 sites
• Southern Africa – 1 site
• Middle East – 1 site
Number of dengue cases: n=1473
13
Top identified specific causes for illnesses among travellers
returning to Australia, New Zealand and Oceania
14 1. Leder, et al. Ann Intern Med 2013;158:456–68
Fly-in-fly-out workers affected by dengue
15
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
Relevant vaccine history
17
1. World Health Organization. Weekly epidemiological record. 2011;86:241–56
2. Messina, et al. Trends Microbiol 2014;22:138–46
3. Bhamarapravati, et al. Bull World Health Organ 1987;65:189–95
4. Huang, et al. J Virol 2003;77:11436–47
5. Frierson. Yale J Biol Med 2010;83:77–85
1940–1950
Four dengue virus
serotypes identified2
1990 2000 1940
1986
DEN-2 PDK-53 virus
vaccine developed at
Mahidol University,
Bangkok3 2000–2003
Chimeric viruses developed
for DENV-1, DENV-3 and
DENV-4 on the PDK-53
background4
1980 1950
May 2010
First Phase 1
clinical trial
(DEN-101)
Nov 2011
Phase 2 age
de-escalation trial in
endemic countries
(DEN-203)
Dec 2014
Phase 2 trial using
established final
formulation
and schedule
(DEN-204)
Sep 2016
First
Phase 3
trial
(DEN-301)
1946
Takeda open facility in Hikari
for vaccine manufacturing
2010
Jan 2012
Takeda launch
Global Vaccine
Business Division
May 2013
Takeda acquire Inviragen
(including dengue
vaccine candidate)
1947–2013
Takeda develop 10 vaccines
(including three co-marketing products)
1937
First human flavivirus vaccine developed (tick-borne encephalitis
inactivated mouse brain vaccine)1
Takeda
1937–1939
Yellow fever (17D) LAV-vaccine developed (embryonated eggs)5
Dengue
Other flavivirus vaccines
• To develop an effective, live-attenuated dengue vaccine with an acceptable
safety profile based on the dengue virus 2 backbone that:
– Elicits a serotype-specific neutralizing humoral immune response to all four dengue
virus serotypes and a multifunctional cellular immune response to dengue antigens in
flavivirus-naïve and exposed individuals
– Protects against infection with all four dengue virus serotypes and all severities
of dengue disease
– Provides durable protection to all individuals, regardless of pre-existing
dengue virus antibody status
Takeda: dengue vaccine development objectives
18
Takeda’s live-attenuated tetravalent dengue vaccine
candidate (TDV) is a DENV-2*-based recombinant vaccine1
• Induces antibody responses to all four serotypes in dengue-naïve and dengue-exposed children and adults2-6
• TDV elicits multifunctional and cross-reactive T cell-mediated responses to dengue structural and non-structural proteins7-8
1, Osorio, et al. Expert Rev Vaccines 2016;15(4):497–508 | 2. George, et al. J Infect Dis 2015;212:1032–41 | 3. Osorio, et al. Lancet Infect Dis 2014;14(9):830–8 | 4. Rupp, et al. Vaccine
2015;33(46):6351–9 | 5. Sirivichayakul, et al. J Infect Dis 2016;213(10):1562–72 | 6. Sáez-Llorens , et al. Lancet Infect Dis 2017; http://dx.doi.org/10.1016/S1473-3099(17)30166-4
|7. Ambuel, et al. Front Immunol 2014;5:263 | 8. Chu, et al. J Infect Dis 2015;212(10):1618–28| 9. Butrapet , et al., Journal of Virology 2000; 74 (7): 3011-3019
TDV-2
(DENV-2 backbone)
TDV-1
TDV-3
TDV-4
C, capsid; E, envelope; NS, non-structural; prM, pre-membrane
Site of
mutation9
5’-
5’-
5’-
5’-
–3’
–3’
–3’
–3’
C prM E NS1 2A 2B NS3 4A 4B NS5
C prM E NS1 2A 2B NS3 4A 4B NS5
C prM E NS1 2A 2B NS3 4A 4B NS5
C prM E NS1 2A 2B NS3 4A 4B NS5
DENV-2, dengue virus 2
Figure © Elsevier B.V., reproduced with permission.
*In this presentation, DENV denotes wild type dengue virus
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
‡The illustration of the phase 1 and 2 studies in non-endemic populations does not depict the end date of
each study.
http://clinicaltrials.gov/
2017 2010 2011 2012 2013 2014 2015 2016
DEN-102 (Colombia) n=96
DEN-101
(US) n= 72
DEN-103
(US) n=67
DEN-104
(US) n=136
DEN-106
(US) n =996
Non-endemic: Phase 1 and 2 (flavivirus-naïve adults)‡
Includes
children Ongoing
Endemic:
Phase 2
and 3
DEN-203: Adults and children n=360
(in dengue endemic: Puerto Rico, Colombia, Singapore, Thailand)
DEN-204: Children only n=1794
(Philippines, Panama, Dominican Republic)
DEN-205: Adults only
n=351 (Singapore)
DEN-301: Children only
N=20,100 (Brazil, Colombia,
Dominican Republic, Nicaragua, Panama,
Philippines, Sri Lanka, Thailand)
More than 17,000 participants have received at least one
dose of TDV in phase 1, 2 and 3 studies, including almost
15,000 children
Ongoing and completed clinical studies
DEN-313: CMI:
Children only
n=200 (Panama,
Philippines)
Phase 1 studies (flavivirus-naïve adults) :
• DEN-101 (US)1,2, DEN-102 (Colombia)3,4: Different dose levels and routes of
administration: intradermal (ID) and subcutaneous (SC)
• DEN-103 (US): ID needle vs needle-free ID administration5,6
• DEN-104 (US): Different dose levels and schedules7,8
TDV: Phase 1 studies
22
ID: intradermal; SC: subcutaneous; TDV: tetravalent dengue vaccine
1. George, et al. J Infect Dis 2015;212:1032–41
2. https://clinicaltrials.gov/show/NCT01110551. Accessed 24/02/2016
3. Osorio, et al. Lancet Infect Dis 2014;14:830–8
4. https://clinicaltrials.gov/show/NCT01224639. Accessed 24/02/2016
5. Chu, et al. J Infect Dis 2015;212:1618–28
6. https://clinicaltrials.gov/show/NCT01765426. Accessed 10/02/2016
7. Rupp, et al. Vaccine 2015;33:6351–9
8. https://clinicaltrials.gov/show/NCT01542632. Accessed 24/02/2016
Phase 2 study (flavivirus-naïve adults):
• DEN-106 (US): Two dose schedule of SC lyophilized vs liquid formulation1
Phase 2 studies (dengue-endemic regions):
• DEN-203: Safety, tolerability and immunogenicity in healthy adults and
children (SC)2,3 – Part 1: Age de-escalation
– Part 2: Expansion phase (age 1.5 -11 years)
• DEN-204: Safety and immunogenicity (S&I) of different schedules in healthy
children (SC)4–6
– Comparison of two dose and one dose schedules & evaluation of booster at
12 months
• DEN-205: S&I of two different serotype 2 potencies of TDV in adults (SC)7
• DEN-313: Cell-mediated immunity & safety in healthy children aged 4-16 years
(SC)8
TDV:Phase 2 studies
23
SC: subcutaneous; S&I: safety and immunogenicity;
TDV: tetravalent dengue vaccine
1. https://clinicaltrials.gov/show/NCT02193087. Accessed 24/02/2016
2. Sirivichayakul, et al. J Infect Dis. 2016;213:1562–72
3. https://clinicaltrials.gov/show/NCT01511250. Accessed 24/02/2016
4. Biswal. Presented at Asia Dengue Summit; Session 1; Jan 13, 2016
5. https://clinicaltrials.gov/show/NCT02302066. Accessed 10/02/2016
6. Sáez-Llorens, et al. Lancet Infect Dis 2017;DOI:10.1016/S1473-3099(17)30166-4
7. https://clinicaltrials.gov/show/NCT02425098. Accessed 10/02/2016
8. https://clinicaltrials.gov/show/ NCT02948829 Accessed August 2017
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
• Takeda’s TDV candidate is generally well tolerated in flavivirus-naïve
volunteers1,2
• TDV induced neutralizing antibodies to all four DENV serotypes1,2
– GMTs for both administration routes and TDV formulations:1
DENV-2 > DENV-1 > DENV-3 > DENV-4
• SC administration may be favoured over ID administration1,3
– Both TDV formulations (via either SC or ID administration) induced neutralizing
antibodies to all four DENV serotypes1,3
Summary of Phase 1 findings
25
DENV: dengue virus; ID: intradermal; SC: subcutaneous; TDV: tetravalent dengue vaccine
1. Osorio, et al. Lancet Infect Dis 2014;14:830–8
2. Osorio, et al. Vaccine 2015;33:7112–20
3. Chu, et al. J Infect Dis 2015;212:1618–28
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
TDV: DEN-203 – Phase 2 trial in dengue-endemic countries
TDV: tetravalent dengue vaccine
1. Sirivichayakul, et al. J Infect Dis. 2016;213:1562–72
2. https://clinicaltrials.gov/show/NCT01511250 Accessed 24/02/2016
Primary objective 2:1,2
To assess the immunogenicity of TDV against all four
dengue serotypes in healthy adults and children
Primary objective 1:1,2
To evaluate the safety and tolerability of a subcutaneously
administered TDV in healthy adults and children (1.5–45 years old)
27
DEN-203 study design1: randomized, double blind,
placebo-controlled Phase 2 study
Part 2
(expansion)
+
28
0 7 14 28 90 97 104 120 180 360 720 1080
Group 2
12–20 yrs.
n = 36
+
28
Group 3
6–11 yrs.
n = 38
Group 1
21–45 yrs.
n = 38 Randomization 2:1
vaccine to placebo
+
28
Group 4
1.5–5 yrs.
n = 36
+
Key:
Dose
Safety review (N ≥ 12)
Viremia + safety samples
Immunogenicity sample
+
Part 1 (age-descending)
Enrolled, n = 148
n=212
1.5-11 yrs
Randomization 3:1
vaccine to placebo
ClinicalTrials.gov identifier: NCT01511250
1Sirivichayakul et al., 2016J Infect Dis. 2016;213(10):1562-72. doi:
10.1093/infdis/jiv762. Epub 2015 Dec 23
The same
vaccination
and sample
schedule
was used for
each group
DEN-203: Neutralizing antibody response – 2 year interim
data
• TDV elicited neutralizing antibody responses that persist through Day 720 in children and adults,
irrespective of initial immune status
MNT positive to ≥1
DENV at baseline
MNT negative to all
4 DENV at baseline
×
DENV-1
DENV-2
DENV-3
DENV-4
Ge
om
etr
ic m
ea
n M
NT
50
Ge
om
etr
ic m
ea
n M
NT
50
Study day Study day
= Vaccination
FAS, full analysis set, Part 1
Day 28, n=133
Day 90, n=131
Day 120, n=130
Day 180, n=39
Day 360, n=38
Day 720, n=40
Day 0, n=116
Day 28, n=115
Day 90, n=115
Day 120, n=115
Day 180, n=45
Day 360, n=44
Day 720, n=50
Takeda: Data on file
MNT- Micro Neutralization Test
TDV: DEN-204 – Safety and immunogenicity of different
schedules in healthy children1-3
30
1.Biswal. Presented at Asia Dengue Summit; Session 1; Jan 13, 2016
2.https://clinicaltrials.gov/show/NCT02302066. Accessed 10/02/2016
3.Sáez-Llorens, et al. Lancet Infect Dis 2017;DOI:10.1016/S1473-
3099(17)30166-4
Key objective:1-3
Comparison of two dose and one dose schedules & evaluation of booster at
12 months
1800 children age 2 to <18 years in Panama, the
Dominican Republic and the Philippines
Enrolment completed February 2015
• Descriptive comparison of two-dose and one-dose schedules, and an assessment of a
booster-dose at 12 months
• First use of the new formulation of TDV (which has 10-fold lower potency of TDV-2 than the
previous formulation)
• Has contributed to a large safety database of the endemic paediatric population
DEN-204: A randomized, controlled phase 2 endemic
paediatric study
ClinicalTrials.gov Identifier: NCT02302066
Enrolment
Injection Month 6
Interim Analysis
Month 12
Month 48
Month 3 Month 0
V = vaccine
P = placebo Group 1 V V P N=200
Group 2 V P P N=400
Group 3 V N=1000
Group 4 P P P N=200
Immunogenicity
subset
V P
100
200
200
100
2 doses
1 dose
Saez-Llorens et al. Lancet ID Volume 17, No. 6, p615–625, June 2017
DEN-204: Summary of immunogenicity data at 6 months
• High GMTs and seropositivity rates
against all the dengue serotypes were
observed in all participants including
those seronegative at baseline
• At 6 months in participants who were
seronegative at baseline:
– One dose resulted in 67.5% tetravalent
seropositivity
– Two doses resulted in 85% tetravalent
seropositivity
• 18 month data to be presented at ASTMH
November 2017
Takeaway: Test a two-dose regimen 3 months apart in the phase 3 efficacy trial to
maximize vaccine take in participants who are seronegative at baseline
Multivalent seropositivity rates at Month 6 in all
participants and those seronegative at baseline
All participants Sero(-) at baseline
GMT, geometric mean titer
Saez-Llorens et al. Lancet ID Volume 17, No. 6, p615–625, June 2017 ClinicalTrials.gov Identifier: NCT02302066
1. Solicited AEs
– Pain (mostly mild and transient) was the most common local adverse event, with the
highest rate (31%) seen in children 6-17 years of age
– Swelling and redness occurred in approximately 5% of vaccinees in this analysis
– Fever, headache and myalgia were commonly reported in both studies and were
observed at similar rates in placebo recipients and vaccinees
2. Unsolicited AEs
– In both studies, the majority of unsolicited AEs were infections common to children in
these age groups (e.g., laryngitis and tonsillitis). Overall, there were no major or
consistent differences in unsolicited AEs between TDV and placebo
– There were no major differences in unsolicited AEs following Dose 1 or Dose 2 observed
in the TDV versus placebo groups. The majority of unsolicited AEs were assessed as
unrelated to the study vaccine
– After Dose 1 and Dose 2, SAEs were reported in fewer than 2% of participants in the TDV
and placebo groups; all SAEs were assessed as unrelated to the study vaccine
DEN-203/204: Integrated safety analysis1
– Summary of AEs in paediatric participants
Takeda: Data on file; AE, adverse event 1Papadimitriou et al., 2016 ,E-poster presented at 8th Asian Congress of Paediatric Diseases, Bangkok, Thailand (post hoc analysis)
• TDV was well tolerated in children and adults, across multiple formulations and
vaccination schedules
• No vaccine-related SAEs were reported
• No safety concerns were identified based on local or systemic reactogenicity
or unsolicited AEs
TDV: pooled analysis of DEN-203 and DEN-204
Summary1
34
AE: adverse event; SAE: serious adverse event; TDV: tetravalent dengue vaccine
1. Papadimitriou, et al. Presented at 8th Asian Congress of Pediatric Infectious Diseases, Thailand, November 2016. Registered at:
https://clinicaltrials.gov/show/NCT01511250 and https://clinicaltrials.gov/ct2/show/NCT02302066 Accessed 09/12/2016
Key clinical findings supporting phase 3 start of TDV
Takeda: Data on file
Over 3500 subjects have received TDV including over 1800 children living in
dengue endemic countries in 8 completed or ongoing Phase 1 or 2 trials
Acceptable safety profile in these phase 1 and phase 2 trials
Sustained antibody responses to all four dengue serotypes, in both naïve and
previously-exposed subjects
T cell-mediated responses to dengue structural and non-structural proteins
Five formulations evaluated, with varying potency of individual serotypes
Lyophilized presentation evaluated in late phase 2 studies, enabling storage
at 5oC.
A two-dose schedule at Months 0 and 3 selected to maximize seropositivity in
subjects seronegative at baseline
35
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
• Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to
Investigate the Efficacy, Safety and Immunogenicity of TDV Administered
Subcutaneously in Healthy Children Aged 4 - 16 Years Old
TDV: tetravalent dengue vaccine
1. https://clinicaltrials.gov/show/NNCT02747927Accessed August 2017
37
Key objective:1
To evaluate the efficacy of 2 doses of TDV in preventing
symptomatic dengue fever of any severity and due to any of the
four dengue virus serotypes in 4 to 16 year old participants
Efficacy, Safety and Immunogenicity of Takeda's Tetravalent
Dengue Vaccine (TDV) in Healthy Children (TIDES)
• 20,100 subjects from Brazil, Colombia, Dominican Republic,
Nicaragua, Panama, Philippines, Sri Lanka, Thailand
TIDES (DEN-301): Overall study design and objectives
Part 1
120 cases of dengue
Minimum 12 months post-
vaccination for each subject
Efficacy against dengue of
any severity and due to any
of the 4 serotypes
Efficacy against dengue by exposure status at baseline,
serotype, severity (Hospitalized and Severe dengue) Long term safety and efficacy
Reactogenicity (post vaccination period) and Immunogenicity in a subset
Optional dry-run part for up to 10 months prior to Part 1 to commence and test febrile
surveillance methodology (Not mandatory for all sites or all subjects)
Part 2
6 months Part 3
3 years
Active surveillance and collection of all SAEs
Modified active surveillance and
collection of related/relevant SAEs
Time points of planned analysis and reporting
ClinicalTrials.gov Identifier: NCT02747927
TIDES (DEN-301): randomization, vaccination, and
sampling
Part 1 120 cases of dengue
+ 12 months post 2nd dose
Part 2 6 months
Part 3 3 years
Modified active surveillance (Part 3)
Placebo - 6,700 subjects, stratified by region and age range (4-5, 6-11 and 12-16 years)
Time in Months 0 1 3 4 15 27 39 51 9
All subjects- 0 and 4 months
Subset (4000 subjects)- All time points Immunogenicity
sample
Dose
Active surveillance (Part 1 & 2)
TDV - 13,400 subjects, stratified by region and age range ( 4-5, 6-11 and 12-16 years)
Takeda: Data on file
20,100
ClinicalTrials.gov Identifier: NCT02747927
• DEN-301 vaccination began in September 2016
• Recruitment is complete:
• 20,100 subjects 4-16 years recruited in 7 months in 26 clinical trial sites in 8
countries
• All subjects have been vaccinated
• First results expected in late 2018
Status update: Takeda’s candidate dengue vaccine pivotal
efficacy trial TIDES (NCT02747927)
1. Dengue disease
2. Dengue in Australia
3. Development of Takeda’s dengue vaccine candidate
4. Overview of ongoing and completed clinical studies
5. Summary of phase 1 trial findings
6. Phase 2 clinical trials:
– DEN-203 Antibody persistence
– DEN-204 Dose schedule selection for phase 3
– DEN-203 and DEN-204 Safety analysis
7. Phase 3 efficacy study design and progress
8. Conclusions
Overview of presentation
Conclusions
• More than 17,000 subjects including almost 15,000 children have received
at least one dose of TDV in 10 completed and ongoing phase1, 2 and 3
clinical studies
• In phase 1 and 2 clinical studies, the vaccine candidate was immunogenic
and showed acceptable reactogenicity in children, adolescents and adults1-6
• In DEN-203 and DEN-204, no vaccine-related Serious Adverse Events
occurred5,6
• A vaccination schedule comprising two doses three months apart was
selected for phase 3 because DEN-204 6-month interim results showed that
a second dose improved tetravalent seropositivity in children who were
dengue seronegative before vaccination
• Takeda’s pivotal phase 3 study DEN-301 began in September 2016,
recruitment and vaccination are complete, and the first results are expected
in 2018
1. Osorio, et al. Expert Rev Vaccines 2016;15(4):497–508 | 2. George, et al. J Infect Dis 2015;212:1032–41 | 3. Osorio, et al. Lancet Infect Dis 2014;14(9):830–8 | 4. Rupp, et
al. Vaccine 2015;33(46):6351–9 | 5. Sirivichayakul, et al. J Infect Dis 2016;213(10):1562–72 | 6. Sáez-Llorens , et al. Lancet Infect Dis 2017;
http://dx.doi.org/10.1016/S1473-3099(17)30166-4
Thank you