First Regional Dengue Symposium, Rio de Janeiro, Brazil – Nov 3-4 2015
Pedro Garbes, MD.
Regional Medical Director, Latin America.
Takeda Pharmaceutical Limited
A Recombinant Tetravalent Dengue Vaccine Candidate Using DENV-2 Backbone
Takeda Pharmaceutical Limited
Takeda’s live-attenuated tetravalent dengue vaccine (TDV)
candidate is a DENV-2-based recombinant vaccine1,2
• Live, attenuated TDV-2 induces immune responses to DENV-2
• Recombinant TDV-1, TDV-3 and TDV-4 induce antibodies against DENV-1, DENV-3 and DENV-4
respectively
• TDV-2 backbone induces multifunctional and cross-reactive CD8+ T-cell responses to dengue non-structural
proteins3,4,5
5. Chu H, et al. J Infect Dis. online May 5, 2015;
doi:10.1093/infdis/jiv258
1.Osorio JE, et al. Am J Trop Med Hyg 2011;84:978:87.
2.Osorio, J. E., et al. Vaccine 2011;29(42):7251–60
3. Ambuel Y, et al. Front Immunol 2014;5:263.
4. Partidos. ASTMH 2014; Poster no. 182
Cpr
ME NS1 2A 2B NS3 4A 4B NS5
Cpr
ME NS1 2A 2B NS3 4A 4B NS5
Cpr
ME NS1 2A 2B NS3 4A 4B NS5
Cpr
ME NS1 2A 2B NS3 4A 4B NS5
Attenuated TDV-2
TDV-1
TDV-3
TDV-4
-3’
-3’
-3’
-3’
5’
5’
5’
5’
Site of
mutation
2 Takeda Pharmaceutical Limited
4
Takeda’s Live Attenuated Dengue Vaccine Candidate in
Non Human Primates (NHP) - Protection Studies
• Seven challenge studies completed in NHPs (more in progress) 1,2
− Formulation ratios, Routes of administration (SC vs ID), Vaccination schedules
• TDV generates immune response to 4 dengue serotypes with higher antibody
titers to DENV-2
• TDV induces cellular immunity
– Adoptive T cell transfer provides partial protection in AG129 mice2
– Takeda’s Live Attenuated Dengue Vaccine Candidate elicits CD8+ T cell responses
to DENV-2 and DENV-4 envelope and non-structural proteins in non-human
primates3
• Protection from viremia after challenge with DENV-4 even when DENV-4 titers
are low has been observed in some experiments1
31Osorio et al doi:10.4269/ajtmh.2011.10-05922Takeda data on file3Ambuel et al doi:10.3389/fimmu.2014.00263
Takeda Pharmaceutical Limited
DEN-203: Adults and children
(in dengue endemic countries:
Puerto Rico, Colombia, Singapore, Thailand)
Part 1: Age de-escalation (1080 days)
Part 2: Expansion phase (1080 days; results
reported up to Day 120)
Safety and immunogenicity assessed over 36 mths
Phase 1 and Phase 2 studies to assess safety and tolerability
of TDV and to establish dose schedule
ID, intradermal;
SC, subcutaneous
2010 2011 2012 2013 2014 2015
DEN-102
(Colombia)
Dose and route of
administration (ID, SC)
DEN-101
(US)
Dose and route
of administration
(ID, SC)
DEN-103
(US multicenter)
ID needle vs
needle free
DEN-104
(US multicenter)
dose and
schedules
Non-endemic: Phase 1 (flavivirus-naïve adults) On-going
Endemic: Phase 2 (Takeda’s live-attenuated dengue vaccine candidate SC)
DEN-204:
Children only
(multicenter)
Includes children
DEN-106
(US multicenter)
DEN-205:
Adults
(Singapore)
4 Takeda Pharmaceutical Limited
DEN-203: Randomized, Double Blind Placebo-
controlled Phase 2 Trial of Takeda’s
• Primary objectives:– Safety and tolerability of a subcutaneously administered recombinant
tetravalent dengue vaccine in healthy adults and children (1.5 – 45 y.o.)
– Immunogenicity of the vaccine against all four dengue serotypes
• Clinical trial sites - dengue endemic countries– Puerto Rico
• Ponce School of Medicine – Dr. Elizabeth Barranco
• Latin Clinical Trial Center – Dr. Carlos Sariol
• University of Puerto Rico – Dr. Ines Esquilin
– Colombia • Universidad de Antioquia - Dr. Ivan Velez
– Singapore• Changi General Hospital - Dr. Helen Oh
• National University Hospital - Dr. Lynette Shek
– Thailand • Phramongkutklao (PMK) Hospital – Dr. Sriluck Simasathien
• Faculty of Tropical Medicine, Mahidol University – Dr. Chukiat Siriwichayakul / Dr
Arunee Sabchareon
5 Takeda Pharmaceutical Limited
DEN-203 study design: randomized, double blind,
placebo-controlled Phase 2 study (Part 1)
Part 2
(expansion)next slide
+
28
0 7 14 28 90 97 104 120 180 360 720 1080
Group 2
12–20 yrs
n = 36
Timelines
= Group 1+
28
Group 3
6–11 yrs
n = 38
Group 1
21–45 yrs
n = 38
Randomization 2:1
vaccine to placebo
(saline)
+
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
Sirivichayakul et al. JID 2015 (submitted)
Days
Takeda Pharmaceutical Limited
DEN-203 study Part 2: expansion in healthy children
Participants administered subcutaneous placebo (PBS) or 2 vaccinations in the deltoid region:
Per dose TDV-1 TDV-2 TDV-3 TDV-4 Total
TDV formulation (Plaque
Forming Units)2 x 104 PFU 5 x 104 PFU 1 x 105 PFU 3 x 105 PFU 4.7 x 105 PFU
10800 28 90 120
Part 2
(expansion)
Enrolled, n = 212
Randomization 3:1
vaccine to placebo
(saline)
1.5–11 yrs
n = 212
followed
for 36
months
Days
Data available to here
Part 1
(age-descending)
Enrolled, n = 148
Total enrolled, n = 360
days
Key:
Dose
Immunogenicity sample
DEN-203: GMTs Across Age Groups (Part 1)
Vaccine Group Placebo Group
= vaccination
Data shown as geometric means with 95% confidence intervals
8
Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
Seronegative at Baseline
(N=38-46)
1
10
100
1000
10000
0 30 60 90 120
Ge
om
etr
ic M
ean
PR
NT 5
0
Days
DENV-1
DENV-2
DENV-3
DENV-4
DEN-203 Immunogenicity (Part 1)
GMTs in All Age Groups by Baseline Seroresponse
= vaccination
Seropositive at Baseline
(N=42-49)
1
10
100
1000
10000
0 30 60 90 120G
eo
me
tric
Me
an P
RN
T 50
Days
DENV-1
DENV-2
DENV-3
DENV-4
Data shown as geometric means with 95% confidence intervals
9
Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
DEN-203 Immunogenicity (Part 1)
Seropositivity Rates to Multiple Dengue Viruses – all ages
• All age groups, combined
• Doses at Day 0 and Day 90
• Seropositive = PRNT50 titer ≥ 10
0
10
20
30
40
50
60
70
80
90
100
4 serotypes ≥ 3 serotypes ≥ 2 serotypes
All Ages (N=88)
Day 0
Day 28
Day 120% S
ero
positiv
eTakeda’s Live Attenuated Dengue Vaccine Candidate
10
Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
DEN-203 Immunogenicity (Part 1)
Seropositivity Rates to Multiple Dengue Viruses – age stratified
% S
ero
positiv
e%
Se
rop
ositiv
e
0
10
20
30
40
50
60
70
80
90
100
4 serotypes ≥ 3 serotypes
Adults (N=23)
0
10
20
30
40
50
60
70
80
90
100
4 serotypes ≥ 3 serotypes
Adolescents (N=22)
Day 0
Day 28
Day 120
0
10
20
30
40
50
60
70
80
90
100
4 serotypes ≥ 3 serotypes
Children, 1.5 - 5 y.o. (N=22)
Day 0
Day 28
Day 120
0
10
20
30
40
50
60
70
80
90
100
4 serotypes ≥ 3 serotypes
Children, 6 - 11 y.o. (N=21)
11
Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
DEN 203; GMTs over time
All subjects
12
Combined Age Groups (N=90)
Takeda Pharmaceutical Limited
DEN 203; GMTs over time
Subjects Seronegative at baseline
13
Combined Age Groups (N=40)
Takeda Pharmaceutical Limited
TDV elicits high rates of seropositivity to DENV-1−4
through Day 720
Percentage of seropositive‡ children and adults – all subjects
% o
f stu
dy p
art
icip
ants
Pa
rts 1
& 2
n=
24
9
Pa
rt 1
n-=
90
*full analysis set, ‡seropositive = MNT50 titer ≥ 10. Sirivichayakul et al. JID 2015 (submitted)
14 Takeda Pharmaceutical Limited
TDV elicits high rates of seropositivity to DENV-1−4,
in participants who were seronegative at baseline
Percentage of children and adults who were seronegative at baseline and became
seropositive‡ after receiving TDV
% o
f stu
dy p
art
icip
ants
Dengue-naïve at baseline
Pa
rts 1
& 2
,
n (
ran
ge
)=14
1-1
67
Pa
rt 1
, n
=4
0
15
*full analysis set, ‡seropositive = MNT50 titer ≥ 10. Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
TDV elicits a tetravalent response in the majority of
children and adults
Percentage of children and adults seropositive‡ to multiple serotypes
% o
f stu
dy p
art
icip
ants
Number of positive serotypes
*full analysis set: includes all participants regardless of baseline seropositivity, Sirivichayakul et al. JID 2015 (submitted)
‡seropositive = MNT50 titer ≥ 10
Pa
rts 1
& 2
,
n=
24
9
Pa
rt 1
,
n=
90
16 Takeda Pharmaceutical Limited
Percentage of children and adults who were seronegative at baseline and became
seropositive‡ to multiple serotypes after receiving TDV
TDV elicits a tetravalent response in children and adults, in
participants who were seronegative at baseline %
of
stu
dy p
art
icip
ants
Number of positive serotypes
Dengue-naïve at baseline
* Sirivichayakul et al. JID 2015 (submitted)
‡seropositive = MNT50 titer ≥ 10
Part
s 1
& 2
,
n=
13
3P
art
1,
n=
40
17 Takeda Pharmaceutical Limited
The incidence of injection site AEs, but not systemic AEs
was greater after TDV administration compared to placebo
18
Safety set, Sirivichayakul et al. JID 2015 (submitted)
TDV, N=249 Placebo, N=111
Within 14-days after dose 1
TDV, N=249 Placebo, N=111
Within 14-days after dose 2
% o
f p
art
icip
an
ts w
ith
se
lf-r
epo
rted
ad
ve
rse
eve
nts
Diary-recorded reaction
(75)
(8)
(57)
(4)
(28)
(5)
(20)
(2)
(31)
(0)
(18)
(1)
(10)
(0)
(10)
(0)
Takeda Pharmaceutical Limited
DEN- 203 Safety Summary
• No discontinuations due to AEs
• No related SAEs
• No constellation of symptoms suggestive of dengue fever
• No serious vaccine-related adverse events (SAEs) assessed, as
related by investigators
• No meaningful changes in blood chemistry, hematology
• Most common AEs
– Self limited mild to moderate systemic adverse events:• Headache, nasopharyngitis, nausea and myalgia were most common
• All grade 3 and 4 AEs not related to the vaccine
• No constellation of symptoms suggestive of dengue fever
– Short-duration (<4 days) mild-to-moderate local injection site reactions
(erythema, edema and pain)
• No deaths
19
Sirivichayakul et al. JID 2015 (submitted)
Takeda Pharmaceutical Limited
Current Status: Subjects Enrolled in TDV Studies
TDV Control Total
Completed Studies
DEN 101 48 24 72
DEN 102 79 17 96
DEN 103 67 0 67
DEN 104 136 0 136
DEN 203 249 111 360
Ongoing Studies
DEN 106 1002 0 1002
DEN 204 1600 200 1800
Total 3181 352 3533
20
As of Aug/2015
Takeda Pharmaceutical Limited
Takeda’s Live Attenuated Dengue Vaccine Candidate:
Clinical Summary
• All dose formulations of Takeda’s Live Attenuated Dengue
Vaccine Candidate tested in phase I and II studies were
well tolerated.
• In a phase II study, Takeda Candidate Vaccine formulation
induced neutralizing antibodies and levels of
seroconversion ≥80% to all four dengue serotypes after
two doses.
• A formulation with an optimized component ratio has been
selected for ongoing and future studies.
• A pivotal phase III efficacy study is in preparation.
21 Takeda Pharmaceutical Limited
Acknowledgements
22
CDC
Claire Huang Siritorn Butrapet
Karen Boroughs Janae Stovall
Melissa Bushey
Collaborators
Eva Harris Aravinda DeSilva
Mike Diamond Alessandro Sette
PDVI/DVI, S. Korea
Harold Margolis, Luiz J. DaSilva, Georges
Thiry
NIAID
Cristina Cassetti, Catherine Laughlin, Cathy
Cai, Dan Stoughton and DMID team (Grant
5U01AI070443 and NIH Contract
HHSN272201000034C)
Phase 1 Sites:
Colombia: Ivan Velez and PECET team
US: Sarah George
Phase 2 Sites:
Puerto Rico: C. Sariol, I. Esquilin, E.
Barranco
Colombia; I. Velez
Singapore: H. Oh, L. Shek
Thailand: A.Sabchareon, S. Simasathien, C.
Sirivichayakul
And all study participants and their families
Takeda Pharmaceutical Limited
Thank you
Takeda Pharmaceutical Limited