a recombinant tetravalent dengue vaccine candidate using ... · takeda’s live-attenuated...

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’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


Cpr


Cpr


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


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)


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


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


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



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




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




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


Adolescents (N=22)

Day 0

Day 28

Day 120

0

10

20

30

40

50

60

70

80

90

100


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


Children, 6 - 11 y.o. (N=21)

11



DEN 203; GMTs over time

All subjects

12

Combined Age Groups (N=90)


DEN 203; GMTs over time

Subjects Seronegative at baseline

13

Combined Age Groups (N=40)


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)


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)


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


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


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)


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



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’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.


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


Thank you


a recombinant tetravalent dengue vaccine candidate using ... · takeda’s live-attenuated...

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