Update on the Clinical Development of the sanofi pasteur Dengue Vaccine

Update on the Clinical Development of the sanofi pasteur Dengue Vaccine Pedro Garbes, MD Regional Director, Clinical Development Latin America - Sano...
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Update on the Clinical Development of the sanofi pasteur Dengue Vaccine

Pedro Garbes, MD Regional Director, Clinical Development Latin America - Sanofi Pasteur [email protected]

Construction of the Sanofi Pasteur dengue vaccine and overall development strategy. Preclinical Evaluation • In vitro and in vivo genetic and phenotypic stability Yellow Fever Virus 17D cDNA C prM

E

• Envelope Glycosylation

Non-Structural genes (NS)

• Safety and immunogenicity - Human cells in vitro (DCs y Hep. Cells) prM

E



PUO-359/TVP-1140

- Monkey model



PUO-218

- Non-clinical safety (NCS)



PaH881/88



1228 (TVP-980)

Exchange with prM/E genes of wt DEN 1– 4

Theoretical issues and GMO aspects

?

• Reversion to virulence

• Vector transmission

4 Recombinant cDNAs Individually transcribed to RNA RNA transfection in Vero cells

• Recombination

X

?

• Viscerotropism

• Breadth of protection    

• ADE



Scale up and Industrial Development 4 individual recombinant dengue viruses (CYD 1-- 4)

 

• Scale up •Phase I to Phase III process • Building od facilities

Clinical Development (Phase I to Phase III, non-endemic / endemic areas) • Safety / Viremia • Immunogenicity (PRNT50, CMI)

B

T 

2

Pre-clinical Summary High stability of recombinant viruses makes it almost impossible to create a wild type yellow fever virus in vaccinees because: 1) YF envelope genes are missing and 2) numerous reversions to wild type of attenuating residues within the seven nonstructural genes and the core protein gene are required Lack or low level of viremia in the host, as well as the lack of transmission by the mosquito vectors are the safeguards against the dissemination of these viruses in the environment A complete GMO technical dossier has been built, describing all what has been done to characterize the CYD dengue vaccine, and an Environmental Risk Assessment (ERA) dossier has been built too. The corresponding data have been presented on regular occasions to Health authorities in different countries (including EMA in Europe and CTNBio in Brazil). The vaccine has been classified as Risk Level 1 and Biosafety Level 1.

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Sanofi-Pasteur CYD Tetravalent Dengue Vaccine profile Description: Live attenuated virus, tetravalent (4 vaccinal strains cultured in serum free Vero cells) Pharmaceutical form: Powder and solvent for suspension for injection (0.5 ml) Route of administration: Sub-cutaneous Schedule: 3 injections 0 - 6 - 12 months Dosage: 5 ± 1 log10 CCID50 of each serotype for one dose Storage: +2°C to +8°C Indication: Prevention of symptomatic dengue disease i.e. covering the spectrum from Dengue Fever to severe Dengue cases due to serotypes 1, 2, 3 or 4. Populations: Children and adults living in endemic areas, people working in (traveling to) endemic areas Priority: Endemic countries (Latin America, Asia/Pacific, Caribbean)

S-P TDV is supported by a thorough CDP Phase I trials completed Trial code

Preparation

Vac. 1

Vac. 2

Vac. 3

Follow up

CSR

CYD01* (USA) § 18-49yo, n=56 CYD02* (USA) 18-40yo, n=99 CYD04* (USA) ‡ 18-45yo, n=66 CYD05 (Phillipines) †† 2-45yo, n=126

Year 4

CYD06 (Mexico) ††† 2-45yo, n=126

*IND. § Guirakhoo et al. Human Vaccines 2006;2(2):607. ‡ Morrison et al. JID; 2010:370-77. †† Capeding et al Vaccine 2011 29(22):3863-72. ††† Poo et al. Pediatr Infect Dis J 2011;30: e9–e17

Phase II trials ongoing/completed in Americas Trial code

Preparation

Vac. 1

Vac. 2

Vac. 3

Follow up

CSR

CYD11 (Mexico) 18-40yo, n=150 CYD12* (USA) 18-45yo, n=250 CYD13* (PR, HN, MX, CO) 9-16yo, n=600 CYD24 (Peru) ‡ 2-11yo, n=300 CYD30* (Brasil) 9-16yo, n=150

*IND. ‡ Lanata et al. ASTMH 59th Annual Meeting, Nov 3-7 2010, Atlanta, Georgia Poster #LB-2289. Lanata et al. A Re-emerging Challenge in the Americas: Opportunities for Dengue Research Collaborations. Puerto Rico, 15-18 Feb 2011

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Phase II Trials completed/ongoing in Asia Code

Population (age)

Country

Curent status

CYD08

Children (12-15m) N=210 Adults (18-40yo) N=35 Children, Adolescents & Adults (2-45yo) N=180 Children, Adolescents & Adults (2-45yo) N=1,200

Phillipines

Ongoing (2nd dosis)

Australia

Completed

Vietnam

Ongoing (3rd dosis completed)

Singapore

Completed (Long term follow up)

CYD10 CYD22 CYD28

www.clinicaltrials.gov 6

CYD24 Seropositivity by Serotype - Peru % of children seropositivity to each serotype

Group TDV Seropositivity with dengue PRNT assay

Balance immune response to the 4 serotypes after dose 3, with respect to percentage of seropositive subjects Timepoints

Baseline

Previous YF vaccination doesn’t interfere with the immune response to dengue serotypes

Post vac 2

Post vac 3

0

Control Group Seropositivity with Dengue PRNT assay

20

40

60

80

Percentage Children with titer >=10

Timepoints

Baseline

Serotype 1 Serotype 2 Serotype 3 Serotype 4

Post vac 2

Post vac 3 0

20

40

60

80

Percentage Children with titer >=10 7

100

100

CYD 23 – First Efficacy trial in Thai children Population

Group 1 (Dengue vaccine)

Group 2 (Control/placebo)

TOTAL

Children (4-11 yr)

2668

1334

4002

Ratchaburi, Thailand

Sample size based on attack rate 1.3%, efficacy of 70% & lower bound of 0% Principal objective: To assess DEN vaccine efficacy post 3 doses in preventing dengue confirmed cases, regardless severity and due to any of the 4 dengue serotypes Status: 3rd doses completed

Months 0

6

12

18

Detection of Dengue cases 12m after 3rd dose

(Immunogenicity in a subset) 8

24

36 Additional follow-up (dengue hospitalized cases)

48

Safety - Global Independent Monitoring Committee (IDMC) IDMC 8 members Asia: 3 pediatricians and clinicians with dengue experience Europe: 1 epidemiologist, 1 member with IDMC experience, 1 expert on clinical trial methodology Latin America: 1 ID specialist with dengue experience, 1 pediatrician/epidemiologist Evaluate: All adverse reactions and severe adverse events All SAEs All dengue cases Face to face meetings, tele or video conferences quarterly

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•Results

of IDMC Deliberation April 2011

Results of IDMC Deliberation April 2011

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Summary of Safety Data so far No mild dengue-like syndrome observed Reactogenicity profile similar to control vaccines No increase in reactogenicity In Flavivirus (FV)-immune subjects in comparison to FV naïve subjects After a 2nd or a 3rd dose In younger subjects (youngest group 2-11 years)

Low vaccine viremia Similar rate of AEs and SAEs reported in Dengue vaccine group and control No evidence to suggest a safety concern with the vaccine (IDMC statement April 19-21 2011 meeting) 11

Summary of Immunogenicity Data so far

Balanced immune response against all 4 serotypes after 3 doses of tetravalent Dengue vaccine Stepwise increase of seropositivity rates against each serotype with 3 doses Higher immune responses observed in children Previous flavivirus vaccination has a priming potential Higher titers in subjects previously exposed to wild type dengue

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Ongoing Extended Efficacy Clinical Trials CYD32 –Safety and immunogenicity of Tetravalent Dengue Vaccine in subjects aged 2-11 yrs in Malaysia CYD17 – Lot consistency trial in healthy adult subjects (18-60 yrs) in Australia

CYD14 & CYD15 Design & Study population Multinational, multicenter, observer-blind, randomized, controlled trial Primary Endpoint: To assess the efficacy of dengue vaccine after three injections in preventing symptomatic, virologically confirmed dengue cases, regardless of the severity, due to any of the four serotypes Sample size: Based on 70% efficacy, lower bound of 25% and attack rate of 1.3% in Asia (CYD14) and attack rate of 0.64% in Latin America (CYD15) Both studies under US IND Code

Populations

Country

Status

CYD14 Phase III Asia-Pacific

Children Adolescents (2 to 14 yo) n=10,278

Thailand Vietnam Philippines Malaysia Indonesia

Started June 3, 2011

CYD15 Phase III Latin America

Children Adolescents (9-16 yo) n=20,875

Puerto Rico Honduras Colombia Mexico, Brazil

Started June 8, 2011

Conclusions (I) The vaccine has been administered to more than 6,000 children and adults, from 2 to 45 years-old, in dengue endemic and nonendemic areas, and no safety concerns have arisen in any of the completed or ongoing trials No vaccine-induced immune enhancement has been observed in clinical trials. S-P TDV safety is similar in children, and immunogenicity even better than in adults. To this date safety data support ongoing clinical development in lactants and younger children 14

Conclusions (II) Three doses are needed to induce a complete balanced response in naive individuals, although more rapid seroconversion is observed in flavivirus immune persons against all 4 serotypes, as well as a Th1 response against all 4 serotypes. Globally, more than 20 clinical trials (phase I and II) are ongoing / completed. Phase III trials ongoing: First dengue vaccine efficacy trial is on going, results are expected in 2012 Successful manufacturing scale up ; early industrial investment to fasten vaccine availability Given the clear medical need, the licensing strategy is to submit directly to dengue endemic countries In a second instance to non-endemic countries for travelers. The Utilities Building

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The Quality control Blg

The Dengue Bulk Blg

Thanks to… Global Investigators and Dengue Experts team IRBs and MoHs of involved countries Medical Societies of involved countries Communities, families and participants of these clinical trials

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Obrigado!

Thank you! 17

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