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
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• Reversion to virulence
• Vector transmission
4 Recombinant cDNAs Individually transcribed to RNA RNA transfection in Vero cells
• Recombination
X
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• 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
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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)
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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