dengue vaccine late stage development: a case...
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DENGUE VACCINE LATE STAGE DEVELOPMENT:
A CASE STUDY
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SANJAY K. PHOGAT, Ph.D.
Director R&D, Project Leader
Innovation and Late-stage Development Projects
PRODUCT DEVELOPMENT BOOT CAMP
NEW YORK NOVEMBER 5-6 2015
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OUTLINE
● Dengue● Unmet medical need
● Vaccine an important prevention tool
● Dengue Vaccine● Challenges
● (Target) Product profile
● Sanofi Pasteur R&D
● Phase III planning and Key results
● Industrial capacity to ensure access and supply● Model for prioritized access to innovation in endemic regions
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DENGUE IS A MAJOR PUBLIC HEALTH CONCERN AND ITS INCIDENCE IS INCREASING 1,3
1. WHO, 2009, Dengue Guidelines for Diagnosis, Treatment, Prevention, and Control.
2. WHO, 2012, Global Strategy for Dengue Prevention and Control.
3. Guzman, 2010, Nat Rev Micro.
4. WHO, 2015, Dengue fact sheet
3.9 billion people live in endemic regions. 4
Spread of dengue parallels expanding range of mosquito vector 2
More than 100 endemic countries 4.
Dengue cases have been reported in several non-endemic countries and territories 4
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CURRENT MEASURES ARE NOT SUFFICIENT TO PREVENT OR CONTROL DENGUE DISEASE
● Despite decades of research, NO dengue-specific treatment available
Prevention measures: mainly vector control that
have not stopped the spread of dengue:
Measures largely reactive1
Aedes aegypti developed widespread
resistance to many common insecticides1
Community engagement necessary to
sustain effective vector control. 1
Even if low vector presence (e.g. Singapore),
dengue incidence dramatically increase. 2
New vector control measures (in-
development) are promising
1. WHO, 2012, Global Strategy for Dengue Prevention and Control.
2. Ooi, 2006, Emerg Infect Dis.
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DENGUE VACCINECHALLENGES and OPPORTUNITY
Challenges:
● No animal model for the disease, no known immune correlates of protection and
theoretical risk of immunepotentiation - Require large-scale safety studies and
long term follow-up
● 4 different dengue virus serotypes requiring a combined tetravalent vaccine and
dynamic dengue epidemiology - Broad Coverage
● Pre-Existing Immunity to Flavi-virus in endemic area – Understand role of Pre-
Existing Immunity
Opportunity:
● Neutralizing antibodies correlate with protection for Flavi-virus vaccines (YF and
JE)
● Dengue vaccine candidate elicited high titer neutralizing antibodies and
showed no safety concerns, which increased the probability of success
(POS)
● High POS allowed for parallel R&D and Manufacturing capabilities to supply
large-scale Phase III studies and subsequent broad vaccination programs
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DENGUE VACCINE (TARGET) PRODUCT PROFILE
Indication
& Use
• The prevention of dengue disease caused by dengue virus serotypes 1, 2, 3, and 4 in individuals from 9 years of age living in endemic areas.
Dosage &
Administration
• Given in 3 doses of 0.5 mL, 6 months apart (0, 6, and 12 months), subcutaneously, after reconstitution with a diluent.
• If flexibility in the vaccination schedule is necessary, a time window of ± 20 days is acceptable.
• The Sanofi Pasteur candidate is a 4-serotype, recombinant,
live, attenuated vaccine.1,2
1. Guirakhoo, 2001, J Virol.
2. Guirakhoo, 2000, J Virol| 5
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SANOFI PASTEUR RESEARCH AND DEVELOPMENT OF A DENGUE VACCINE FOR ~20 YEARS: ACCELERATED DEVELOPMENT WITH INCREASED POS
1. sanofi pasteur, data on file, 2013, Dengue fact
sheet.
2. Sabchareon, 2012, Lancet.
3. Capeding, 2014, Lancet.
4. Villar 2015, N Engl J Med.
1994Partnership
with the
Mahidol
University
in
Thailand1
2001Clinical
evaluation
of Sanofi
Pasteur's live
attenuated
dengue
vaccine1
2004Recombinant,
live,
attenuated
vaccine
adopted as
a new
approach1
2007Positive
results in
phase II
clinical
Studies1
High POS
2009First
pediatric
clinical
efficacy
study1
2010Fast track
status
granted
from the
US FDA1
2010–
2011First
phase III
clinical
study1
2012Results of
phase IIb
clinical
efficacy
study
published2
2014Results of
phase III
efficacy
studies3,4
FDA=US Food and Drug Administration.
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RIGOROUS SELECTION OF ENDEMIC SITES PRIOR EPIDEMOLOGY STUDIES AND PHASE II TRIALS (ENDPOINTS AND GOOD CLINICAL PRACTICES)
CYD15 efficacy study
in Latin America and the Caribbean
N=20,869
Mexico
Puerto Rico
Honduras
Colombi
aBrazil
CYD14 efficacy study
in Asia
N=10,275
1 Capeding, 2014, Lancet.
2 Villar, 2015, N Engl J Med.
*Lack of clinical trial expertise in some countries (sites, EC,
HA, CRO…)
Endemic area are often in Remote area (not in capital city)
Lack of infrastructure and trained investigator sites
Logistic issues
*Dependence to EC/HA decision
Dependence to virus circulation in the given country/site
* LatAm & Asia Operational Challenges
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COUNTRY/COMMUNITY ENGAGEMENT INSTRUNMENTAL FOR CAPACITY BUILDING AND KNOWLEDGE TRANSFER
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PHASE III PLANNING AND MONITORING TEAM COMPOSITION, EXPERTISE AND LOCALIZATION
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Multiple Ph I (5),II (14) and III (6) clinical studies conducted to support
licensure.
Global team, all R&D sites involved
10 Countries in Phase III
Since 2006, >1,200 people have reported time working on Dengue Program
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Pooled results (CYD14+CYD15; ITT) VE (%) and 95% CI
Any serotype
DENV-1
DENV-2
DENV-3
DENV-4
Severe dengue
DHF (WHO)
Hospitalized cases
In dengue-seropositive subjects
In dengue-seronegative subjects
SUMMARY OF POOLED EFFICACY: EFFICACY WAS CONSISTENTLY DEMONSTRATED IN SUBJECTS AGED 9–16 YEARS IN THE 25-MONTH ACTIVE PHASE1
DENV=dengue virus; DHF=dengue hemorrhagic fever; ITT=intent to treat; VE=vaccine efficacy;
WHO=World Health Organization.
65.6
58.4
47.1
73.6
83.2
93.2
92.9
80.8
81.9
52.5
0 20 40 60 80 100
60.7 69.9
47.7 66.9
31.3 59.2
64.4 80.4
76.2 88.2
77.3 98.0
76.1 97.9
70.1 87.7
67.2 90.0
5.9 76.1
Villar et al. N Engl J Med 2015; 372:113-123
Hadinegoro et al. Engl J Med 2015; 373:1195-1206| 10
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AN INNOVATIVE REGULATORY STRATEGY BOTH FOR SANOFI PASTEUR AND FOR REGULATORY AUTHORITIES
Starting with multiple submissions in “international countries” without
approval in the country of origin or a country of reference
Frequent meetings with Authorities to prepare submissions and
associated activities (test transfer, inspections …) including scientific
advices in Europe and type C meetings in the US
Fast-track review process with Authorities accepting rolling submission
or a file with missing sections to gain time on review timelines
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UNPRECEDENTED INDUSTRIAL COMMITMENT TO ENSURE EQUITABLE ACCESS AND CONSISTENT SUPPLY
Manufacturing Site, Neuville-sur-Saone, France
State-of-the-art facilities
developed specifically for
production of dengue vaccine
Designed to produce 100 million
doses of vaccine per year and
respond to public vaccination
needs
Vaccine can be supplied as early
as Q4 2015
Vaccine filing and registration is
ongoing in endemic countries
Ready to produce >1 billion doses over the next 10 years.
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DENGUE VACCINE IS FLIPPING THE CLASSICAL VACCINE INDUSTRY MODEL
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For the 1st time, prioritized access to innovative vaccine for endemic
populations, balancing cost of innovation with sustainable access
Investment in this vaccine were at the same levels as any other recently
launched vaccine
Aim is to have an impact on the disease, ensuring protection for
populations most at-risk
Paving the way: Dengue can contribute to strengthen the existing
vaccination channels/ current vaccination programs.
Volume for production has been anticipated, even before the results of trials
to ensure a broad access from registration.
The company can produce the vaccine at economies of scale, translating
into expanded access
From vaccine producer to vaccination partner: collaborating now with public
health community to create solutions that can result in maximal public
health impact
Beyond that, this model needs to succeed to drive new investments into
R&D and production of vaccines/ drugs tackling tropical or emerging
countries diseases
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5As INITIATIVE: A SYSTEMATIC APPROACH TO BUILD AND SUSTAIN VACCINATION COVERAGE
• Simple, intuitive framework to disaggregate problem & develop targeted solutions
• Evidence-based decision making
• National Coverage Plan
• Ongoing monitoring & evaluation
• Collective impact
• Local engagement with Health Authorities & key stakeholders
• Country ownership of solution
Grow market & Build partnerships
5As value proposition
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LESSONS LEARNED
● Define vaccine attributes and understand limitation and challenges
● Clearly defined risk-management plan which allowed for Leadership
support and commitment to perform activities at-risk is key
● Large scale efficacy studies are key to success
● Planning and execution
● Selection of sites
● CRO’s for monitoring
● Country/community engagement
● Early-on investment in manufacturing capabilities to supply large-
scale Phase III studies and subsequent broad vaccination programs
● New model for prioritized access to innovation in endemic regions
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Thank you!!!
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