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

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

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

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

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

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

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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