DENGUE VACCINE LATE STAGE DEVELOPMENT: A CASE STUDY 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

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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 1. 2. 3. 4.

WHO, 2009, Dengue Guidelines for Diagnosis, Treatment, Prevention, and Control. WHO, 2012, Global Strategy for Dengue Prevention and Control. Guzman, 2010, Nat Rev Micro. WHO, 2015, Dengue fact sheet

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CURRENT MEASURES ARE NOT SUFFICIENT TO PREVENT OR CONTROL DENGUE DISEASE ●

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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 (indevelopment) are promising 1. 2.

WHO, 2012, Global Strategy for Dengue Prevention and Control. Ooi, 2006, Emerg Infect Dis. |

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DENGUE VACCINE CHALLENGES and OPPORTUNITY Challenges:

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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 PreExisting Immunity

Opportunity:

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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 • The Sanofi Pasteur candidate is a 4-serotype, recombinant, live, attenuated vaccine.1,2

Indication & Use

Dosage & Administration

• 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.

• 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.

1.

Guirakhoo, 2001, J Virol.

2.

Guirakhoo, 2000, J Virol |

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SANOFI PASTEUR RESEARCH AND DEVELOPMENT OF A DENGUE VACCINE FOR ~20 YEARS: ACCELERATED DEVELOPMENT WITH INCREASED POS

1994

2001

2004

2007

2009

2010

Partnership with the Mahidol University in Thailand1

Clinical evaluation of Sanofi Pasteur's live attenuated dengue vaccine1

Recombinant, live, attenuated vaccine adopted as a new approach1

Positive results in phase II clinical Studies1

First pediatric clinical efficacy study1

Fast track status granted from the US FDA1

FDA=US Food and Drug Administration.

High POS

1. 2. 3. 4.

sanofi pasteur, data on file, 2013, Dengue fact sheet. Sabchareon, 2012, Lancet. Capeding, 2014, Lancet. Villar 2015, N Engl J Med.

2010– 2011 First phase III clinical study1

2012

2014

Results of phase IIb clinical efficacy study published2

Results of phase III efficacy studies3,4

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RIGOROUS SELECTION OF ENDEMIC SITES PRIOR EPIDEMOLOGY STUDIES AND PHASE II TRIALS (ENDPOINTS AND GOOD CLINICAL PRACTICES) Puerto Rico Mexico

Honduras

Colombi a

*Dependence to EC/HA decision Dependence to virus circulation in the given country/site

Brazil

*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

CYD15 efficacy study in Latin America and the Caribbean N=20,869

CYD14 efficacy study in Asia N=10,275 1 Capeding, 2014, Lancet. 2 Villar, 2015, N Engl J Med.

* 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 Global team, all R&D sites involved 10 Countries in Phase III Since 2006, >1,200 people have reported time working on Dengue Program

Multiple Ph I (5),II (14) and III (6) clinical studies conducted to support licensure. |

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SUMMARY OF POOLED EFFICACY: EFFICACY WAS CONSISTENTLY DEMONSTRATED IN SUBJECTS AGED 9–16 YEARS IN THE 25-MONTH ACTIVE PHASE1 Pooled results (CYD14+CYD15; ITT)

VE (%) and 95% CI 65.6

Any serotype

60.7

69.9

58.4

DENV-1

47.7

66.9

47.1

DENV-2

31.3

59.2

73.6

DENV-3

64.4

80.4

83.2

DENV-4

76.2

88.2

93.2

Severe dengue

77.3

98.0

92.9

DHF (WHO)

76.1

97.9

80.8

Hospitalized cases

70.1

In dengue-seropositive subjects

67.2

87.7

81.9

90.0

52.5

In dengue-seronegative subjects

5.9

0

76.1

20

40

60

80

100

DENV=dengue virus; DHF=dengue hemorrhagic fever; ITT=intent to treat; VE=vaccine efficacy; WHO=World Health Organization.

Villar et al. N Engl J Med 2015; 372:113-123 Hadinegoro et al. Engl J Med 2015; 373:1195-1206

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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

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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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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

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UNPRECEDENTED INDUSTRIAL COMMITMENT TO ENSURE EQUITABLE ACCESS AND CONSISTENT SUPPLY Ready to produce >1 billion doses over the next 10 years.

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State-of-the-art facilities developed specifically for production of dengue vaccine

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Designed to produce 100 million doses of vaccine per year and respond to public vaccination needs

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Vaccine can be supplied as early as Q4 2015 

Vaccine filing and registration is ongoing in endemic countries

Manufacturing Site, Neuville-sur-Saone, France

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DENGUE VACCINE IS FLIPPING THE CLASSICAL VACCINE INDUSTRY MODEL 

For the 1st time, prioritized access to innovative vaccine for endemic populations, balancing cost of innovation with sustainable access   

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Volume for production has been anticipated, even before the results of trials to ensure a broad access from registration. 

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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.

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 5As value proposition • 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 14

LESSONS LEARNED ● ●

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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 ● ● ● ●

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Planning and execution Selection of sites CRO’s for monitoring Country/community engagement

Early-on investment in manufacturing capabilities to supply largescale 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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