Jacqueline Keith, J.D. New York Pharma Forum October 16, 2013 J - - PowerPoint PPT Presentation

Jacqueline Keith, J.D. New York Pharma Forum October 16, 2013

J Keith Consulting Corp.

 Global Environment  Vaccine Milestones  Public-Private Partnerships  Innovative Financing  Economic Context  Evolving Landscape

J Keith Consulting Corp.

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 Under-5 mortality has declined by ½ over the past 50 years  But in least developed countries (LDC’s), 1,500 people die

every hour from infectious disease (ID); ½ of them children

 LDC’s bear 90% of the burden of global infectious disease –

but ID represents only 10% of global R&D

 New approaches are needed to foster R&D and timely delivery

for these “neglected tropical diseases” (NTDs)

 The solution lies in inn

nnovative ative scien ience, ce, partners tnerships hips, , and d finan nancing cing

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• The past 10 years have seen the introduction of new

generation vaccines against the two of the leading vaccine-preventable causes of death in the developing countries -- pneumococcal and rotavirus disease

• Of 374 neglected tropical disease (NTD) projects

currently underway, 201 (54%) are vaccines targeted at 16 diseases affecting the poorest countries*

• Many are the result of collaboration between large

pharma companies, small biotech enterprises, academia, and public partners

* Source: Bio Venures for Global Health 2012

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Product Development Partnerships (PDPs)

 Meningitis Vaccine Project: Gates/NIH/Serum Institute of India  Aeras: R&D for tuberculosis vaccines  International AIDS Vaccine Initiative (IAVI)  Dengue Vaccine Initiative (DVI)  WIPO* Re:Search Consortium (offering shared access to intellectual property (e.g. compound libraries, regulatory dossiers, and platform technologies) to support research into neglected diseases.)

* World Intellectual Property Organization

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1970’s : WHO Expanded Program on Immunizations (EPI)

• Objective: universal access to 6 routine pediatric vaccines
• Challenge: only 5% coverage of children in some LDCs
• Price: <$1.00 (all 6 vaccines) – differential pricing

1980’s/l990’s: Children’s Vaccines initiative (CVI)

• Objective: enhance immunization coverage in LDCs
• Coverage of EPI vaccines grew to 80%

1990’s: New Generation Vaccines

• Complex new technologies/more expensive
• Time lag between introduction in high-and low-income countries(15 years)

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2000: Global Alliance for Vaccines and Immunization (GAVI)

• Objective: accelerate access to new vaccines in the LDCs
• Public-private partnership
• Immunized 288 million children, saving est. 5.5 million lives (to date)

2010: Decade of Vaccines (DOV)

• Announced in 2010: $10 billion (Gates Foundation)
• Collaboration between Gates Foundation, WHO, UNICEF, NIAID
• By 2020, save 6.4 million lives/avert $151 billion in treatment costs/lost

productivity – via increased vaccines R&D and access

• Global Vaccine Action Plan approved at 2012 World Health Assembly

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2011-15: GAVI Replenishment Cycle

• Concluded on June 13, 2011 in London
• US$ 4.3 billion was pledged
• Multi-year predictable funding to immunize a quarter of a billion children in

developing countries

2012-2020: Global Vaccine Action Plan (GVAP)

• Implementation of DOV mission
• 6 strategic immunization objectives
• Monitoring and Evaluation Framework (indicators)
• Annual progress reports: country/regional
• World Immunization Week (2013)

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 Launched 2000  Public Private Partnership  72 GAVI-eligible countries (<$1,550 GNI per

capita)

 Vaccines:

• Phase 1 (2000-2006): Hep B, Hib, Yellow Fever
• Phase 2 (2006-2015): Pneumococcal, Rotavirus
• Phase 3 (2015-2020): malaria, cholera, yellow fever, rabies*

* Subject to funding availabliity

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Source: GAVI Alliance

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• GAVI

I Alli lian ance: Gates Foundation/donor countries (US $7.6 billion: 2010-2015)

• Inter

ternati national al Fina nance nce Facility acility for Immu mmunizat izatio ion (IFF FFIm Im)  Launched 2006  Raises funds by issuing bonds in the capital markets – backed by long-term government pledges (UK, France, Italy, Spain, Sweden, Norway, South Africa)  US$ 5.3 billion over 20 years (triple-A rating)

• Advan

vance e Market ket Comm

• mmit

itmen ent t (AMC) MC)  Sustainable markets for needed new vaccines (“pull”)  Demand “guarantee”  AMC price/tail price  Pneumococcal pilot launched 2009 (UK, Canada, Italy, Norway, Russia Gates Foundation):  US $1.5 billion/ 18 countries (2012)

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 Vaccines as “Public Good”  Public vs. private market  Prevention vs. Treatment  Cost-Benefit Ratios/QALYs  Tiered Pricing/Access in LDCs  Lower-Middle Income Countries (LMICs)  GAVI “graduating” countries  Price Referencing/Transparency

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

Tiered Pricing – the charging of lower prices in poorer countries, taking into account their economic status – has been a fundamental aspect of current global vaccine procurement, and has contributed to enhanced vaccine access.



The launch of initiatives such as GAVI, are providing -- for the first time -- sufficient funding to support introduction of new vaccines in the least developed countries (LDCs)



By targeting these LDCs, these initiatives have had the unintended consequence of the MICs/LMICs falling behind in introduction of new vaccines



In recognition of this disparity, the international community is debating how to address the lack of vaccine uptake in MICs



This evolving situation – combined with rising costs of new vaccines – is raising challenges to traditional concepts of tiered pricing.



It is also prompting calls for the speedy market entry of emerging country producers through technology transfer, voluntary licensing, and patent pools.

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GAVI can prevent four million future death deaths by immunizing 243 million children from 2011-2015.
 


• See more at:

http://www.gavialliance.org/about/#sthash.bpD7j2s5.dpuf 14

Building a Global Vaccine Business

Rajeev Venkayya, MD Head, Vaccines Business Division Takeda Pharmaceuticals International, Inc. New York Pharma Forum

Quotes from Gro Brundland, Jeffrey Sachs, Kofi Annan, Julio Frenk, Bill Gates and others

Vaccination is high-impact, focused on prevention, and driven by innovation

“The most successful and cost-effective health care intervention, second only to clean drinking water” “Vaccines prevent 3-4M deaths/ year” “New vaccines / better global use of existing vaccines could prevent another 4-7M deaths” “The single most important tool to reach the 2000 UN Millennium Development Goals” “We must make this the Decade of Vaccines”

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Sources: CDC, MMWR April 2, 1999. 48:242-264 and August 24, 2007/56(33);851-863

Vaccination is one of the greatest medical advances in human history

Disease Annual Morbidity in the US (20th Century) 2006 Percent Decrease Smallpox 48,164 100% Diphtheria 175,885 100% Polio (paralytic) 16,316 100% Rubella 47,745 11 >99% Measles 503,282 55 >99% Hib 20,000 208 99% Mumps 152,209 6,584 96% Pertussis 147,271 15,632 89% Hep A 117,333 3,579 87% Varicella 4,085,120 48,445 85% Hep B 66,232 4,713 80%

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Vaccination is a major contributor to child health

Global childhood mortality declined by half over the past 50 years

Source: UNICEF and Johns Hopkins University.

The global mortality for children has declined by half over the past 50 years

.

Novel vaccines and advances in delivery mortality can be cut in half again by 2025 More than 100 million infants are immunized each year with over 2 billion doses of vaccines

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Vaccination remains one of the most cost- effective public health interventions

Reduction in mortality for diseases prevented

• r treated with innovative medicines

(vaccines, pharmaceuticals; 1965-1999)

• 75%
• 67%
• 61%
• 41%

Rheumatic fever and rheumatic heart disease Hypertensive heart disease Peptic ulcer disease Ischemic heart disease

≥97%

Infectious Diseases

VACCINATION THERAPEUTICS

Source: EFPIA 1999 – 2002 Source: Zhou F et al. Arch Pediatr Adolesc Med 2005; 159:1136-44.

Costs prevented or saved by routine childhood vaccination programs, US

24,930 5,874 4,890 3,545 2,689 1,456 1,121 993 380 Costs ($M)

(polio, measles, Hib, HBV, Hib etc)

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Why is Takeda pursuing a global vaccine business?

• Extends Takeda’s commitment to global

public health

• The vaccine market is expanding rapidly,

and has higher R&D success rates than pharmaceuticals

• Better long term investment than pharma
• No threat of rapid decline in sales post

patent expiry

• Significant barriers to entry limits

competition

• Complex intellectual property issues
• Long development timelines
• Complex manufacturing
• Large scale investments needed to become

established in the industry

• Takeda has the ambition, capability and

commitment to overcome these barriers

Source: EvaluatePharma, Extracted April 2012; Sanofi Aventis 2008 FY Consolidated Income Statement for Vaccines OpInc 29.8% on Net Sales of EURO 2,861 million; quote from Q12010 Conference Call - CFO Julian Hislop ; industry PTS survey 20

Takeda’s Vaccine Strategy

Building upon a strong Japanese Vaccine Business

• Reinforce Takeda’s position

in Japan through innovation

• Achieve excellence in quality,

product range and value Developing innovative vaccines for unmet needs

• Build a pipeline of innovative

vaccines for the global market

• Ensure these vaccines reach

those who need them most

Acquire the talent and establish the infrastructure required to build a world-class business with global reach Vision: To establish a top-tier vaccine business that makes a major contribution to global public

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Evolution of the Immunization Schedule in Japan

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From 2014 Current Schedule

○Live vaccine ●Inactivated vaccine

August, 2011 Major Japanese government subsidy for pandemic Flu vaccine development May 2013 Acquired Inviragen (Dengue, EV71 candidates) May 2009 Hib vaccine licensed from Novartis December 2010 Vero-cell based influenza vaccine technology licensed from Baxter January, 2012 Launched Global Vaccine Business Division October 2012 Acquired LigoCyte Pharmaceuticals (Norovirus vaccine; VLP technology) 1781 Takeda founded by Chobei Takeda I 1946 Opened manufacturing facility in Hikari for vaccine manufacturing

Key Milestones for Takeda Vaccines

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LigoCyte brought a first-in-class vaccine to address Norovirus and a Virus-Like Particle (VLP) platform

Norovirus

 Leading causes of outbreak and foodborne

gastroenteritis

 220K deaths world wide, mostly infants and

elderly, affects rich and poor

 Causes an outbreak every day in the US (on

average), but believed to be underreported

 No vaccine is available

Norovirus Vaccine

 The most advanced clinical-stage vaccine

against norovirus in the world

 Ph 2 candidate for adults & children, with

potential to be included in childhood immunization programs as 2-3 dose course

 Once launched, could become the most widely

used product in Takeda’s history.

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Dengue is “the most important mosquito-borne viral disease in the world” affecting populations across Asia, Latin America and Africa2

Estimated annual global burden of Dengue

• 400 million people infected
• 100 million develop clinical illness
• 500 thousand hospitalized
• 20 thousand deaths, mostly in children

Annual infections In 2010

Inviragen’s vaccine candidates target unmet needs in emerging markets:

• Dengue (Phase 2)
• Enterovirus 71 (Phase 1)
• Chikungunya (preclinical)

And extends Takeda’s vaccine R&D capabilities to inactivated and live viral vaccines, building upon LigoCyte’s capabilities

Inviragen added the most promising vaccine in development for Dengue

• 1. Hand, foot and mouth disease caused by Enterovirus 71 (EV71) 2. http://www.who.int/csr/disease/dengue/impact/en/

Source of graphic: Bhatt, S et al. Nature Vol. 496, 504-507 (2013)

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Singapore

• CMC (live virus technology)
• Clinical development, Asia

Bozeman, MT Legacy LigoCyte capabilities, including CMC (recombinant technology) and Research. Zurich Clinical development and commercial capabilities Fort Collins, CO Clinical testing, early clinical development, corporate operations Madison, WI Preclinical research and vaccine testing capabilities Deerfield, IL VBD Headquarters Hikari Vaccine manufacturing and process development Osaka Clinical development Rio de Janeiro Clinical development, LATAM

Global Footprint of Takeda Vaccines

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We are building a pipeline of vaccines with global impact

Preclinical Phase II Phase III Phase I DTaP + sIPV (Pediatric Combination) Dengue Tetravalent Live Attenuated Virus Norovirus Bivalent VLP Submitted Marketed DTaP Japanese encephalitis Pandemic Flu Cell Culture based inactivated virus Hib (Conjugated Polysaccaride) EV71 Inactivated Virus Chikungunya Live Attenuated Virus RSV (VLP) Rotavirus (VLP) Seasonal Flu Cell Culture based inactivated virus Mumps Measles Rubella Varicella

Pipeline expansion since the launch

• f the Vaccine Business Division*

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*Excluding the DTaP+sIPV combination, which preceded the launch of VBD

The Miracle of Vaccines

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“Vaccines are a miracle because with three doses, mostly given in the first two years of life, you can prevent deadly diseases for an entire lifetime.

Bill Gates Annual Letter (2010)

October 16, 2013

Building on Opportunities in the Global Vaccine Marketplace: Perspectives from a Biotech

Piers Whitehead, Vice President, Business Development

• Introduction
• Key trends in global vaccine market and implications for

small (and large) vaccine developers – Shifts in sources and rate of growth – Change in composition of vaccine industry – Increasing need for novel approaches

Outline

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• Founded 2006 in response to H5N1 pandemic threat

– Started as non-profit; incorporated 2007 – Preserved double bottom line – Focused on oral, live, Adenovirus 4 vaccine platform for H5 – Successfully developed with Wellcome Trust

• Today: Leading VC-backed vaccine company

– 3 technology platforms (Ad4/7, live attenuated bacteria, flaviviruses) – 4 clinical candidates (cholera, flu, HIV, anthrax) – 65 employees (Menlo Park, San Diego)

• Future: Market specialty vaccines
• Focus on travelers and biodefense
• First product launch 2015 (cholera in US)

– Aggregator of vaccine technologies/products – Partner broad vaccine candidates (HIV, HSV)

PaxVax in one slide: Better Vaccines to Better the World

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Historical growth context

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CAGR: 2% Lipitor Humira CAGR: 14%

Vaccine sales have grown faster that pharmaceutical industry sales

• verall

• Predominantly “Blockbuster” pediatrics ($8.9bn):

– Pneumococcal conjugate, $4.1bn – HPV, $1.9bn – Varicella1, $1.9bn – Rotavirus, $1bn

• GAVI spend: $884m2

What has driven growth?

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• 1. Varicella includes adult Zoster sales
• 2. GAVI spend includes in-country delivery

investment

• Pediatric “Blockbusters” (?): Meningitis
• Nosocomials: Pseudomonas, C Difficile
• Biodefense: Smallpox
• Travelers’/Endemic: Malaria, Dengue, Cholera

What is in the pipeline?

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Source: Clinical Trials.gov

PaxVax “Dual Use” Oral Cholera Vaccine

NY Pharma Forum

• Cholera found primarily in Africa and Asia

– Estimated 3-5 M cases; 120 K deaths/year – Greatest impact on poorest populations

• Caused by V. cholerae in contaminated water

– Toxin in intestine causes severe diarrhoea and rapid death if untreated

• Risk of epidemics in developing nations
• Risk to travellers from developed nations

– Shown to be as high as 5-13 in 100,0001

• No vaccine available in U.S.
• Dukoral, Shanchol available ex U.S. require two

doses and 30+ days to become protective

• PXVX-0200 single oral dose in powder added

to water protects within 7 days

1) Wittinger, J Travel Medicine 1995 – Surveillance of all returning Japanese travellers 35

PaxVax Cholera Vaccine: Very Low Risk and High Value

NY Pharma Forum

• Previously approved as Orochol by Berna Biotech

– Marketed in 6 countries for about 4 years to about 1 M people – Switzerland, Austria, Canada, Australia, New Zealand, Argentina – Berna Biotech acquired and vaccine abandoned – PaxVax acquires rights in 2009 (from U. Maryland)

• Proven safety and immune efficacy demonstrated

– >12 clinical trials with over 80,000 adults and children – > 90% efficacy in placebo controlled challenge studies – Only single dose vaccine in the world

• Rapid and low risk return to market

– Biosimilar-like development plan approved by FDA and EMA – Phase 1 results confirmed comparable immunogenicity to original vaccine – Phase 3 study underway, with filing anticipated in 2014 – Eligible for priority review voucher

• Target market

– Initially targeted towards travelers, aid workers and military from the developed world – Will also be developed for LICs after process development to reduce COGS and increase dosage

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• Highly concentrated industry structure, due to high cost of

entry and lengthy development time (10-15 years)

• Growth has attracted “big pharma” entrants by acquisition

– J&J, Pfizer

• Renewed interest from Japanese companies

– Takeda, Astellas, Daiichi Sankyo, Mitsubishi Tanabe

• Expanding role of emerging manufacturers

– India, Chinese, Brazilian, Korean manufacturers meeting growing needs of low- and middle-income countries – Indian companies beginning to invest in “developed country” industry eg SII/Bilthoven – First Chinese vaccine WHO-prequalified 10/9/13

Key trend 2: Change in composition of vaccine industry

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This shift drives a much more varied & active partnering environment

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• “Easy” targets already addressed through established

vaccine technologies

• Remaining infectious disease targets present significant

scientific challenges, and require non-traditional approaches and likely greater design complexity

• Novel approaches needed:

– Novel adjuvants - show promise but face safety and regulatory concerns – Novel vectors – Prime-boost regimens

Key trend 3: Increasing need for novel approaches

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• U.S. Military’s oral live vaccine for Ad4 and Ad7 protects recruits
• Used for 30 years successfully and safely in 10 million recruits
• PaxVax Strategy: Insert vaccine-relevant genes from desired indications
• Proof of concept established in 160 subject H5N1 influenza Phase 1 study
• Anthrax and HIV now starting Phase 1 trials
• In-house GMP production (NIH, CA state, 3rd party inspected)
• Essentially identical manufacturing process for different vaccines
• Scalable to 200 L bioreactors; millions of doses
• Proprietary A549 production cells (VRBPAC and BBMF at FDA)
• Use standard enteric-coated capsules for early phase trials
• Scale to pressed tablets for high volumes

Adenovirus 4/7 Oral Vaccine Platform

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Ad4 Clinical & Commercial Advantages Allow it to Overcome Key Hurdles

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• 1. Replicating vector – Activates both arms of the

immune system – cellular & humoral. Self- adjuvanting as replicating virus represents “natural” infection. Most other vectors are not replicating

• 2. Mucosal delivery – exposure to gut wall, as
• pposed to parenteral, triggers innate immune

response

• 1. Oral delivery – convenient for patients/

caregivers: Unique tablet/capsule delivery – avoids injections and inhalation

• 2. Low COGS – high yielding cell substrate and low

cost tableting instead of expensive pre-filled syringes Creates ideal prime in heterologous prime/boost for diseases where traditional methods do not generate adequate immune response Allows market expansion

• f traditional vaccines

providing greater access, especially in developing world

NY Pharma Forum

Proof of Concept Ad4-H5: Superior Seroprotection after Prime Boost

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18% 58% 80% 89% 0% 25% 50% 75% 100%

Sanofi 90 mcg single dose (placebo group post-boost ) Sanofi 90 mcg two doses (NEJM study) Ad4-H5-Vtn 1E10 Protein Boost Ad4-H5-Vtn 1E11 Protein Boost

4-fold increase in HAI and titer > 40

166 subjects; placebo controlled; groups received 3 oral doses of Ad4-H5 (or placebo) plus a single injection of licensed Sanofi H5N1 vaccine.

Thank you

Better Vaccines to Better the World

www.paxvax.com pwhitehead@paxvax.com lefros@paxvax.com