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A STATE-OF-THE-ART BIVALENT VLP VACCINE AGAINST HFMD
SENTINEXT THERAPEUTICS
David Lawrence, CEO
August 2014
OUR STORY STARTS WITH AN UNUSUAL CLUSTER OF DEATHS OF YOUNG CHILDREN IN MALAYSIA IN 1997
AND IT CONTINUES TO SPREAD AROUND THE WORLD
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HUMAN ENTEROVIRUS 71 (EV71) • Small RNA virus; naked capsid
• Oral fecal route transmission
• Causes hand, foot and mouth disease
• Highly infectious new variants in Asia, potential to spread globally
• Since detection in Malaysia, Singapore & Taiwan, severe HFMD with CNS disease has spread throughout the region
• Young children are at risk of brainstem encephalitis, polio-like flaccid paralysis and death
Year Outbreaks reported
1997 Malaysia, Singapore
1998 Taiwan
1999 Perth, Australia
2000 Malaysia, Singapore, Taiwan, Japan, Korea, China
2001 Singapore, Thailand, Taiwan, Japan, China
2002 Singapore
2003 Singapore, Malaysia, Japan, China
2004 Japan, Taiwan, China
2005 Vietnam, Taiwan
2006 Malaysia, Singapore, Japan, Thailand
2007 China
2008 Malaysia, Singapore, Taiwan, China
2009 China, Vietnam
2010 China, Vietnam, Japan
2011 China, Vietnam – both south and north
2012 Cambodia, Thailand, Philippines, Malaysia, Singapore, Vietnam, China, India
2013 Most notably Australia with fatal cases recorded
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SEVERE EV71 DISEASE REMINDS US OF POLIOMYELITIS: EVEN IF POLIO IS ERADICATED, POLIO-LIKE OUTCOMES WILL NOT BE ERADICATED BY POLIO VACCINES
EV71, 1999
Polio, 1950’s
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WHY SHOULD THE VACCINE BE BIVALENT?
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HFMD SENTINEL DATA: 1998 – 2008, MALAYSIA
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CVA16 Other CVAs HEV71
MANY NON-EV71 ENTEROVIRUSES CO-CIRCULATE PRE AND POST OUTBREAK
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EXAMPLE FROM HO CHI MINH CITY: 2005
1. Emergence of EV71 subgenogroup C5
2. Two HFMD seasons in a year
3. CA16 is dominant in the first season
4. EV71 dominant in the second season
Courtesy of Dr Phan Van Tu, Institute Pasteur, HCMC; data published in EID, 2007
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A VACCINE FOR ONE VIRUS DOES NOT COVER HFMD
Top serotypes of enterovirus isolated from HFMD patients in Singapore, 2001–2007.
Lee M-S, Tseng F-C, Wang J-R, Chi C-Y, et al. (2012) Challenges to Licensure of Enterovirus 71 Vaccines. PLoS Negl Trop Dis 6(8): e1737. doi:10.1371/journal.pntd.0001737 http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0001737
EV71 may tend to cause more severe disease but it is not possible to determine who is at risk of severe disease when they have HFMD, CVA can also cause severe disease, parents will prefer a bivalent vaccine
SURVEILLANCE SYSTEMS ROUTINELY REPORT HFMD NOT EV71 ONLY
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Seasonality can change, note previous charts and Macao, below
27 August 2014
HFMD SURVEILLANCE 2014
COUNTRY CASES DEATHS COMMENTS
China 1,688,640 220 1.6x 2013
Hong Kong 232 N.A. 0.5x 2013, similar to 2012
Macao 2,179 N.A 1.7x 2013, very high week 16 peak
Japan 28,265 N.A Lower than 2013, similar to 2012
Singapore 13,070 N.A Similar to 2013
Vietnam 40,015 2 Similar to 2013
• Year to date report as at 12th August (China to 15th July) • Exemplifies year on year change, Japan still higher than 2012
http://www.wpro.who.int/emerging_diseases/HFMD.Biweekly.12aug2014.pdf http://www.wpro.who.int/emerging_diseases/HFMD/en/index.html
DIFFERENTIATION FROM COMPETITORS
• A vaccine targeting both enterovirus 71 and Coxsackievirus A16, not just one of them
– These two viruses cause up to 95% HFMD in children
– Addresses public health needs (control of HFMD, not control of EV71 encephalitis alone)
– Facilitates efficacy trials
– Does not require identification of specific enterovirus serotype for clinical endpoints in large efficacy trials
• State of the art technical approach - Virus like particles (VLPs)
– Eliminate hazards during propagation of the virus and incomplete inactivation.
– The virus mutates, potentially creating batch-to-batch variations in vaccine production.
– Molecular approach allows agility, able to respond to evolving virus.
– What we learn from EV71, CV-A16 and polioviruses can be applied to other enteroviruses.
– Elicit high quality neutralizing antibodies - required for protection.
• Highly scalable production technology.
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SENTINEXT’S STRATEGY FOR ADDRESSING HFMD
• Two recombinant baculoviruses expressing EV71 and CVA16 VLPs have been generated, and Master Virus Seed (MVS) Stocks of both recombinants have been produced, released and stored under GMP
• The Sf9 cell Master Cell Bank (MCB) has been produced, released and stored under GMP.
• The USP for EV71 VLPs has been completed.
– EV71 VLP yields from the USP stock are >100 mg/L.
• The USP for CVA16 VLPs is currently ongoing
• The DSP for EV71 has been completed in house and tech transfer to our CMO takes place in the coming weeks
• The DSP for CVA16 is ongoing in house, good progress has been made
• Animal immunogenicity and protection studies for EV71 show good protection and high neutralizing antibody titres (see next 2 slides)
• Animal immunogenicity studies for CVA16 in process
• Analytical package for in process monitoring and release is in advanced stage of development
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STATUS OF BIVALENT VACCINE PROJECT
• Immunogenic in mice and monkeys
• Antibodies are elicited to all capsid proteins in the capsid
• Antibodies are able to neutralize all EV71 genotypes
• EV71 monovalent protects mice against heterologous genotype challenge in a passive protection model
• Protects non human primates from
– Viraemia
– CNS infection
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PROOF OF CONCEPT WITH SENTINEXT’S EV71 VLPS
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T im e p o s t- in o c u la tio n (d a y s )
EV71 VLPs ELICIT HIGH TITRES OF NEUTRALIZING ANTIBODIES IN MONKEYS
Note: Individual monkeys are coded by colour; open squares – alum + VLP; closed circles – alum alone
SENTINEXT’S HFMD VACCINE IS HIGHLY DIFFERENTIATED FROM THE COMPETITION
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ORGANISATION TYPE STATUS COMMENTS
SINOVAC Inactivated Monovalent EV71 whole Virus
Phase III Recently completed and published phase III study – shows efficacy only against EV71 with no cross protection against CV-A16
BEIJING VIGOO (PART OF SINOPHARM)
Inactivated Monovalent EV71 whole Virus
Phase III Recently completed and published phase III study – shows efficacy only against EV71 with no cross protection against CV-A16
PEKING UNION MEDICAL COLLEGE (CHIN ACAD SCI)
Inactivated Monovalent EV71 whole Virus
Phase III Recently completed and published phase III study – shows efficacy only against EV71 with no cross protection against CV-A16
INVIRAGEN (now TAKEDA) Inactivated Monovalent EV71 whole Virus
Phase I Phase I trial in Singapore commenced June 2011; completed; safe and immunogenic.
TAIWAN NATIONAL HEALTH RESEARCH INSTITUTES ADIMMUNE (TW) MEDIGEN BIOTECH (TW)
Inactivated Monovalent EV71 whole Virus
Phase I March 2012 Press Release suggests a Phase I completed with good Results; However, antibodies generated did not neutralize CV-A16
• High proportion of non infectious particles to infectious particles.
– Therefore particles purified from an EV71 culture will have at least two, probably three, different types of particles
– The proportions of these particles are not likely to be the same from culture to culture causing issues for manufacturing inactivated vaccines
– Regulatory authorities require careful characterization of the drug substance, and in this case will require characterization of each type of particle present
• There are manufacturing safety issues associated with producing inactivated whole virus vaccines:
– Wild type escape
– Incomplete inactivation
• Inability to respond to important genetic changes without making a completely new vaccine
DISADVANTAGES OF AN INACTIVATED WHOLE VIRUS APPROACH
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• Differentiated product: broader spectrum vaccine against HFMD
– Protects against majority of viruses causing HFMD
– Bivalent formulation – taking into account the two major viruses that cause HFMD in the Asia Pacific region
– Bivalent HFMD vaccine will facilitate efficacy trials with protection against HFMD as the clinical endpoint
• This is advantageous as an EV71 monovalent vaccine will not protect against HFMD caused by CV-A16 and virological diagnosis will be required in efficacy trials
– Ineffective public health intervention such as school closures can be avoided.
• Economic disruption also avoided
• Able to respond rapidly to changing epidemiology with “plug and play” molecular approach
• No manufacturing safety concerns such as virus escape or incomplete inactivation
• Modern manufacturing process, EMEA compliant, can distribute globally
COMPETITIVE ADVANTAGE OF SENTINEXT’S VLP APPROACH
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CEO : David Lawrence CSO and Founder: Jane Cardosa NXD : Tom Monath Scientific Advisors: Ian Jones, Richard Kuhn, Sasithon Pukritayakkamee, Jeffrey Almond Focus: • Novel, safe and efficacious vaccines for human enteroviruses • Bivalent HFMD vaccine – enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) Technology: • Virus Like Particles (VLPs), using baculovirus as the expression vector Main assets/activities : • Platform for chimeric human enterovirus VLPs displaying target antigens from other
pathogens • Hand foot and mouth disease (HFMD) bivalent VLP based vaccine, strong IP • Poliovirus VLP based vaccines for polio endgame funded by grants from the Bill and
Melinda Gates Foundation
HFMD - Manufacturing: • State-of-the-art upstream and downstream processes • EMEA compliant, experienced CMO in Brussels, Belgium • MCB completed • MVS completed for both components of the bivalent vaccine HFMD – Clinical Development • Phase I clinical trial planned in Australia H2 2015, CRO appointed, preparations
underway
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SENTINEXT - A KEY VACCINE PLAYER IN ASIA
Founders Peter Wulff
Jane Cardosa
Investors MLSCF MTDC
Employees 15 (+ CMO/CRO etc)
HQ Penang, Malaysia
Pipeline HFMD
Polio VLP Platform for EVs
Web www.sentinext.com
• Experienced new CEO, David Lawrence, formerly Chiron, GSK, Acambis + strong Board and advisors
• Strong core Research team based in Penang, Malaysia
– Led by Jane Cardosa, CSO, renowned expert in HFMD and other infectious diseases
– Design and engineering of recombinant baculoviruses
– Reagent and assay development
– Process development at lab scale
• Partnering with highly experienced companies and experts
– Execution of process development and manufacturing in Belgium, Europe
• GMP upscaling and production by strong, VLP experienced CMO
• Close oversight provided by Project Director Consultant Rene Djurup (and Jane Cardosa)
– VLP and virus Characterization by leaders in the field • Biophysical characterization by Protagen AG, Dortmund, Germany • Virus Structure by Michael Rossman and Richard Kuhn, Purdue University, USA • Vironova, Stockholm, Sweden • Anton Middleburg & Linda Lua, AIBN, UQ, Australia
– Epidemiology, clinical, regulatory being managed in/from Australia • TGA strong reference body
– Preclinical animal studies • Monkey Challenge Study by Katharine Bossart, USA • Mouse Potency and Challenge by Peter McMinn, Australia
– IP management expert based in California, USA
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SENTINEXT IS WELL PLACED TO SUCCEED
• In China a bivalent HFMD using a VLP approach is expected to be superior and differentiable to the inactivated EV71 monovalents
• Sentinext has strong IP and VLP know how
• EV71 monovalents expected to develop the market
• SFDA requires biologics to be developed in China and that clinical trials take place in China
• Sentinext ready to discuss partnership in China
– License deal
– JV to develop and commercialise vaccine
• Possibly to include VLP Polio vaccine
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PARTNERING OPPORTUNITIES WITH SENTINEXT …
Sentinext Therapeutics 19H Menara Northam
55 Jalan Sultan Ahmad Shah 10050 Penang, Malaysia
www.sentinext.com Office tel: +604 2268872 Mobile: +6013 8028394
E-mail: [email protected]
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