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YaleMarch 14, 2006. 2. Scientific breakthrough: innate immunity plays a fundamental role in the induction and regulation of adaptive immune responseVaxInnate opportunity: exclusively focused on exploiting this new field of immunology to develop prophylactic vaccines and and immune therapy. The VaxInnate Approach Linking Innate and Adaptive Immunity.
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March 14, 2006 3 A Brief History of VaxInnate 1997: Medzhitov publishes seminal paper describing the critical link between innate and adaptive immunity; forms the basis for a new vaccine technology
2000-2001: Initial business plan discussions between scientific founders, Yale OCR, and business advisors; pre-financing activities begin
May, 2002: Venture capital firm CHL helps refine the business plan and provides Series A round of $1.5M
2002-2003: VaxInnate launched; staffing, facilities, strategies established; critical proof of concept studies done in-house
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March 14, 2006 4 A Brief History of VaxInnate December, 2003: syndicate of four VC firms invests $23.125M in Series B round
2004: corporate headquarters and product development site established in Cranbury, NJ; three product opportunities identified; NIH funds TLR ligand discovery effort
2005: first IND candidate selected for novel influenza vaccine; management team strengthened
2006: additional product opportunities identified; pre-IND efforts in progress
2007: first clinical trial – 10 years after first publication
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March 14, 2006 5 VaxInnate Key Players Founders:
Ruslan Medzhitov (Yale)
Richard Flavell (Yale)
Mike Sherman (ex-Roche)
Management
Alan Shaw, CEO (Biogen, Merck)
Bob Becker, VP Business Development (Sanofi)
Jeff Powell, VP Research (SUGEN, CuraGen)
David Jackson, VP Manufacturing (Entremed, Lonza)
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March 14, 2006 6 VaxInnate Key Players Scientific Advisors:
Ruslan Medzhitov (Yale)
Richard Flavell (Yale)
Erol Fikrig (Yale)
Rafi Ahmed (Emory)
Jim Allison (MSKCC)
Investors
CHL Medical Partners (Stamford, CT)
HealthCare Ventures (Cambridge, MA)
Oxford Biosciences (Boston, MA)
Medimmune Ventures (Gaithersburg, MD)
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March 14, 2006 7 Innate Immune Recognition by Toll-Like Receptors
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March 14, 2006 8 Toll Signaling Pathway
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March 14, 2006 9 Innate Immune Recognition by Toll-like Receptors
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March 14, 2006 10 Toll Signaling Pathways
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March 14, 2006 11 Innate Immune Recognition by Toll-like Receptors
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March 14, 2006 12 Toll Signaling Pathways
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March 14, 2006 14 Control of antibody responses
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March 14, 2006 15 Defective CD4 T-cell Response in MyD88-/- Mice
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March 14, 2006 16 Defecient Antigen-specific IgG2a Response in MyD88 -/- Mice
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March 14, 2006 17 Rational Vaccine Design by Combining Signals for the Innate and Adaptive Immune Systems(An Antigen of Interest With TLR Ligands)
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March 14, 2006 18 Expression of TLRs on DC Subsets
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March 14, 2006 19 Tailoring Protective Immunity by Targeting Appropriate TLR Subsets
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March 14, 2006 20 The VaxInnate Concept TLRs and Vaccine Development Stimulation of TLRs is essential for the induction of adaptive immunity
TLR signaling is coupled with control mechanisms of peripheral tolerance, i.e., co-stimulation and TREG
Vaccines targeting TLRs can induce adaptive immune responses to pathogen-derived antigens
Vaccines targeting TLRs can eliminate the need for complex and toxic adjuvant formulations
21. Yale
March 14, 2006 21 The VaxInnate ConceptLinking Innate with Adaptive Immunity Hypothesis: Manipulation of the innate immune system via TLR signaling translates into specific activation of the adaptive immune response to cognate antigen
Candidate design: Antigen physically linked to a PAMP
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March 14, 2006 22 The VaxInnate ConceptSummary of Results Understanding in vivo mechanism of action of multiple PAMP.Ag fusion proteins
STF2.OVA: TLR5L + ovalbumin (B- and T-cell epitopes):
B-cell responses – multiple isotypes of antibody
Advantage of fusion vs. mixture
Superiority to conventional adjuvants
CD8 T-cell responses – IFNg ELISPOT
Protection in Listeria.OVA challenge model – CFU burden
Protection in B16.OVA challenge model – delayed tumor growth
STF2.LIST: TLR5L + LLO and p60 epitopes of Listeria
CD8 T-cell responses – IFNg ELISPOT
Protection in wild type L. monocytogenes model – CFU burden
STF2.4xM2e: TLR5L + conserved influenza antigen
Potent antibody responses to a minimally immunogenic epitope
Protection from challenge with live virus
Selected as first IND candidate
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March 14, 2006 23 Product ApplicationInfluenza A M2e Vaccine Limitations of current vaccine strategy:
Genetic instability of HA and NA
Annual reformulation and immunization
Egg-based production
Advantages of M2e vaccine strategy:
The only genetically stable external peptide of influenza A
Small size and defined sequence lends itself to recombinant technology
Antibodies to M2e protect mice from influenza A mortality
Advantages of PAMP conjugation strategy
M2e is poorly immunogenic in native state or in synthetic peptide form
Conjugation to TLR ligand converts M2e to highly immunogenic epitope, and generates protective antibody response
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March 14, 2006 24 Influenza M2e VaccineLead Candidate: STF2.4xM2e STF2.4xM2e:
TLR5 ligand fused to four tandem repeats of M2e human concensus
efficiently produced in E. coli
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March 14, 2006 25 Influenza M2e VaccineSTF2.4xM2e Immunogenicity in Mice
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March 14, 2006 26 Influenza M2e VaccineSTF2.4xM2e Immunogenicity in Mice
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March 14, 2006 27 Influenza M2e VaccineSTF2.4xM2e Efficacy in Mice
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March 14, 2006 28 Influenza M2e VaccineConclusions Fusion of the TLR5 ligand flagellin (STF2) to influenza A M2e yields a promising cross-protective influenza A vaccine candidate, STF2.4xM2e:
Induction of antibody responses that recognize a known protective epitope of M2e
Immunogenic in multiple species
Provides protection against lethal influenza challenge in mice
Cross-reactive with M2e from most human viral strains
Easily scaleable and manufacturable in E. coli
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March 14, 2006 29 Influenza M2e VaccineStatus of STF2.4xM2e Product Development Efficacy in mouse, immunogenicity in two species established
Examining dose regimen, memory, cross-strain protection
Completing preclinical package (analytical, toxicology, GMP)
Finalizing clinical plan and support assays
Clinical evaluation initiating 1Q07
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March 14, 2006 30 VaxInnateCritical Components of a Successful Start Yale:
Excellent science that can be applied to a real problem
Founders committed to the success of the company
Institutional support (technology licensing, resources, people)
Investors:
Understand the science
See the limitations and time constraints
Have a vision for how to commercialize the product
Defined exit strategy, but committed for the long-haul
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March 14, 2006 31 VaxInnateCritical Components of a Successful Start People:
Energetic, excellent, risk-takers
Flexible, comfortable wearing lots of hats
Teamwork above all else!
Facilities:
Start-up requirements are usually small but specialized
Important to get out of the academic lab to establish identity, strategy, motivation
Moved into 6000 sq ft in 300 George St; seemed cavernous with only four employees, but with 13 employees and growing…
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March 14, 2006 32 VaxInnateLessons Learned Success in academia or big companies is no guarantee of success in the hectic, uncertain world of the start-up
Not exactly a turn-key operation
You can’t do science without equipment, phones, desks, computers, file cabinets, carpet, personnel, payroll, internet service, coffee service, accounting, human resources management, waste management, safety procedures, insurance, purchasing
There is not a mature department to handle each of these on a daily basis, so roll up your sleeves
Do whatever is needed, when it is needed!
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March 14, 2006 33 VaxInnateLessons Learned The investor is your friend
VCs often get a bad rep, perhaps worse than deserved
You are in business to do excellent science and make a better product or service
They are in business to make money
Find a common ground
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March 14, 2006 34 VaxInnateLessons Learned An excellent investor:
Understands your science
Is already active in the same or a closely-related field
Has start-up experience
Has a network of connections in academia, industry, government, finance, and consultants
Is willing to let you burn through a lot of money in the first few years
Sleeps well at night
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March 14, 2006 35 VaxInnateLessons Learned Exit strategy
VCs make money via IPO, merger or acquisition
Turnaround time for biotechs is generally longer than for hardware/software
Respect your potential investor’s exit strategy and timetable
Expect them to respect the science
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March 14, 2006 36 VaxInnateLessons Learned How much money do you need?
More than you think, less than might be offered
Repeated rounds of financing at the same price are bad for future valuation
Taking too much money dilutes the stock and may lead to too many cooks (i.e., Directors)
Be realistic – raise sufficient cash to last for 2 to 3 years; resist the temptation to sell out so early
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March 14, 2006 37 VaxInnateLessons Learned Employees – your most valuable asset
Hire the right attitude in addition to the right skills
Challenge each person to step outside their technical comfort zone
Give room for reasonable risks, and remember mistakes happen
Everyone is on a first-name basis
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March 14, 2006 38 Your New Company Start with excellent science
Add a top-notch business specialist to develop the business plan (very few excellent scientists are also excellent business people)
Budget carefully and resist temptation
Identify risks, alternative strategies, contingencies
Know the competition and find a way to carve out your niche – be realistic, you can’t do it all!
Hire the right people, challenge and reward them
Adapt