the vaxinnate approach linking innate and adaptive immunity

2. Yale March 14, 2006 2

3. Yale 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

4. Yale 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

5. Yale 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)

6. Yale 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)

7. Yale March 14, 2006 7 Innate Immune Recognition by Toll-Like Receptors

8. Yale March 14, 2006 8 Toll Signaling Pathway

9. Yale March 14, 2006 9 Innate Immune Recognition by Toll-like Receptors

10. Yale March 14, 2006 10 Toll Signaling Pathways

11. Yale March 14, 2006 11 Innate Immune Recognition by Toll-like Receptors

12. Yale March 14, 2006 12 Toll Signaling Pathways

13. Yale March 14, 2006 13

14. Yale March 14, 2006 14 Control of antibody responses

15. Yale March 14, 2006 15 Defective CD4 T-cell Response in MyD88-/- Mice

16. Yale March 14, 2006 16 Defecient Antigen-specific IgG2a Response in MyD88 -/- Mice

17. Yale March 14, 2006 17 Rational Vaccine Design by Combining Signals for the Innate and Adaptive Immune Systems(An Antigen of Interest With TLR Ligands)

18. Yale March 14, 2006 18 Expression of TLRs on DC Subsets

19. Yale March 14, 2006 19 Tailoring Protective Immunity by Targeting Appropriate TLR Subsets

20. Yale 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

22. Yale 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

23. Yale 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

24. Yale 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

25. Yale March 14, 2006 25 Influenza M2e VaccineSTF2.4xM2e Immunogenicity in Mice

26. Yale March 14, 2006 26 Influenza M2e VaccineSTF2.4xM2e Immunogenicity in Mice

27. Yale March 14, 2006 27 Influenza M2e VaccineSTF2.4xM2e Efficacy in Mice

28. Yale 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

29. Yale 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

30. Yale 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

31. Yale 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…

32. Yale 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!

33. Yale 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

34. Yale 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

35. Yale 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

36. Yale 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

37. Yale 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

38. Yale 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