Aeras A Product Development Partnership for New TB Vaccines

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Aeras Global TB Vaccine Foundation. ModelNon-profit, Product Development Partnership, est. 2003Employ 136 people in Rockville, MD, and Cape Town, South AfricaPartner with industry, academia, philanthropy and governmentsDevelop TB vaccines in own labManufacture vaccines in own plant GoalsTo ad

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Aeras A Product Development Partnership for New TB Vaccines

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1. Aeras A Product Development Partnership for New TB Vaccines Robert Walker, MD Aeras Global Tuberculosis Vaccine Foundation May 6, 2010

2. Aeras Global TB Vaccine Foundation Model Non-profit, Product Development Partnership, est. 2003 Employ 136 people in Rockville, MD, and Cape Town, South Africa Partner with industry, academia, philanthropy and governments Develop TB vaccines in own lab Manufacture vaccines in own plant Goals To advance the world’s leading TB vaccine candidates forward to licensure and availability To rationalize the TB vaccine development process To maintain a robust TB vaccine pipeline

3. Tuberculosis Pandemic (2008 data) >2 billion people infected with Mtb 5-10% will reactivate 9.4 million people newly infected (1.4 million were HIV-coinfected) HIV-infected individuals are 20-40 times more likely to reactivate 1.8 million deaths Emergence of MDR-TB and XDR-TB and the interaction of HIV and TB pose a serious risk to TB control

4. Currently Available BCG Vaccine is Not Controlling the TB Pandemic Reduces risk of severe pediatric TB disease Unreliable protection by newborn immunization against adult pulmonary TB, which accounts for most TB burden worldwide Not known to protect against latent TB Despite wide-scale use, no apparent impact on the growing global TB epidemic Not recommended for use in infants infected with HIV

5. Challenges to TB Vaccine Development and Distribution Preclinical Antigen selection – 4000 proteins! Lack of immunologic markers of protection Unknown correlation between animal challenge model experiments and human protection Clinical Induction of cellular immunity in humans difficult TB case definition especially for infants problematic Large sample sizes required for Phase III efficacy studies Limited numbers of field sites for efficacy studies Post Approval Need for affordability Ease of delivery GMO (genetically modified organism) issues

6. TB Vaccine Projected Development Timeline and Costs

8. Products in Clinical Development

9. MVA85A/AERAS-485 Modified Vaccinia Ankara (MVA) vector Attenuated poxvirus, replication deficient in mammalian cells Administered to ?120,000 vaccinees (smallpox eradication) Vector construct for HIV, malaria, HPV Safe and immunogenic (CMI) Mtb antigen 85A expressed Mycolyl transferase Immunodominant secreted antigen, highly conserved Protects animals from Mtb challenge after BCG prime-MVA85A boost administered ID

10. MVA85A/AERAS-485 Clinical Trial Summary

11. IFN-? ELISPOT Responses to Ag85A Peptides in Adults

12. Polyfunctional Ag85A-Specific CD4+ T Cells after MVA85A Vaccination in BCG-primed Adults (MVA85A dosage = 5 x 107 pfu ID)

13. Duration of Responses in South African Adolescents and Children

14. AERAS-485/MVA85A: Cumulative Experience 14 clinical trials completed or ongoing involving >1000 vaccinees, at dose levels ranging from 1x107 to 1x108 (healthy adults/adolescents/children/ infants; HIV-infected adults; LTBI) Acceptable safety profile in all populations studied Site of injection reactions in most subjects Preferentially induces CD4+ (vs. CD8+) T cell responses Appears more immunogenic in adults Is currently in phase IIB efficacy trials Infants (Univ of Cape Town/SATVI, N?2800) initiated July 2009 HIV-infected adults (South Africa, Senegal, N=1400) to start 2H 2010

15. AERAS-402: Ad35-Vectored TB Vaccine Developed by Crucell NV, Leiden, Netherlands; manufactured by Aeras Derived from Adenovirus Serotype 35 (Ad35) Lower seroprevalence of neutralizing Abs than other serotypes, e.g., Ad5 Produced in Per.C6 cells

16. AERAS-402: Preclinical Data Summary Immunogenicity Immunogenic alone (mice, mini-pigs) and after BCG-prime (mice) Protection Protects from M.tb challenge (mice) Toxicology Negative other than mild site-of-injection reactions (guinea pigs, mini-pigs) Biodistribution Genome detected at site of injection, draining lymph nodes, spleen, kidneys (day 30), with persistence at site of injection and draining lymph nodes (day 91) (rabbits, mini-pigs)

18. AERAS-402: Clinical Experience Over 40 infants and 150 adults have received AERAS-402 in completed and ongoing studies Phase I initiated in 2006 Populations studied include healthy as well as LTBI, active TB, and HIV-infected Dosing range: 1.5x108- 1x1011 viral particles administered IM Both adults and infants have received the highest dose as a 2-dose regimen Acceptable safety profile; no SAEs related to AERAS-402 Immunogenic (CD8+ T cell responses preferentially) Studies of 3-dose regimen have commenced

19. BCG Prime, AERAS-402 Boost in U.S. Adults Intracellular Cytokine Staining for IFN ?, IL-2, or TNF? (3 x 1010 dosage, N=8)

20. 2010 Studies: AERAS-402 Phase IIB Efficacy studies Infants 16-26 weeks of age Kenya, Mozambique, South Africa, Uganda Adaptive design, N=1600-4000 HIV-infected adults, CD4>350 Aurum Institute, South Africa Adaptive design, N=800-1200

21. M72 Rationale Suboptimal stability of Mtb72F May be due to putative serine protease site (Mtb32A) (Skeiky et al. Inf. & Immun, 1999) M72 = Mtb72F with a point mutation (Ser ? Ala) in active site No predicted T cell epitope in the region of the mutation Preclinical comparison of Mtb72F and M72 Cell-mediated and antibody response comparable in mice Equivalent protection in guinea pigs

23. Safety of M72/AS01E in 37 HIV-Infected Adults with CD4>200 on ARV Well tolerated and no vaccine-related serious AEs were reported. Causally related AEs were mainly local, transient and lasted usually between 1-3 days and resolved without sequelae in all groups Mild and moderate injection site pain, fatigue and headache were the most frequently reported solicited AEs. The M72/AS01E vaccine had no clinically relevant adverse effect on biological safety tests, HIV viral load and CD4 count, and on individual HAART regimens

24. M72 Next Steps 2010 and 2012 Safety and immunogenicity of the M72/AS01E vaccine in adolescents Safety and immunogenicity of 1 or 2 doses of the M72/AS01E vaccine given either concomitantly with EPI vaccines or after EPI vaccines POC in infants outside of EPI age range Non inferiority study EPI antigens vs M72/AS01E M72/AS01E vs EPI antigens

26. AERAS-404 Pre-Clinical Murine Immunogenicity: H4 Improves Immune Response Against TB10.4

28. AERAS-404: Current Status 3 studies completed in BCG-vaccinated adults (N=138) evaluated different antigen/adjuvant combinations Acceptable safety profile Local reactions at sites of recent (but not remote) tuberculin skin tests Preliminary evidence of immunogenicity Elispot: responses detected to Ag85B Next steps Dose selection for future development BCG prime/AERAS-404 boost study in BCG-naïve adults (2010) Regimen selection for pediatric studies

29. Recombinant BCG Prime Vaccine AERAS-422: Background Derived from BCG SSI Over-expresses Mtb antigens: Ag85A, Ag85B, Rv3407 Encoded on multicopy plasmid Plasmid complements chromosomal deletion of panCD; no need for antibiotic resistance marker Expresses perfringolysin Mutated to reduce half-life and eliminate cytotoxicity Allows antigens into cytosol for MHC Class I presentation Addition of perfringolysin increases immunogenicity compared with antigen over-expression alone

30. AERAS-422 Over-expresses Mtb Antigens Compared with Its Parent Strain AERAS-413

31. Comparative Immunogenicity of AERAS-422 and BCG SSI At 4 and 8 Weeks Post-Prime

32. Comparative Immunogenicity of AERAS-422 vs. BCG SSI Prime and AERAS-402/Crucell Ad35 Boost

33. SCID Mouse Survival

34. AERAS-422 Phase I Study Timeline (Projected) File IND July 2010 First subject dosed Sep 2010 First study to include AERAS-422 prime/AERAS-402 [Ad35] boost arm

35. Concluding Remarks Given the lack of an optimal animal model and lack of immunologic correlates of protection, sponsors should be prepared to take each construct through Phase IIB efficacy 4 Aeras-supported TB booster vaccines are currently in the clinic 2 are in Phase IIB rBCG prime vaccine should enter Phase I trials this year

36. Acknowledgments University of Capetown, South African TB Vaccine Initiative (SATVI) University of Oxford Aurum Institute European and Developing Countries Clinical Trials Partnership (EDCTP) Saint Louis University Karolinska Institute University of Tampere Statens Serum Institut Sanofi Pasteur GlaxoSmithKline Crucell N.V. Emergent Biosolutions

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