Hope in the TB Vaccine Pipeline Sebastian Gelderbloem Aeras Global TB Vaccine Foundation 25 January 2011

AERAS GLOBAL TB VACCINE FOUNDATION Aeras Global TB Vaccine Foundation Mission To develop new, more effective TB vaccines and ensure their availability to all who need them Method Non-profit PDP; collaborate with academic, biotech, pharma and NGO partners to develop and test new TB vaccines Pursue a Prime-Boost strategy by developing a modern replacement for BCG plus booster vaccines Develop vaccines in our own lab and manufacturing plant

AERAS GLOBAL TB VACCINE FOUNDATION Existing TB Vaccine Ineffective BCG introduced in 1921

AERAS GLOBAL TB VACCINE FOUNDATION WHO 2007 Recommendations on BCG Children with HIV infection regardless of symptoms should not be BCG vaccinated All high risk infants need HIV screening –Maternal antibody masks antibody tests –Detection of virus required –Very difficult to implement in many places Disseminated BCG in HIV infected infants recently (2009) estimated to be 992 per 100,000 (Hesseling, et al)

AERAS GLOBAL TB VACCINE FOUNDATION Predicted Impact of 50% Effective New TB vaccine Young and Dye Cell 2006

AERAS GLOBAL TB VACCINE FOUNDATION Goals for Better TB Vaccines Eliminate TB as a public health threat Safe and effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe) Protect against all forms of TB – including MDR and XDR

AERAS GLOBAL TB VACCINE FOUNDATION TB Vaccine Pipeline VPM 1002 Max Planck, Vakzine Projekt Mgmt, TBVI rBCG30* UCLA, NIH, NIAID, Aeras AdAg85A McMaster University Hybrid-I+CAF01 SSI Hyvac 4/ AERAS-404 SSI, Sanofi-Pasteur, Aeras, Intercell RUTI Archivel Farma M smegmatis* Hybrid-I+IC31 SSI, TBVI, Intercell M72 GSK, Aeras MVA85A/ AERAS-485 Oxford-Emergent Tuberculosis Consortium (OETC), Aeras AERAS-402/ Crucell Ad35 Crucell, Aeras M vaccae* Immodulon, NIH Preclinical Phase IIPhase IIIPhase IIbPhase I *indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trials Source: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines As of November 2009 AERAS-422 Aeras Mtb [∆lysA ∆panCD ∆secA2] Albert Einstein College of Medicine MTBVAC01 [∆phoP, ∆fad D26] University of Zaragoza, Institute Pasteur, TuBerculosis Vaccine Initiative (TBVI) HBHA Institute Pasteur of Lille, INSERM, TBVI Hybrid 56 Statens Serum Institute (SSI), Aeras, Intercell, TBVI HG85 A/B Shanghai H&G Biotech Prime Boost Post-infection Immunotherapy Preclinical vaccine candidates are not yet in clinical trials, but have been manufactured under Good Manufacturing Practice (GMP) for clinical use and have undergone some preclinical testing that meets regulatory standards.

AERAS GLOBAL TB VACCINE FOUNDATION 12 candidates have entered clinical trials; 9 currently being tested; 10 th will enter trials this year Robust pipeline of candidates in preclinical development Capacity and infrastructure developed or being developed at several sites Manufacturing capacity being developed and agreements explored, with particular emphasis on emerging economies Regulatory pathways and market/economic impact research laying groundwork to accelerate adoption and uptake of new TB vaccines Progress in TB Vaccine Development

AERAS GLOBAL TB VACCINE FOUNDATION Approach to a New TB Vaccine Improve BCG – make a recombinant rBCG Prime-Boost regimen Give booster vaccinations in infants Give booster vaccinations in adolescents who have received BCG at birth

Aeras TB Vaccine Candidates in Clinical Trials Potential Boost Vaccines SSI HyVac4 / AERAS-404Status: Phase I Recombinant protein vaccine intended to be a booster vaccine Phase I clinical trials being conducted in Europe and Africa GSK M72Status: Phase II Recombinant protein vaccine intended to be a booster vaccine Phase I and II trials conducted in Europe, Africa and Asia, including a Phase I trial in HIV+ in Europe AERAS-402 / Crucell Ad35Status: Phase IIb Viral vectored vaccine utilizing adenovirus 35; intended to be a booster vaccine Phase I and II trials conducted in North America and Africa; Phase IIb recently initiated in HIV+ in S. Africa MVA85A / AERAS-485Status: Phase IIb Viral vectored vaccine utilizing modified vaccinia Ankara; intended to be a booster vaccine The most clinically-advanced booster vaccine for tuberculosis with an ongoing proof-of-concept Phase IIb trial in infants Previous clinical trials in the UK and Africa, including in HIV+ Awarded orphan drug status by EMEA AERAS-422 rBCG Status: Phase I Recombinant BCG Phase I conducted in the US

AERAS GLOBAL TB VACCINE FOUNDATION Clinical Trials: Field Site Development Large-scale community-based clinical trials are conducted in high burden countries Aeras partners with local research institutions to establish field sites and conduct clinical research Build local infrastructure and health care/research capacity to perform future Good Clinical Practice (GCP) compliant Phase III clinical trials

AERAS GLOBAL TB VACCINE FOUNDATION SATVI/University of Cape Town South Africa Makerere University Uganda KEMRI/CDC Kenya St John’s Research Institute India Aeras Partnerships in Clinical Development –Africa and Asia Manhiça Health Research Center Mozambique Le Dantec Dakar Senegal CHC/GHC Cambodia AURUM Johannesburg South Africa

AERAS GLOBAL TB VACCINE FOUNDATION Site Development South Africa Partnership with South African Tuberculosis Vaccine Initiative (SATVI) and AURUM Field site developed in Worcester (~120 km from Cape Town); most advanced site in the world for TB vaccine trials Infrastructure developed both for clinical and laboratory work

AERAS GLOBAL TB VACCINE FOUNDATION Aeras-Sponsored Trials in South Africa SATVI is conducting Phase I, II and IIb studies of four vaccine candidates in Worcester CIDRI will be conducting a Phase IIb in HIV positive adults in Kayalisha UCT Lung Institute conducted a Phase II clinical trial in adults with active or previous TB in Cape Town Aurum Institute is enrolling adults living with HIV in Phase IIb trial in Klerksdorp (mining community)

AERAS GLOBAL TB VACCINE FOUNDATION Key Accomplishments at Other Partner Sites State-of-the-art immunology and mycobacteriology laboratory established in South Africa and India GeneXeprt role-out for vaccine trials in South Africa, Mozambique, Uganda and Inida Mycobacterial and Immunology lab capacity is completed in Kenya and Uganda Local staff trained in clinical research in Kenya, Uganda and India Epidemiological cohort studies in Cambodia and Kenya Quality management and data management infrastructure developed in Kenya, India and Uganda New state-of-the-art Clinical Research Center established at a District Hospital in western Kenya First multicenter TB vaccine clinical trial initiated in Kenya

AERAS GLOBAL TB VACCINE FOUNDATION Local Benefits of Clinical Research Retain local talent and expertise Raise awareness about TB in the community Support and enhance local clinical research capacity Community health and education Infrastructure remains in the community Leverage investment in infrastructure to use for clinical trials of other diseases

AERAS GLOBAL TB VACCINE FOUNDATION Drivers of Future Uptake Wide recognition that TB is serious and neglected problem; MDR-TB threat Widespread dissatisfaction with current BCG Likely demand for partially effective vaccine better than BCG Willingness to commit to rapid introduction FDA or EMEA approval will speed adoption Willingness to spend money out of existing budgets for prime-boost; private sector

AERAS GLOBAL TB VACCINE FOUNDATION Barriers to Future Uptake Clarify expected benefits (20-30 years) Fatalism about TB – competing priorities, e.g., HIV/AIDS Funding Waiting for strong efficacy data Some resistance to adolescent boosting (transient populations) Some skepticism about aerosol delivery

AERAS GLOBAL TB VACCINE FOUNDATION Lessons Learned Heterogeneity of responses within and between countries Strong efficacy data will be a critical success factor for introduction, including in-country data Cost, if kept low, not likely to be major issue; not an issue in private markets Education and preparation will be necessary, but raising awareness and expectations too high needs to be avoided

AERAS GLOBAL TB VACCINE FOUNDATION Aeras gratefully acknowledges the support of the following major donors but also acknowledges the need for Government support to effectively fight TB Netherlands Ministry of Foreign Affairs US Food and Drug Administration

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