Hope in the TB Pipeline: Vaccines

Dr. Michael Brennan Senior Advisor, Global Affairs

J2J Lung Health Media Training 42nd Union World Conference on Lung Health Lille, France 27 October 2011

WHO Global Tuberculosis Control 2011 Report

Major progress in TB care and control has been achieved since the introduction of the DOTS strategy in the mid-1990s and the launch of its successor, the Stop TB Strategy, in 2006. However, progress is constrained by old technologies. To achieve the Stop TB Partnerships target of eliminating TB by 2050, a transformation in TB prevention, diagnosis and treatment is required.

This presentation will include

Why the world needs new TB vaccines Predicted impact of new TB vaccines Challenges in TB vaccine development How the Product Development Partnership model is advancing new TB vaccines Progress in TB vaccine clinical development Clinical trial field sites conducting TB vaccine studies Regulatory capacity Funding needs to develop TB vaccines that will be affordable and available worldwide

The Tuberculosis Pandemic

Source: World Health Organization (WHO) 2010

Global incidence rate = 128 cases/100,000 1.4 million TB-related deaths 8.8 million new cases of TB 80% of the TB burden is in 22 countries TB/HIV co-infection and TB drug resistance are key barriers to progress

The Need for a New TB Vaccine

BCG developed 90 years ago, not improved upon since Reduces risk of severe pediatric TB disease, but:
Unreliable protection when given to newborns against adult pulmonary TB, which accounts for most TB worldwide Wide use, but no apparent impact on the growing global TB epidemic

Not known to protect against latent TB

Not recommended for use in infants infected with HIV

The Pathway of TB Infection and Pathogenesis

Transmission 10% 90%

Pulmonary Lung Disease

Reinfection 5%

Latent Disease

Dissemination

The Pathway of TB Infection and Pathogenesis

Transmission 10% 90%

Pulmonary Lung Disease

Reinfection 5%

Latent Disease

Dissemination

Meeting the Public Health Need: Target Populations for TB Vaccines

Active Disease
Covered by existing vaccine

Latently Infected

No coverage or impact from existing vaccine

Pre-infection

Infants

Adolescents

Adults

HIV+ All Ages

Target vast, unmet need for new, more effective TB prevention in multiple populations Potential replacement and/or boost for widely used BCG: 180 countries recommend BCG 100M+ doses per year
7

TB Epidemiology: Differences in Disease Populations

in Different Countries Can Impact Vaccine Approach

TB Disease Primary Infection Re-infection

India 62% 20% 19% 9%

Reactivation

18%

72%

* Adapted from Chris Dye, WHO

The Potential of New TB Vaccines

A new, more effective TB vaccine could: Contribute significantly to global efforts to eliminate TB as a public health threat Be safer and more 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 Reduce the cost and burden of TB on patients, health care systems and national economies

Impact of Immunization on Vaccine Preventable Disease

From: Understanding Vaccines USDHHS NIH/NIAID Science Education)

Potential Impact of a 50% Effective Vaccine

TB (all types) Incidence
2000

All age groups

Neonatal pre-exposure Neonate pre-exposure + add effects Post-exposure Mass pre-exposure Mass pre-exposure + post-exposure

1600
Incidence per million

1200

39 & 37% 52% 80% 92%

2015 2020 2025 2030 Year 2035 2040 2045 2050

800

400

0 2010

Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME. Epidemiological benefits of more effective tuberculosis vaccines, drugs and diagnostics. Proc Natl Acad Sci USA. 2009;106(33):13980-5

Better TB Vaccines: Reasons for Optimism

Most people (80-90%) do not get disease when infected with Mtb = natural resistance
Evidence of limited BCG vaccine efficacy in children New TB vaccine candidates provide some protection in animals New TB vaccines boost immune responses in early human clinical studies

Critical Needs in TB Vaccine Field

Advance the pipeline of TB vaccine candidates Work with partners to market affordable, safe and effective TB vaccines for all who need them

Evaluate surrogate immune assays and animal models that predict vaccine induced protection
Develop clinical trial site infrastructure and conduct clinical trials Manufacture good manufacturing practice (GMP) lots of TB vaccines Develop regulatory strategies that advance the testing and licensure of TB vaccines

Aeras Mission and the PDP Model

Founded in 2003 with offices in Rockville, Maryland and Cape Town, South Africa Non-profit biotechnology organization created as a product development partnership

Public-Private Partnerships with industry, academia, governments, NGOs and others to catalyze product development Mission: Develop effective TB vaccines/biologics to prevent TB across all age groups in an affordable and sustainable manner.

Aeras Africa Office Cape Town, South Africa

Established in 2008 to focus on Site Development and Epidemiology Started Clinical Trials Management throughout Africa in 2010 13 staff members Expertise in - Clinical Trials Management - Clinical Data Management and Biostatistics - Laboratory Capacity Development - Clinical Training - Advocacy Focus on African collaboration in vaccine development

Pre-clinical Development at Aeras

Goal: Choose best vaccine portfolio & facilitate pre-clinical development Antigen selection Platform development Product selection Process development Good Laboratory Practice (GLP)/regulatory testing Animal modeling and immunology Assay development

Technical Operations at Aeras

Fully integrated biopharmaceutical manufacturing facility

Upstream (fermentation) 6,000 sq ft completed in 2006

Downstream (Purification and fill/finish) 9,000 sq ft. completed in 2009 Biosafety Level-2 compliant Meets US and European regulatory standards Staff expertise in technical operations, quality assurance, and quality control

New Paradigm: Partnership & Collaboration

Aeras

Foundations Government NGOs Civil Society

Academia

Pharma & Biotech Industry

TuBerculosis Vaccine Initiative (TBVI)

European efforts to develop more effective, safe vaccines against tuberculosis that will be globally accessible and affordable. R&D support and advocacy

Focus:
Discovery Preclinical Phase I/IIa - early clinical stages

TB Vaccine Development
A Decade of Progress but much more to do!

2000
No new 2000 preventive TB vaccines in clinical trials

2002
1st preventive 202 vaccine enters clinical trials (MVA85A)

2009
1st Phase IIb 2009 proof-of-concept of preventive vaccine initiated

2011
15 vaccines have 2011 entered clinical trials, 12 currently in clinical trials

15 novel TB vaccine candidates have been in clinical trials in the last decade but no winner yet
Robust pipeline of 2nd generation candidates, novel vaccine constructs and new delivery platforms continue to be explored

Currently 12 novel TB Vaccines are in Clinical Trials

Phase I
AERAS-422
Aeras

Phase II
M72+AS01
GSK, Aeras

Phase IIb
MVA85A/ AERAS-485
Oxford-Emergent Tuberculosis Consortium (OETC), Aeras

Phase III
Mw [M. indicus pranii (MIP)]
Dept of Biotechnology (India), M/s. Cadila

AdAg85A
McMaster University

RUTI
Archivel Farma

Hybrid-I+CAF01
SSI

VPM 1002
Max Planck, Vakzine Projekt Mgmt, TBVI

AERAS-402/ Crucell Ad35

Crucell, Aeras

Hyvac 4/ AERAS-404
SSI, Sanofi-Pasteur, Aeras, Intercell\

Hybrid-1+IC31
SSI, TBVI, EDCTP, Intercell

SSI H56-IC31
SSI, Aeras, Intercell, TBVI

Prime TB Vaccine Types Viral-vectored: MVA85A, AERAS-402, AdAg85A Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56 rBCG: VPM 1002, AERAS-422 Killed WC or Extract: Mw, RUTI Boost Post-infection Immunotherapy

Source: Tuberculosis Vaccine Candidates 2010; Stop TB Partnership Working Group on New TB Vaccines
With updates from sponsors

Clinical Studies Sponsored by Aeras

TB Vaccines
Adeno35 with transgene for 85A, 85B & TB10.4 [AERAS-402/Crucell Ad35]

Partnerships
Crucell / Aeras

Clinical Status
Ph I adults India Ph IIb infants S Africa, Kenya, Mozambique Ph II HIV+ adults S Africa Ph IIb infants S Africa Ph IIb HIV+ adults Senegal, S Africa Ph I adults EU

Modified Vaccinia with 85A [Oxford MVA85A/AERAS-485]

Oxford / Emergent and Aeras

Fusion protein 85B & TB10.4 in IC31 adjuvant [HyVac4/AERAS-404] Fusion Protein M72 in AS02 adjuvant [GSK M72] rBCG with endosome perturbation and over-expression of Mtb antigens [AERAS 422-rBCG]

Sanofi Pasteur/ SSI/Intercell and Aeras GSK / Aeras

Ph II infants Gambia

Aeras

Ph I adults US

Clinical Trial Sites for Phase IIb Proof-of-Concept Trials

If successful next step licensing trial to prove effectiveness
MVA85A 2 Phase IIb trials underway HIV+ Adults

AERAS-402/Crucell Ad35 1 Phase IIb trial underway

Infants
Trial Locations Senegal (HIV+) South Africa (HIV+, infants) Partners Aeras, OETC, EDCTP, MRC, UCT/IIDMM, Laboratoire de BacteriologieVirologie du Centre Hospitalier Universitair Aristide Le Dantec

Infants
Trial Locations Kenya Mozambique

South Africa
Uganda (future) Botswana (future) Partners - Aeras, Crucell, EDCTP, KEMRI/CDC, CISM, SATVI, NIH

TB Vaccine R&D Manufacturing

TB disease and Clinical Trials [Aeras]

St. John's National Academy Palamaner, India Makerere University Kampala, Uganda KEMRI/CDC Kisumu, Kenya Cambodian Health Committee Svay Rieng, Cambodia

SATVI/U of Cape Town Worcester, South Africa

Manhica Health Research Centre Manhica, Mozambique

Regulatory Authorities used in Aeras studies

TB Vaccine Clinical Site Clinical Trial Regulatory Agency MCC CNERS FDA DCGI MCC KEMRI MoH DRU NDA DCGI MCA FICORA MCC CHUV FDA MCC / DAFF MCC

MVA85A/AERAS485 AERAS-402/Crucell Ad35

South Africa Senegal US India South Africa Kenya Mozambique Botswana Uganda India Sweden Finland South Africa Switzerland US South Africa South Africa

Phase IIb Phase IIb Phase I Phase I Phase I; Phase IIb Phase IIb Phase IIb Phase IIb Phase IIb Phase I Phase I Phase I Phase II Phase I Phase I Phase I Phase 1

SSI/SP H4-IC31

AERAS-422

SSI H56-IC31

Regulatory Agency Capacity for Aeras Studies

COUNTRIES
US Europe South Africa Brazil India China Uganda Kenya Botswana Mozambique Senegal Gambia Ethiopia

TB INCIDENCE
Very low Low Very High Medium Very High Very High Very High Very High Very High Very High Very High Very High Very High

REGULATORY AGENCY
Very Good Very Good Good Good Good Good Weak Weak Weak Weak Weak Weak Weak

Collaboration at Trial Sites: Example South Africa

Partnerships with the South African Tuberculosis Vaccine Initiative (SATVI) & The Aurum Institute
Currently conducting clinical trials in infants and HIV+ adults Most advanced site for large-scale TB vaccine trials in the world

Capacity Development & Utilization

State-of-the-art immunology laboratory Local staff trained in clinical trial research

Accomplishments in South Africa

Approximately $14 million invested over 7 years to build infrastructure Additional funding provided by European and Developing Countries Clinical Trials Partnership (EDCTP) Clinical trials of TB vaccines ongoing in 2009:
- 3 Phase I trials - 3 Phase II trials - 1 Phase IIb Proof of Concept trial

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

New Partners: Emerging Countries

China, India, Brazil, South Africa

Expanding manufacturing capability

Evolving regulatory agency

Improving scientific research Approving and distributing own products

Ready to enter the global stage

Funding Needs 2011-2015 $1.9 billion

Funding for TB research and development has increased in recent years, reaching US$ 614 million in 2009, but still falls far short of the annual target of US$ 1.8 billion that is included in the Global Plan to Stop TB 20112015. - WHO Global Tuberculosis Control 2011 Report

Summary TB Vaccine Development

New TB vaccines could have a significant impact on the global TB epidemic

Tremendous progress is being made in the field of TB vaccine development, with two preventive vaccine candidates now in Phase IIb trials
GMP manufacturing capacity being developed and manufacturing agreements are being explored with particular emphasis on emerging economies Regulatory pathways and market and economic impact research being conducted now to lay the groundwork to accelerate adoption and uptake of new TB vaccines Scientific, infrastructure and financial challenges remain; solutions will require global partnership and commitment

With sufficient resources and positive results for current clinical trials, a new TB vaccine could be available by the end of the decade

Conference Sessions Featuring TB Vaccine R&D

October 28 Symposium on Partnerships to Accelerate TB Vaccine

2:30-4:30 pm in Room Rotterdam

October 28 satellite session on Synergies in the development of new diagnostics, drugs and vaccines for tuberculosis
4:45-6:45 pm in Room Faidherbe

Aeras and the TuBerculosis Vaccine Initiative (TBVI) have a booth in the Exhibit Hall (Booth #35) where visitors can learn more about progress in tuberculosis vaccine research and development

Aeras gratefully acknowledges the support of the following major donors and contributors

Netherlands Ministry of Foreign Affairs

US Food and Drug Administration

Thank You!
For more information: www.aeras.org Twitter: @aerasglobaltb Facebook: Aeras Dr. Michael Brennan mbrennan@aeras.org