Acceleratingthe development of faster acting and

affordable drug combinationsto fight tuberculosis.

Community Advocacy for New Tools and Strategies to Address TB/HIV:

TB Treatment Christo van Niekerk

Tuberculosis (TB)

• Tuberculosis, an ancient and relentless pandemic, continues to ravage continents, societies and families.

• Yet today the world still depends on outdated drugs delivered in a complex multi-drug regimen for six or more months.

• No new drugs have been introduces in 30 years

Global Epidemic

• 2 billion people are infected with M. tb• 9 million new active TB cases a year• 2 million people die/year; 1/15 sec• ~ 400,000 new cases of MDR-TB a year• 12 million persons are TB/HIV co-infected• Biggest killer of women of childbearing age• Economic toll: $12 billion a year

Current TB therapy, though efficacious, is inadequate to control the global TB epidemic - too long and too complex

Factors Contributing to Current TB Epidemic

• HIV epidemic

• failing public health infrastructures

• increasing poverty and homelessness

• IV drug use (living conditions)

Tuberculosis (TB)

• A disease caused by a bacterium (bug): Mycobacterium tuberculosis (M. tb; MTB)

• 50 years after introduction of an effective drug, TB remains 2nd only to AIDS as the leading infectious cause of death in the world

Natural History of TB(in the absence of HIV infection)

50% 50%

10%

90%

Clinical Presentations

• Latent TB Infection• Pulmonary TB

– Smear positive (cavitating)– Smear negative

• Extra Pulmonary TB• TB in children

– Miliary TB– TB meningitis– Pulmonary TB– Other

State of the Field

• Lengthy - 6-8 months of 4 drugs taken in combination

• Outdated – drugs discovered in 1940s, 1950s, armamentarium dwindling

• Cumbersome - direct monitoring by healthcare workers, <50% of smear+ cases receive standard of care

• Poor results - Incomplete treatment results in drug-resistant strains, and relapse

• TB and HIV treatment not easily co-administered

We need a new treatment!

TB and HIV• A total of 12 million people worldwide are co-

infected with both diseases, with a majority of them living in Southern Africa.

• In sub-Saharan Africa, two-thirds of TB patients are co-infected with AIDS.

• When someone with latent TB becomes co-infected with HIV, the risk of developing active TB increases by a factor of 30 - 50.

• For those who are HIV+, risk is almost 10% per year. (In some countries, over 70% of TB patients are also HIV+)

TB and HIVThe are several important associations between

epidemics of HIV and TB:

• TB is harder to diagnose in HIV positive people • TB progresses faster in HIV-infected people • TB in HIV positive people is more likely to be fatal if

undiagnosed or left untreated • TB occurs earlier in the course of HIV infection than

other opportunistic infections • TB is the only major AIDS-related opportunistic infection

that poses a risk to HIV-negative people.

History of the TB Alliance• Cape Town Declaration – Feb 2000

– Hosts: Rockefeller Foundation & MRC S. Africa– Over 120 organizations (health, science,

philanthropy and private industry)

• Results

– Support goals of Stop TB Initiative– Create Scientific Blueprint– Develop Pharmacoeconomic Analysis

Build a global alliance forTB drug development

The TB Alliance

• International Public-Private Partnership (PDP)

• Independent, not-for-profit organization

• Based in New York, Brussels and Pretoria

• Entrepreneurial, virtual R&D approach– Out-source R&D to public or private partners

The TB Alliance

Mission

Develop new, better drugs for TB

Ensure affordability, access and adoption (AAA)

Coordinate and catalyze TB drug development activities worldwide

Affordability, Access and Adoption (AAA)

• Develop cost effective, affordable new anti-tuberculosis drugs for all those who need them most

• Ensure equitable access of new TB treatments, especially for patients in high-burden countries.

• Working closely with communities, governments and National TB Programme coordinators to ensure the future drugs will be adopted into TB Programmes

1. Active disease

2. TB/HIV co-infection

3. MDR-TB

4. Latent infection (LTBI)

TB Alliance Priorities Based on impact and feasibility

Active TB – Near Term Goal

130 doses130 doses

Shorten: 6 months to 2-3 months

Simplify: daily to weekly

10 doses10 doses

Long-term Goal Active Disease

7-10 days of treatment

But - very difficult to achieve without advances in understanding the biology of

“persistence”

TB Alliance PortfolioDiscovery Preclinical Clinical Testing

Nitroimidazole Analogs (University of Auckland/Novartis Institute for Tropical Diseases/National Institute of Allergy & Infectious Diseases)

Quinolones (KRICT/Yonsei University)

Nitroimidazole PA-824 (Chiron)

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Contracted Program

Program in discussion

Screening and Target Identification (AstraZeneca)

Nitroimidazole OPC-67683 (Otsuka)

Moxifloxacin (Bayer)

Global Alliance for TB Drug Development www.tballiance.org March 2006

InhA Inhibitors(GlaxoSmithKline)

Isocitrate Lyase Inhibitors(GlaxoSmithKline)

Focused Screening (GlaxoSmithKline)

Pleuromutilins (GlaxoSmithKline)

Nitroimidazole Backup Compound (Otsuka)

Oxazolidinones(Pfizer)

Bifunctional Molecules(Cumbre)

Macrolides (University of Illinois at Chicago)

Malate Synthase Inhibitors(GlaxoSmithKline/Rockefeller University)

Protease Inhibitors(Medivir)

Riminophenazines(Institute of Materia Medica)

Capuromycins(Sankyo/Sequella)

Diamine SQ-109(Sequella)

New Targets(University of Pennsylvania/Evotec)

Proteasome Inhibitors(Cornell University)

Quinolone DW-224(Dongwha)

Global TB Drug PortfolioSeptember 2005

Discovery Preclinical Clinical Testing

Dihydrolipoamide Acyltransferase InhibitorsCornell University, NIAID

InhA InhibitorsGlaxoSmithKline, TB Alliance

Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance

MacrolidesTB Alliance, University of Illinois at Chicago

Methyltransferase InhibitorsAnacor Pharmaceuticals

Translocase I InhibitorsSequella Inc., Sankyo

Synthase Inhibitor FAS20013FASgen Inc.

Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance

Diarylquinoline TMC207Johnson & Johnson

Nitroimidazo-oxazole OPC-67683 Otsuka

Natural Products Exploration BIOTEC, California State University, ITR, NIAID, TAACF, University of Auckland

Dipiperidines (SQ-609) Sequella Inc.

Diamine SQ-109Sequella Inc.

GatifloxacinOFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR

Cell Wall InhibitorsColorado State University, NIAID

Novel Antibiotic ClassGlaxoSmithKline, TB Alliance

Picolinamide ImidazolesNIAID, TAACF)

PleuromutilinsGlaxoSmithKline, TB Alliance

QuinolonesKRICT/ Yonsei University, NIAID, TAACF, TB Alliance

Screening and Target IdentificationAstraZeneca

Thiolactomycin AnalogsNIAID, NIH

Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance

Nitrofuranylamides NIAID, University of Tennessee

Pyrrole LL-3858Lupin Limited

Nitroimidazole PA-824Chiron Corporation, TB Alliance

Non-Fluorinated QuinoloneTaiGen

CarboxylatesTB Alliance, Wellesley College

Nitroimidazo-oxazole Back-up Otsuka

STOP TB New Drugs Working Group

TB and HIV

While policymakers are currently developing better technical

frameworks to improve today’s strategies for TB control in HIV

hotspots, better drugs that eliminate TB in HIV patients are key to halting

the dual infection.

Antituberculosis drugs and HIV

• Rifampicin should be avoided because of its strong inducing effect resulting in an increased risk of virological failure and development of resistance.

• Serious side effects can occur in combination with Protease inhibitors

• Rifampin should be avoided if concurrent ART with NNRTIs (nucleoside reverse transcriptase inhibitors.)

Acceleratingthe development of faster acting and

affordable drug combinationsto fight tuberculosis.