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PROGRESS & MAIN CHALLENGES IN TB DRUG R&D. Expert consultation Geneva 11 Apr 2008. Martina Casenghi, PhD Biologist. An improved landscape for TB drug R&D. Establishment of TB Alliance in 2000-Associated approximately with half of projects in the pipeline.

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slide1

PROGRESS & MAIN CHALLENGES IN TB DRUG R&D

Expert consultation

Geneva 11 Apr 2008

Martina Casenghi, PhD

Biologist

slide2

An improved landscape for TB drug R&D

Establishment of TB Alliance in 2000-Associated approximately with half of projects in the pipeline

Few multinational Pharma companies (Novartis, GSK, AstraZeneca, Eli-Lilly, Sanofi Aventis, J&J, Pfizer) engaged in R&D for anti-TB drug on a “no-profit-no-loss” basis

Several other small-middle size Pharma companies -i.e. Otsuka, Lupin, Chiron, FasGen, Sequella etc.- engaged in R&D for anti-TB drug

TB Alliance strategy for identification of novel compounds

-shortening of treatment

-active against MDR-TB

-no interactions with ARVs

slide3

DISCOVERY

(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

slide4

HIV drug preclinical pipeline: ~ 100 compounds!

(TAG report http://www.aidsinfonyc.org/tag/tx/pipeline2006a.html)

Pre-clinical

(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

slide5

HIV drug clinical pipeline: ~ 30 compounds!

(TAG report http://www.aidsinfonyc.org/tag/tx/pipeline2006b.html)

Clinical Development

(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

slide6

Limitations of current pipeline

  • Approximately 40 compounds in the pipeline-That’s not enough
  • In average in a drug discovery program for anti-infectives only 1 compound in 20 makes it (Payne et al., 2007)
  • Glickman et al. (Glickman et al., Science 2006):
  • likelihood of introducing at least one successful anti-TB drug by 2010 is < 5%
  • likelihood to introduce a novel regimen with at least 2 new drugs by 2015 is < 1%
slide7

Chronic under-funding

Problem of chronic under-funding

- 2006 funding to TB R&D= $400 M

- 5 fold increase funding necessary to meet targets of Global Plan

C. Feur, Nov 2007, TB R&D: a critical analysis of funding trends 2005-2006. Treatment Action Group

slide8

Critical bottlenecks in TB drug R&D

Gaps in the TB drug R&D pipeline:

-MSF/Weill Cornell Medical college supported symposium to discuss roadblocks and possible solutions (Jan 2007)

RESEARCH:

  • Drug Discovery

DEVELOPMENT:

  • Clinical Trial Capacity
  • Accelerate TB drug development

-Test new drugs in MDR-TB patients

-need for reliable biomarkers that correlates with clinical cure

slide9

DRUG DISCOVERY

Academia

Basic science: identification molecular pathways essential for bacterial survival

Lead to preclinical candidate

Pre-clinical development

Clinical Trials

Early discovery

Hit to lead

Target identification

Target validation

Biotech and Pharma companies

Preclinical and Clinical development

Drug candidate

Validated hits

Leads

Inhibitors

drug

Phenotypic screenings

slide10

Filling the TB drug pipeline

THE PROBLEM:

A) TB drug R&D too risky from a commercial perspective

limited engagement from private sector

Drugs

Pharma companies

DALYs

(MSF TB drug pipeline report, Oct 2006)

- Small number of compounds in the pipeline is reflected by low number of Pharma companies involved in TB R&D

slide11

Filling the TB drug pipeline

THE PROBLEM:

B) Academic scientists carry out drug discovery projects but in sub-optimal conditions because of:

  • ACCESS TO TOOLS & EXPERTISE BARRIER

Lack of access to:

-appropriate compound libraries

-screening facilities

-medicinal chemistry and pharmacology expertise

2) FUNDING BARRIER: limited access to funding streamlines to run applied research projects

C) TB Alliance had limited capacity to impact early stage drug discovery

slide12

Academia

Basic science: identification molecular pathways essential for bacterial survival

TB Alliance

Target identification

?

Target validation

Preclinical and Clinical development

Drug candidate

Validated hits

Leads

Inhibitors

drug

Biotech and Pharma companies

slide13

Filling the TB drug pipeline

PROBLEM PERSIST DESPITE THE CONTRIBUTION OF RECENT INITIATIVES:

- NIH/NIAID funded facilities for compound screenings (TACCF) and comprehensive target validation (TARGET)

  • Gates foundation funded projects

a) Grand Challenges for Global Health # 11 “Drugs for treatment of latent TB infection” : grant awarded in 2005, $20M

b) TB drug Accelerator: launched beginning of 2006, $40M over 2 years

  • EU funded New Medicines for TB (NM4TB) project (about 10 M euro over 5 years)
  • TB drug R&D facilities established by few multinational companies (often represent private partner of grant funded consortia)
slide14

Filling the TB drug pipeline

MAJOR CHALLENGE THAT THESE RECENT INITIATIVES HAVE TO FACE:

  • Run drug discovery projects on a VIRTUAL basis
  • Big consortia, collaborators spread all over the world-coordination is a challenge

Certainly helpful contributions but NOT able to trigger the substantial boost in TB drug R&D that is necessary

slide15

Filling the TB drug pipeline

PROPOSAL EMERGED at the MSF TB drug symposium (Jan 2007):

(Nathan, Nat. Med 2007)

slide16

Critical bottlenecks in TB drug R&D

RESEARCH:

  • Drug Discovery

DEVELOPMENT:

  • Clinical Trial Capacity
slide17

Clinical Trial capacity gap

THE PROBLEM:

-Clinical Trials need to be performed in high burden countries

- High-burden countries have poor capacity to run clinical trials conforming to international guidelines (ICH/GCP and GLP)

  • CLINICAL TRIAL CAPACITY:
  • Infrastructures (lab and health facilities adequate to run research projects conforming to international standards)
  • Trained personnel
  • Functioning Institutional review boards/ethics committees
  • Regulatory guidance at national level
slide18

Clinical Trial capacity gap

  • BUILDING of CLINICAL TRIALS CAPACITY in HIGH BURDEN COUNTRIES: (Schluger et al., PLoS Med. 2007):
  • -Currently, specific funding for clinical trials capacity building is tied to individual drugs in the pipeline
  • Important to make direct investments in the infrastructure rather than taking a product-by-product approach
  • Big funding gap:
  • 2005 worldwide expenditures in clinical trials= US $20-30M
  • Experts estimation of needed funding= US$ 300-US$500M annually
slide19

CONCLUSIONS

  • TB DRUG R&D landscape significantly improved in the last 10 years
  • Current approaches and initiatives represent useful contribution to revitalize the field BUT they are NOT sufficient to:
  • ensure the creation of a sustainable pipeline
  • ensure the delivery of new products with timeframes that reflect the urgency of the situation
  • Alternative mechanisms and approaches to fund and organize R&D activities are required if we want to trigger a real change that can radically solve the problem
slide21

CONCLUSIONS

(Nathan, Nat. Med 2007)