1. PROGRESS & MAIN CHALLENGES IN TB DRUG R&D
Expert consultation
Geneva 11 Apr 2008
Martina Casenghi, PhD
Biologist

2. 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

3. DISCOVERY (STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)
b-Sulfonylcrboxamides
Johns Hopkins Univ, NIH
Cell Wall Biosynthesis Inhibitors
Several Institutions
Mycobacterial Siderophore Biosynthesis Inhibitors-CDD Univ Minnesota, NIAID, NIH
Dihydrolipoamide Acyltransferase Inhibitors
Cornell Univ, NIAID
Diphenyl ether based inhibitors of FabI (InhA) Stony Brook, NIH,NIAID, CSU, NJRMC, Univ Wuzburg
Nitroimidazole analogs
TB Alliance, Univ Auckland
Ftsz Inhibitors
Stony Brook, Colorado State Univ, SRI
Indole Derivatives
Colorado State Univ, NIH, INEOS Moscow
Novartis portfolio
Novartis
Myocobacterial Sulfation Pathway Inhibitors-Univ California Berkley, NIH
Malate Synthase Inhibitors
GSK, Rockefeller Univ, Texas A&M, TB Alliance
Pleuromutilines
GSK, TB Alliance
Natural Products Exploration
Several institutions
Mycobacterial Gyrase Inhibitors
Promazine Analogs
Salisbury University
Nitrofuranylamides
NIH, NIAID, Univ Tennessee, Colorado State Univ
Peptide Deformylase Inhibitors
Quinolones
KRICT, Yonsey Univ, TB Alliance
Oxazolidinonones
Pfizer
Proteasome Inhibitors
Small molecules Inhibitors of validated target-Seattle Biomed research Inst., BMGF
Phenotypic Whole cell Screening
(1) Univ Illinois Chicago,TB Alliance (2) NIH, NIAID, TAACF (3) Astra zeneca
Sanofi Aventis Portfolio
Sanofi-Aventis
NM4TB
AstraZeneca, European Commission
Protease Inhibitors
IDRI
Type II NADH-menaquinone oxireductase Inhibitors
Univ Pennsylvania, Univ Illinois Chicago, NIH
Multi-Functional Molecules
Cumbre, TB Alliance, Colorado State Univ
Riminophenazines
Inst. of Materia Medica, BTTRI, TB Alliance
Energy Metabolism
InhA Inhibitors
Target Based Screening
AstraZeneca
(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

4. Pre-clinical HIV drug preclinical pipeline: ~ 100 compounds!
Dipiperidine SQ-609
Sequella Inc.
Gyrase Inhibitor
Pharma
Compounds with in vivo activity against M.tb in animal models-NIH, NIAID, Colorado Univ
Nitroimidazole Backup compound
Otsuka Pharm.
Non-fluorinated Quinolone
TaiGen
Oxazolidinones
Pfizer
Synthase Inhibitor FAS20013
Fasgen Inc
Translocase I Inhibitors
Sequella Inc., Sankyo
HIV drug preclinical pipeline: ~ 100 compounds!
(TAG report
(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

5. Clinical Development HIV drug clinical pipeline: ~ 30 compounds!
Moxifloxacin
(1) Bayer, TB Alliance, CDC TBTC, JHU, TB Alliance (2) DMID/NIAID/NIH, TBRU
Diamine SQ-109
Sequella
Vitamin D
Christian Medical College Vellore, Dalhousie Univ
Gatifloxacin
OFLOTUB Consortium
Pyrrole LL-3858
Lupin Limited
Linezolid
(1)DMID/NIAID/NIH, TBRU;
(2) CDCTBTC
Diarylquinoline TMC 207
Tibotec Pharm. Ltd
Levofloxacin
DMID/NIAID/NIH, TBRU
Rifapentine
Sanofi-Aventis, TBTC
Nitrodihydro-imidazooxazole OPC
Otsuka pharm
Capreomycin for Inhalation
MEND, NIAID, BMGF
Metronidazole for Latent Infection
Imperial College London, BMGF, Wellcome Trust
Nitroimidazole PA-824
TB Alliance
High dose Rifampicin
Univ. of Nijmegen, EDCTP
HIV drug clinical pipeline: ~ 30 compounds!
(TAG report
(STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

6. 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%
Glickman et al., 2006 Because of attrition and need for combination therapy, there is a high risk that number of compounds is not sufficient to develop a new regimen in a reasonable time frame

7. Chronic under-funding
Problem of chronic under-funding
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 Treatment Action Group

8. 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

9. Biotech and Pharma companies Academia
Early discovery
Hit to lead
Lead to preclinical candidate
Pre-clinical development
Clinical Trials
DRUG DISCOVERY
Biotech and Pharma companies
Academia
Validated hits
Target validation
Inhibitors
Target identification
Leads
Drug candidate
Preclinical and Clinical development
drug
Basic science: identification molecular pathways essential for bacterial survival
Phenotypic screenings

10. 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

11. 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

12. Target identification Preclinical and Clinical development
Validated hits
Target validation
Inhibitors
Target identification
Leads
Drug candidate
Preclinical and Clinical development
drug
Basic science: identification molecular pathways essential for bacterial survival
Academia ?
TB Alliance
Biotech and Pharma companies

13. 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)

14. 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

15. Filling the TB drug pipeline
PROPOSAL EMERGED at the MSF TB drug symposium (Jan 2007):
(Nathan, Nat. Med 2007)

16. Critical bottlenecks in TB drug R&D
RESEARCH:
Drug Discovery
DEVELOPMENT:
Clinical Trial Capacity

17. 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

18. 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

19. 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

21. CONCLUSIONS
(Nathan, Nat. Med 2007)

22. Types of tuberculosis clinical trials
Endpoint
Size
Duration of study
What is being studied?
Phase I
Safety/tolerability
small
days-weeks
drug
PK/PD
PK/PD data; drug interactions
drug(s)
Phase IIa
EBA
Phase IIb
2-month culture conversion; SSCC; time to conversion
Medium
( patients/arm)
months
regimen
Phase III
Failure/relapse
large
years
Phase IV
Detection of uncommon side effects