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 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

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)

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 http://www.aidsinfonyc.org/tag/tx/pipeline2006a.html) (STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

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- 67683 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 http://www.aidsinfonyc.org/tag/tx/pipeline2006b.html) (STOP TB WG on new Drugs Annual Meeting, Cape Town Nov 2007)

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

CONCLUSIONS (Nathan, Nat. Med 2007)

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 (100-150 patients/arm) months regimen Phase III Failure/relapse large years Phase IV Detection of uncommon side effects