PROGRESS & MAIN CHALLENGES IN TB DRUG R&D

PROGRESS & MAIN CHALLENGES IN TB DRUG R&D

Martina Casenghi, PhD

Biologist

Expert consultation

Geneva 11 Apr 2008

An improved landscape for TB drug R&D An improved landscape for TB drug R&D

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

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

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

b-SulfonylcrboxamidesJohns Hopkins Univ, NIH

Cell Wall Biosynthesis InhibitorsSeveral Institutions

Mycobacterial Siderophore Biosynthesis Inhibitors-CDD Univ Minnesota, NIAID, NIH

Dihydrolipoamide Acyltransferase InhibitorsCornell Univ, NIAID

Diphenyl ether based inhibitors of FabI (InhA) Stony Brook, NIH,NIAID, CSU, NJRMC, Univ Wuzburg

Nitroimidazole analogsTB Alliance, Univ Auckland

Ftsz InhibitorsStony Brook, Colorado State Univ, SRI

Indole DerivativesColorado State Univ, NIH, INEOS Moscow

Novartis portfolioNovartis

Myocobacterial Sulfation Pathway Inhibitors-Univ California Berkley, NIH

Malate Synthase InhibitorsGSK, Rockefeller Univ, Texas A&M, TB Alliance

PleuromutilinesGSK, TB Alliance

Natural Products ExplorationSeveral institutions

Mycobacterial Gyrase InhibitorsGSK, TB Alliance

Promazine AnalogsSalisbury University

NitrofuranylamidesNIH, NIAID, Univ Tennessee, Colorado State Univ

Peptide Deformylase InhibitorsGSK, TB Alliance

QuinolonesKRICT, Yonsey Univ, TB Alliance

OxazolidinononesPfizer

Proteasome InhibitorsCornell Univ, NIAID

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 PortfolioSanofi-Aventis

NM4TBAstraZeneca, European Commission

Protease InhibitorsIDRI

Type II NADH-menaquinone oxireductase InhibitorsUniv Pennsylvania, Univ Illinois Chicago, NIH

Multi-Functional MoleculesCumbre, TB Alliance, Colorado State Univ

RiminophenazinesInst. of Materia Medica, BTTRI, TB Alliance

Energy MetabolismGSK, TB Alliance

InhA InhibitorsGSK, TB Alliance

Target Based ScreeningAstraZeneca

DISCOVERY

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

Pre-clinical

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

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

HIV drug preclinical pipeline: ~ 100 compounds!

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

Clinical Development

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

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

HIV drug clinical pipeline: ~ 30 compounds!

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

Limitations of current pipelineLimitations 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%

Chronic under-fundingChronic 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 Critical bottlenecks in TB drug R&D

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

Gaps in the TB drug R&D pipeline:

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

Early discovery Hit to lead

Lead to preclinical candidate

Pre-clinical developme

nt

Clinical Trials

DRUG DISCOVERY

Biotech and Pharma companies

Academia

Validated hits

Target validation

Inhibitors

Target identification

LeadsDrug

candidate

Preclinical and Clinical

development

drug

Basic science: identification molecular pathways

essential for bacterial survival

Phenotypic

screenings

Filling the TB drug pipelineFilling the TB drug pipeline

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

limited engagement from private sector

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

(MSF TB drug pipeline report, Oct 2006)

Drugs Pharma companies

DALYs

Filling the TB drug pipelineFilling the TB drug pipeline

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

1) ACCESS TO TOOLS & EXPERTISE BARRIERLack 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

?

TB Alliance

Validated hits

Target validation

Inhibitors

Target identification

LeadsDrug

candidate

Preclinical and Clinical

development

drug

Basic science: identification molecular pathways essential

for bacterial survival

Academia

Biotech and Pharma companies

Filling the TB drug pipelineFilling 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 projectsa) Grand Challenges for Global Health # 11 “Drugs for treatment of latent TB infection” : grant awarded in 2005, $20Mb) 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 pipelineFilling 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 pipelineFilling the TB drug pipeline

(Nathan, Nat. Med 2007)

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

RESEARCH:• Drug Discovery

DEVELOPMENT:• Clinical Trial Capacity

Critical bottlenecks in TB drug R&D Critical bottlenecks in TB drug R&D

Clinical Trial capacity gapClinical 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 gapClinical 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

CONCLUSIONSCONCLUSIONS

• 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

CONCLUSIONSCONCLUSIONS

(Nathan, Nat. Med 2007)

Types of tuberculosis clinical trials

Type Endpoint Size Duration of study

What is being studied?

Phase I Safety/tolerability small days-weeks drug

PK/PD PK/PD data; drug interactions

small days-weeks drug(s)

Phase IIa EBA small days-weeks drug

Phase IIb 2-month culture conversion; SSCC; time to conversion

Medium(100-150 patients/arm)

months regimen

Phase III Failure/relapse large years regimen

Phase IV Detection of uncommon side effects

large years regimen