The role of FIND and NDWG

Claudia Denkinger, MD PhD MScHead of TB, FIND

29th October 2014

The Global TB Epidemic

25 November 2014

MDRDiagnosed Multi-drug resistant TB

Undiagnosed TBUndiagnosed TB

Untreated TB

All cases of TB

Facts:• 9 million TB cases • 1.5 million TB deaths• 3 million undiagnosed• Up to 30% of cases

diagnosed never get treated

Facts:• 480 000 with MDR• 3.5% of new + 20.5% of

previously treated TB cases• Only 8.5% new + 17% prev.

treated are diagnosed

WHO Global TB report 2014

Existing Drug Susceptibility Testing

Phenotypic• Long time to diagnosis• Complex, requiring high skill• Biosafety requirements

Genotypic• Xpert: limited drug portfolio• LPA: Complex, requiring high skill

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Molecular Pipeline

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Our Vision

Resistance po

rtfolio

2011                            2014                            2017                            2020

closed systemMTB/Rif

central POC

Sequencing for direct patient 

care

Open platform(s)multi‐drug PCR

2014 Q3Discovery

LEAD IDENTIFICATION

LEAD  OPTIMIZATION PHASE 1

Late DevelopmentPHASE 3PHASE 2APRECLINICAL 

DEVELOPMENT PHASE 2B

PA‐824/Moxifloxacin/Pyrazinamide

STANDATP Synthesis Inhibitors               Calibr

POA ProdrugsYonsei

Whole‐Cell Hit‐to‐Lead Program Sanofi

Whole‐Cell Hit‐to‐Lead Program GSK

RNA Polymerase  Inhibitors           Rutgers University

Energy Meta‐bolism Inhibitors AZ/Upenn

InhA Inhibitors

Hit ID ProgramDaiichi Sankyo

Hit ID Program Shionogi

Hit ID Program Takeda

MacrolidesSanofi

UreasSanofi

DiarylquinolinesJanssen/University of Auckland/UIC

IndazolesGSK

ThiopheneCarboxamidesCalibr

CyclopeptidesSanofi

Mmmpl3 Inhibitors

AzaindolesAZ

TBA‐354

Preclinical TB Regimen DevelopmentJHU

Bedaquiline/  Clofazimine/      Pyrazinamide

PA‐824/ Bedaquiline/   Clofazimine/   Pyrazinamide

PA‐824/ Bedaquiline/  Clofazimine

PA‐824/ Bedaquiline/ Pyrazinamide

NC‐003

AstraZeneca (AZ)Bayer Healthcare AG (Bayer)Beijing Tuberculosis and Thoracic Tumor Research InstituteCalibrDaiichi SankyoGlaxoSmithKline (GSK)Institute of Materia Medica (IMM)IMPAACTJanssen [Johnson & Johnson]Johns Hopkins University (JHU)Medical Research Council (MRC)

New York Medical College Rutgers UniversitySanofiShionogiStellenbosch UniversityTakeda PharmaceuticalsUniversity College London (UCL)University of Auckland University of Illinois at Chicago (UIC)University of Pennsylvania School of MedicineYonsei University

TB Alliance R&D Partners: 

Early DevelopmentPHASE 4

Optimized Pediatric 

Formulations

Ethambutolfor children  > 5kg

Pyrazinamide       for  children > 5kg

Isoniazid                 for children  > 5kg

Isoniazid/ Rifampicin              for children  > 5kg

Ethambutol/ Rifampicin/ Pyrazinamide        for children  > 5kg

Pharmacokinetics of first‐line drugs in children < 5kgStellenbschUniversity

Convergence of Drugs with Diagnostics

New regimensNew drugs

Molecular Test Development

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The Approach

Two Step Approach

What do we know now?

TPP development

Identification of high confidence markers of resistance

Inform developers of molecular tests

Enhance sequencing for surveillance• Country capacity strengthening• Integration of data in database

Sequencing to directly inform patient care• Optimization of sample

preparation for sequencing• Development of more

automated solutions

FIRST Step SECOND Step

Key principles

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DatabaseDatabase

High qualityHigh

quality

Divers data

Divers data

Collaborative

Collaborative

Sustainable

Sustainable

Open accessOpen

access

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The FIRST Step

TB Drug Resistance Data Sharing Platform

CPTR - a strong partner • With established capabilities in management of large amounts

of data• With linkage to drug development

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The Role of FIND/NDWG

To provide the coordination and communication with stakeholders in order to facilitate

• The data contributions to the database• The common work towards enriching the data available• The communication with test developers• The linkage to WHO

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WHOWHO

FIND/NDWGFIND/NDWG

Stake-holdersStake-holders

The Role of FIND/NDWG

In partnership with lead experts in the field

• Ensure the quality of the data included in the database• Drive the development of criteria for the validation of mutations

that are associated with resistance • Create a ‘living’ list of relevant resistance mutations• Define algorithms for the interpretation of genotypic data and

their correlation with clinically relevant resistance in M. tuberculosis.

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Thank you! Questions?

FINDCatharina BoehmePeter KasparDavid Dolinger

NDWGDaniela CirilloAlessandra Varga