Transcript WTBD2004 31 Investing in new tools for TB control

TB Drug Discovery at the
Novartis Institute for
Tropical Diseases (NITD)
Alex Matter, Director
Mission of NITD
• The Novartis Institute for Tropical Diseases aims
to discover novel treatments and prevention
methods for major tropical diseases. Initially,
dengue fever and tuberculosis will be addressed.
• In those developing countries where these
diseases are endemic, the Novartis Group intends
to make treatments readily available and without
profit.
• The Institute will recruit the best scientific
specialists in the world, and as a major center of
excellence, will offer exceptional teaching and
training opportunities for post-doctoral fellows
and graduate students.
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Quick Facts
• Location: Singapore
• Operations started Jan 2003
• Total Employment: 74 FTEs
anticipated + ~ 30 students by
beginning 2005
• Long term commitment to
advance medical research in
the developing world
• US$122 million total cost
covered by Novartis and
Singapore Economic
Development Board (EDB)
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Singapore
Leveraging Novartis Pharma Drug Discovery
Resources and Expertise
 Scientists: their skills/know how/experience
 Databases/IT Infrastructure
 Integrated Knowledge Management
 Compound Archives/Natural Product Libraries
 Technologies/Structural Biology
 HT and uHT Screening Facilities/Robotics
 Synergistic Drug Discovery Projects/Leads
 Help/Support in Preclinical Development
 Effective Project Management
 Resources and expertise far exceed what is and
can be made available at NITD
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Scientific Advisory Board
Professor
Sydney Brenner
Salk Institute, La Jolla, CA
Nobel Laureate
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Professor
Duane J Gubler
Professor
Professor
Professor
Max Planck Institute for
Infection Biology, Berlin
Institute of Experimental
Immunology, ETH Zurich
Barbara Imperiali Stefan HE Kaufmann Rolf Zinkernagel
Centers for Disease Control
Massachusetts Institute
and Prevention, Fort Collins, CO of Technology, Cambridge MA
Nobel Laureate
NITD @ Biopolis
Institute of
Bioengineering
& Nanotechnology
Institute of Molecular
and Cell Biology
BioInformatics
Institute
Helios
Ministry
of Education
Bioprocessing
Technology Centre
Genome
Institute of
Singapore
Chromos
NITD to move to Biopolis in mid-April, 2004 with
official opening in July, 2004
Source: Singapore Economic Development Board
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NITD’s TB unit
Sabine Daugelat, Angeline Seet, Boon Heng Lee, Pamela Thayalan
Siew Siew Pang, Calvin Boon, Jeanette Teo
Amelia Yap, Mahesh Nanjundappa, Bee Huat Tan
Kakoli Mukherjee, Sabai Phyu, Thomas Dick
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Research & Development Cycle / Activities
Clinical Need
Product
(Drug)
Clinical
Trials
Basic Research
Clinical Research
Applied Research
Academic
Research
Biology:
-Concepts
-Assays
Clinical Drug
Candidate
Biology
Units
In Vitro Screens
Drug
Discovery
Pre-clinical
Development
Development
Candidate
Chemistry
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Pharmacology:
-PK, Biomarkers,
Efficacy models
Clinical Needs : Key Problems in TB Chemotherapy
 Multi drug resistant (MDR) TB
 Treatment of active disease in severely
immunocompromised patients
 Prolonged treatment of active disease and latent
infection (compliance / implementation problem)
is only partially effective
   ‘Persistence of TB’ despite prolonged
drug treatment
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Current TB Chemotherapy is directed against
growth-essential targets of TB bacilli
TB drugs
First line:
 Isoniazid (INH)
 Rifampicin (RIF)
 Pyrazinamide (PZA)
 Ethambutol (EMB)
 Streptomycin (STR)
Second line*:
 Fluoroquinolones (FQ)
 Ethionamide (ETA)
 p-aminosalicylic acid (PAS)
 Cycloserine (CS)
 Thiacetazone (TA)
*‘less effective, more toxic, more expensive’
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New Tools are Needed
 New Diagnostics: fast, reliable, cheap
 Biomarkers: capable to measure accurately via
non-invasive technologies pharmacodynamic
endpoints in early clinical trials
 New clinical trial methodologies based on stateof-the-art technologies
 New Drugs / new drug targets / new modes of
action
 Vaccines: early and predictive immunological
endpoints
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Biomarkers have revolutionized clinical trial
methodology in cancer
Example #1: Measuring the rate of
metabolism in tumors by PET
Example #2: Induction of histone
acetylation in prostate tumor tissue
after administration of HDAI (SAHA)
Predose
7 July 2000
Postdose
7 August 2000
18FDG
-PET Scan Results Pre/Post Glivec®
Prostate Biopsies (40X)
SAHA 900 mg/m2/day i.v.
X 3 DAYS
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Our Objective
Apply All Currently Available Technologies
Bioinformatics, Biology, Chemistry, Genomics, High
Throughput Screening, Imaging, Modeling, Pharmacology,
Structural Sciences, Transgenic Animals.
To Satisfy Patients and Authorities Develop
Drugs that are:
Affordable, Convenient To Use, Effective, Innovative, Safe,
Suitable for Combination Therapy
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What Does This Mean?
Take Advantage of the Availability of TB Genome
Target based drug discovery allows the medicinal chemists to
optimize drugs for improved efficacy, safety, pharmacokinetics
Enzyme
Inhibition
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Antimicrobial
activity
Animal
Model
NITD Drug Discovery Process: Timelines
6 months
Target
Finding
Screening
Assay
Development
3 months
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12 months
Preclinical
Development
Lead
Optimization
24 months
Success Factor for Drug Discovery
Do Animal Models Predict Human Disease
 Inappropriate animal models have delayed progress in
cancer and asthma research
 In both areas many drugs that are very effective in mouse
models turned out to be useless in humans
 TB animal models are very lengthy and difficult to
perform
 Do these models accurately model human disease
 If not – they should not be used as decision criteria in drug
discovery
Remember: HIV drugs have been developed
without animal models
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Success Factor For Clinical Studies
Rapid Clinical Feedback is Crucial
 Long term clinical studies (e.g. relapse rates) are not
suitable for early drug development
 A successful pipeline of drugs can only be created if the
drug discovery scientist as well as the development
organisation get quick answers about new treatment
modalities
• The TB field urgently needs biomarkers for
use in preclinical and clinical studies!
• NITD is committed to develop biomarkers for
drug development
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MDR TB vs Persistence of TB:
Genetic vs Phenotypic Drug Resistance
Non-replicator
MDR mutant
mutations
TB drugs
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environment
TB drugs
TB drugs
The Traditional and Proven Concept of Chemotherapeutic
Intervention: Growth-essential Targets applied to MDR
MDR mutants
mutations
Existing TB drugs
New growth-essential targets
with novel modes of action
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Peptide deformylase (PDF)
 Essential for growth in a broad variety
of bacteria
 Specific for bacterial protein synthesis
 PDF-Inhibitor project pursued at
Infectious Disease Therapeutic Area,
Novartis Institutes for BioMedical
Research in Cambridge, MA
 High quality leads available
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Objectives for TB Drug Development*
*Aligned with Global Alliance for TB Drug Development
Development of oral anti-mycobacterials with
new modes of action that fulfill at least one of
the following criteria:
 active against MDR TB
 improved ‘sterilizing’ activity, allowing shorter
(‘2 month’) and more effective treatment of
active and / or latent TB
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Physiologically Different Sub-Populations
Replicating - Drug susceptible
Non-replicating – Phenotypic drug resistance
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Models for Persistence of TB
Stable number of cfu‘s
Cell culture models
induced by low oxygen/
low nutrient concentration
Wayne /
Loebel
model
cfu/ml
Stable number of lung cfu‘s
Animal model
induced by immune response
Low-dose
mouse
Lung cfu
model
time
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Relevance (predictive quality) of Persistence
Models for TB?
Wayne /
Loebel
model
cfu/ml
? ?
Low-dose
mouse
model
Lung
cfu
negativ
Sputum
cfu
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?
Need to Provide More Evidence for Relevance of Model
Systems and to Identify Attractive Persistence Targets
 Gene expression profiling / metabonomics of
bacilli in human TB lesions and model systems
(followed by genetics)
 Genetics of candidate survival-essential targets
in model systems
 Chemogenomics in culture models
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New Targets Essential for Survival of TB Bacilli
MDR mutants
mutations
New growthessential targets
(e.g. PDF)
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Non-replicator
environment
New survivalessential targets
(e.g. PA824, Isocitrate Lyase?)
Persistence Compounds: Drug Candidates
(Stover et al. 00)
Nitroimidazopyran PA824 and analogs
• Global Alliance for TB Drug Development
(Chiron)
• Combines good MIC against growing bacilli (incl.
MDR TB) and cidal activity against nonreplicators
• Pro-drug, activation by F420-dep Glucose-6-Pdehydrogenase
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Validated and Feasible Persistence Targets?
Review of
published data
on MTB
persistence
Filter: Strong phenotype in
persistence culture and / or
mouse model and feasible for
HTS
ICL* ONLY!#
*Isocitrate lyase (McKinney et al. 00)
#
(Dahl et al. 03): transition phase issue
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04
Isocitrate Lyase (ICL)
• Strong survival phenotype in low-dose mouse
model
• Glyoxylate shunt
• Growth on fatty acids
• NADH re-oxidation via Glycine Dehydrogenase
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New Concept for Chemotherapeutic Intervention:
Targets Essential for Intra-Cellular Survival?
Intra-cellular
bacilli
Extra-cellular
bacilli
Phagosome
Macrophage
Bacterial macrophage-modifying targets?
(e.g. Protein kinase G [PKNG]?)
(Koul et al. 01)
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Conclusions: Where do we stand regarding the
new tools?
 New Diagnostics: fast, reliable, cheap: New
initiatives are afoot (Working Group/Find)
 Biomarkers: capable to measure accurately via noninvasive technologies pharmacodynamic endpoints
in early clinical trials: Research to be initiated
 New clinical trial methodologies based on state-ofthe-art technologies: To be determined
 New Drugs / new drug targets / new modes of
action: interesting possibilities arising based on new
concepts and novel drug targets
 Vaccines: early and predictive immunological
endpoints: new project started (GSK, Genesis, John
Radcliffe Hospital)
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Acknowledgements
• TB Research Unit, NITD, lead by Thomas Dick
• Chemistry Unit, NITD, lead by Thomas Keller
• Infectious Disease TA, Novartis Institutes for BioMedical Research
(NIBR), Cambridge, MA
• Discovery Technologies (DT), NIBR-Basel
• Clif Barry, NIAID, Bethesda, MD
• The Global Alliance for TB Drug Development
• Axxima, Munich, Germany
• Max-Planck Institute for Infection Biology, Berlin, Germany
• Grand Challenges in Global Health Foundation, (Grand Challenge#11,
TB consortium, lead by Douglas Young)
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Thank you
www.nitd.novartis.com
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