Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. T2 March 04 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) T2 March 04 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 T2 March 04 Scientific Advisory Board Professor Sydney Brenner Salk Institute, La Jolla, CA Nobel Laureate T2 March 04 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 T2 March 04 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 T2 March 04 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 T2 March 04 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 T2 March 04 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’ T2 March 04 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 T2 March 04 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 T2 March 04 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 T2 March 04 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 T2 March 04 Antimicrobial activity Animal Model NITD Drug Discovery Process: Timelines 6 months Target Finding Screening Assay Development 3 months T2 March 04 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 T2 March 04 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 T2 March 04 MDR TB vs Persistence of TB: Genetic vs Phenotypic Drug Resistance Non-replicator MDR mutant mutations TB drugs T2 March 04 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 T2 March 04 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 T2 March 04 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 T2 March 04 Physiologically Different Sub-Populations Replicating - Drug susceptible Non-replicating – Phenotypic drug resistance T2 March 04 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 T2 March 04 Relevance (predictive quality) of Persistence Models for TB? Wayne / Loebel model cfu/ml ? ? Low-dose mouse model Lung cfu negativ Sputum cfu T2 March 04 ? 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 T2 March 04 New Targets Essential for Survival of TB Bacilli MDR mutants mutations New growthessential targets (e.g. PDF) T2 March 04 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 T2 March 04 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 T2 MarchREL 04 Isocitrate Lyase (ICL) • Strong survival phenotype in low-dose mouse model • Glyoxylate shunt • Growth on fatty acids • NADH re-oxidation via Glycine Dehydrogenase T2 March 04 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) T2 March 04 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) T2 March 04 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) T2 March 04 Thank you www.nitd.novartis.com T2 March 04