TB Drug Discovery at the Novartis Institute for

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. T 2 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) T 2 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 u. HT 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 T 2 March 04

Scientific Advisory Board Professor Professor Sydney Brenner. Duane J Gubler Barbara Imperiali Stefan HE Kaufmann Zinkernagel Rolf Salk Institute, La Jolla, CA Centers for Disease Control Massachusetts Institute Max Planck Institute for Institute of Experimental and Prevention, Fort Collins, of Technology, Cambridge MA Infection Biology, Berlin Immunology, ETH Zurich CO Nobel Laureate T 2 March 04

NITD @ Biopolis Institute of Bioengineering & Nanotechnology Institute of Molecular and Cell Biology Bio. Informatics 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 T 2 March 04

NITD’s TB unit Sabine Daugelat, Angeline Seet, Boon Heng Lee, Pamela Thayalan Siew Pang, Calvin Boon, Jeanette Teo Amelia Yap, Mahesh Nanjundappa, Bee Huat Tan Kakoli Mukherjee, Sabai Phyu, Thomas Dick T 2 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 Candidate Chemistry T 2 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 T 2 March 04

Current TB Chemotherapy is directed against growth-essential targets of TB bacilli TB drugs First line: Ø Isoniazid (INH) Ø Rifampicin (RIF) Ø Pyrazinamide (PZA) Ø Ethambutol (EMB) Ø Streptomycin (STR) Second line*: Ø Fluoroquinolones (FQ) Ø Ethionamide (ETA) Ø p-aminosalicylic acid (PAS) Ø Cycloserine (CS) Ø Thiacetazone (TA) *‘less effective, more toxic, more expensive’ T 2 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 T 2 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 18 FDG -PET Scan Results Pre/Post Glivec® T 2 March 04 Prostate Biopsies (40 X) SAHA 900 mg/m 2/day i. v. X 3 DAYS

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 T 2 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 T 2 March 04 Antimicrobial activity Animal Model

NITD Drug Discovery Process: Timelines 6 months Target Finding Screening Assay Development 3 months T 2 March 04 12 months Preclinical Development Lead Optimization 24 months

Success Factor for Drug Discovery Do Animal Models Predict Human Disease Ø Inappropriate animal models have delayed progress in cancer and asthma research v In both areas many drugs that are very effective in mouse models turned out to be useless in humans Ø TB animal models are very lengthy and difficult to perform v Do these models accurately model human disease v If not – they should not be used as decision criteria in drug discovery Remember: HIV drugs have been developed without animal models T 2 March 04

Success Factor For Clinical Studies Rapid Clinical Feedback is Crucial Ø Long term clinical studies (e. g. relapse rates) are not suitable for early drug development Ø 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 T 2 March 04

MDR TB vs Persistence of TB: Genetic vs Phenotypic Drug Resistance Non-replicator MDR mutant mutations TB drugs T 2 March 04 environment TB drugs

The Traditional and Proven Concept of Chemotherapeutic Intervention: Growth-essential Targets applied to MDR mutants mutations Existing TB drugs New growth-essential targets with novel modes of action T 2 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 Bio. Medical Research in Cambridge, MA · High quality leads available T 2 March 04

Objectives for TB Drug Development* *Aligned with Global Alliance for TB Drug 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 T 2 March 04

Physiologically Different Sub-Populations Replicating - Drug susceptible Non-replicating – Phenotypic drug resistance T 2 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 T 2 March 04

Relevance (predictive quality) of Persistence Models for TB? Wayne / Loebel model Low-dose mouse model cfu/ml Lung cfu negativ Sputum cfu T 2 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 T 2 March 04

New Targets Essential for Survival of TB Bacilli MDR mutants mutations New growthessential targets (e. g. PDF) T 2 March 04 Non-replicator environment New survivalessential targets (e. g. PA 824, Isocitrate Lyase? )

Persistence Compounds: Drug Candidates (Stover et al. 00) Nitroimidazopyran PA 824 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 F 420 -dep Glucose-6 -Pdehydrogenase T 2 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 (Mc. Kinney et al. 00) #REL (Dahl et al. 03): transition phase issue T 2 March 04

Isocitrate Lyase (ICL) • Strong survival phenotype in low-dose mouse model • Glyoxylate shunt • Growth on fatty acids • NADH re-oxidation via Glycine Dehydrogenase T 2 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) T 2 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) T 2 March 04

Acknowledgements • TB Research Unit, NITD, lead by Thomas Dick • Chemistry Unit, NITD, lead by Thomas Keller • Infectious Disease TA, Novartis Institutes for Bio. Medical 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) T 2 March 04

Thank you www. nitd. novartis. com T 2 March 04