Preclinical journey of a new antibiotic

1. Making of an antibiotic Pre Clinical Journey Dr. Ashok Rattan Chief Executive, Fortis Clinical Research Ltd., Adviser, Religare SRL Diagnostics in Fortis / Escorts Hospitals, Delhi & NCR

2. We are overwhelmed as it is, with an infinite abundance of vaunted medicaments; and here they add a new one….. Thomas Sydenham, MD (1624 - 1689)

5. New Drug Discovery and Development (Timelines) DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE II PHASE I SHORT-TERM PHASE III LONG-TERM PHASE IV ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING 24 + 18 months. AVG: 5 YEARS AVG: 12 MOS. IND NDA APPROVAL

6. 5000 compounds evaluated Phase-I 20-100 healthy volunteers 0 2 4 6 8 10 12 16 14 Years Phase-II 100-500 patient volunteers Phase-III 1000-5000 patient volunteers Review and approval by Food & Drug Administration 1 Compound approved 5 INDs Discovery and preclinical testing Source: Tufts Centre For Study Of Drug Development in C&EN, June 2000 Bringing a new drug to the market can take 15 years

7. Cost of bringing a new drug to the market is 800M to 1B US$

8. NCE In vitro In vitro Acute tox DRUG Insoluble New Drug Discovery is like snakes and ladder failure is the norm Active

9. Understand Disease & Identify unmet needs Select Mechanism/ Target Design NCEs & Screens Virtual Screening Synthesize NCEs Convert Lead-to-IND Candidate New Drug Discovery Road Map Preclinical work-up IND directed regulatory studies Convert Hit-to-Lead Screen/ Identify Hit

14. Microarray chip

15. Image from Gene-Chips (Microarray)

17. TARGET IDENTIFICATION & VALIDATION R&D Technology HIT IDENTIFICATION LEAD SEARCH & OPTIMIZATION CANDIDATE SELECTION GLP PHASE PHASE I-II PHASE II - III EXPLORATORY RESEARCH DRUG DISCOVERY DRUG PROFILING PRE- DEVELOPMENT DEVELOPMENT GENOMICS PROTEOMICS PHARMACOGENETICS BIOINFORMATICS HTS ASSAY DEVELOPMENT SUBSTANCE LIBRARY MOLECULAR MODELING COMBINATORIAL CHEMISTRY IN VITRO & ANIMAL PHARMACOLOGY TOXICOLOGY NEW FORMULATION PILOT PLANT PHARMACOGENETICS DATA MINING DATA BASE

18. Next advance will be availability of complete genomic sequences from multiple strains of a single pathogen .

23. Efficacy studies

25. IFs Elongation Tetracyclines Macrolides, Streptogramins Protein Biosynthesis Rifampicin, Aminoglycosides 30S subunit 50S subunit AUGCCGGGUUAC UAA 5’ 3’ mRNA AUGCCGGGUUAC UAA 5’ 3’ 30S + mRNA fMet-tRNA AUGCCGGGUUAC UAA 5’ 3’ 70S Initiation Complex EFs Elongation factors + t-RNAs Peptide product

26. RBx7644 IFs Initiation Complex not formed Site of action of RBx 7644 Protein synthesis inhibition at a novel site 30S subunit 50S subunit AUGCCGGGUUAC UAA 5’ 3’ mRNA AUGCCGGGUUAC UAA 5’ 3’ 30S + mRNA fMet-tRNA

32. SAR

33. Regulatory studies