A New Paradigm for TB Drug Development Mel Spigelman, M.D. Stakeholders’ Association Meeting October 17, 2005

TB Alliance Drug Portfolio 2004 DiscoveryPreclinicalClinical Testing Nitroimidazole Analogs (Novartis Institute for Tropical Diseases, NIAID) Carboxylates (Wellesley College) Quinolones (KRICT/Yonsei University) Macrolides (University of Illinois at Chicago) Novel Targets (Partner to be announced) New Compound Classes (Partner to be announced) Methyltransferase inhibitors (Anacor Pharmaceuticals) Rifalazil Analogs (ActivBiotics) Pyrrole LL-3858 (Lupin Limited) Non-Fluorinated Quinolone (Procter & Gamble) Quinolone KRQ (KRICT/ Yonsei University) Moxifloxacin (Bayer Pharmaceutical, EDCTP) Compounds, Analogs and Derivatives Novel chemical entities Under contract In discussion/finalization stages Terminated TB Alliance support Nitroimidazole PA-824 (Chiron)

Global TB Drug Portfolio September 2005 DiscoveryPreclinicalClinical Testing Dihydrolipoamide Acyltransferase Inhibitors Cornell University, NIAID InhA Inhibitors GlaxoSmithKline, TB Alliance Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Macrolides TB Alliance, University of Illinois at Chicago Methyltransferase Inhibitors Anacor Pharmaceuticals Translocase I Inhibitors Sequella Inc., Sankyo Synthase Inhibitor FAS20013 FASgen Inc. Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance Diarylquinoline TMC207 Johnson & Johnson Nitroimidazo-oxazole OPC Otsuka Natural Products Exploration BIOTEC, California State University, ITR, NIAID, TAACF, University of Auckland Dipiperidines (SQ-609) Sequella Inc. Diamine SQ-109 Sequella Inc. Gatifloxacin OFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR Cell Wall Inhibitors Colorado State University, NIAID Novel Antibiotic Class GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Pleuromutilins GlaxoSmithKline, TB Alliance Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Screening and Target Identification AstraZeneca Thiolactomycin Analogs NIAID, NIH Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance Nitrofuranylamides NIAID, University of Tennessee Pyrrole LL-3858 Lupin Limited Nitroimidazole PA-824 Chiron Corporation, TB Alliance Non-Fluorinated Quinolone TaiGen Carboxylates TB Alliance, Wellesley College Nitroimidazo-oxazole Back-up Otsukai

The Challenge and Opportunity of Success

Active TB - Strategy 130 doses Shorten: 6 months to 2-3 months Simplify: daily to weekly 10 doses then

Long-term Goal Active Disease 7-10 days of treatment But - very difficult to achieve without advances in understanding the biology of “persistence”

“TB Crystal Ball” All present first-line drugs (HRZE) have suboptimal profiles –pharmacokinetics –cytochrome P450 interactions –poor sterilizing activities (except R) –antagonistic interactions (E with HRZ; H with RZ) None of present first-line drugs will ultimately be part of an “optimized” regimen H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol

Conventional TB Clinical Paradigm Goal of a development program is to substitute one new drug for one of the conventional drugs HRZE MRZE or HRZM Approximate (aggressive) timelines: Phase I1 year Phase II2 years Phase III3 years 6 years H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol; M = moxifloxacin

Dilemma Conventional TB Clinical Development Paradigm 6 years 24 years ABCDBCDECDEFDEFGEFGH 6 years ABCDEFGH EABGCHDF

Strategic Shift Advancing novel COMBINATIONS rather than single drugs through the later drug development pipeline.

Alternative TB Clinical Development Paradigms ABCDCDEF EFAB EFGH CD 12 years ABCDEFGH #1: GH 6 years

Alternative TB Clinical Development Paradigms #2: ABCD EFGH ABCD 6 years EFGH 6 years

“Milestones” of Combination Development Paradigm All preclinical candidates potentially included in combination in vitro/in vivo studies Compounds tested individually through standard Phase I and EBA studies Phase I combination studies EBA combination studies Phase II and III combination studies

The Unfolding Solution

CFU Counts after 2 Months’ Treatment

Meeting the Regulatory Challenge TB Drug Development Forum December 6-7, 2005 in DC area Co-sponsored by TB Alliance, STOP TB Working Group on New Drugs and Bill and Melinda Gates Foundation Funded primarily by unrestricted grant from AstraZeneca Significant FDA participation; EMEA and SA MCC invited

A New TB Drug Development Paradigm Process begins at the preclinical stage once individual compounds meet preset criteria Feasible with present technologies Engage major regulatory authorities Think and act “comprehensively”– all compounds are part of one large portfolio new concepts of partnerships