Scott Butler Infection Innovative Medicines Group AstraZeneca R&D, Boston

1. AZD5847 Oxazolidinone for the treatment of Tuberculosis CPTR Workshop, 2012 Arlington, VA Scott Butler Infection Innovative Medicines Group AstraZeneca R&D, Boston

2. AZD5847: An oxazolidinone to treat tuberculosis MIC distribution – 163 TB isolates Product Concept: Antimicrobial to be incorporated into novel combination therapies to treat DS and/or MDR/XDR tuberculosis (including HIV co-infected) AZD5847 • Originally targeted as once daily IV/oral treatment for staphylococcal infections • Development was discontinued in 2002 when pharmacokinetics in healthy volunteers did not support QD IV dosing* • Now re-positioned for the treatment of tuberculosis by oral administration • Ready to start Phase 2 *Gravestock MB et al.. Bioorg. Med. Chem. Lett. 2003. 13:4179-86

3. AZD5847 is bactericidal against intracellular TB • Bone marrow derived macrophage model: AZD5847and rifampicin are effective against intracellular TB, whereas isoniazid and linezolid are weakly active

4. AZD5847 retains PKPD index vs. slowly dividing TB in mouse model • AZD5847 and Linezolid are equally effective versus rapidly dividing TB in mouse lung TB model • AZD5847 has higher efficacy versus slowly dividing TB, that is key to achieving sputum sterilization. Once daily oral dosing for 4 weeks

5. Lower risk of toxicities related to inhibition of Mitochondrial Protein Synthesis • Inhibition of mammalian MPS (by oxazolidinones) has been associated with myelotoxicity, lactic acidosis, and neuropathies1,2,3 • AZD5847 maintains lower exposures relative to in vitro IC50 for MPS at therapeutic doses doses AZD5847 Rx Dose Garrabou, G., Soriano, A., et al.. (2007). Antimicrob. Agents Chemother. 51, 962-967. Nagiec, E. E.; Swaney, S. M.; et al.. (2005) Antimicrob. Agents Chemother. 49, 3896-3902. McKee, E. E.; Ferguson, M.; et al.. (2006) Antimicrob. Agents Chemother. 50, 2042-2049. Wallis R. S. et al.. (2011) Antimicrob Agents Chemother. 55(2):567-74.

6. Modelling of Ph1 data for likely attainment of preclinical PD target • Accounted for: Inter-subject PK variability and the MIC distribution against M. tuberculosis • Monte-Carlo simulation - target attainment in 85% patients • Modeling predicts efficacy @ 800 mg QD / 400 mg BID %patients to achieve PD target q24 q12 q8 Human Dose (mg)

7. AZD5847 Ph1 Clinical safety summary AZD5847 was generally well tolerated over 14 days in healthy volunteers at doses predicted to drive efficacy in humans • n=42 single-dose (SAD) subjects; n=45 multiple-dose (MAD) subjects • Maximum administered dose 2400mg per day x 14 days • Predicted therapeutic dose 400mg BID / 800mg QD • No SAEs; 3 DAEs: pustular rash, self limited rectal bleed, migraine/scotoma • Most common AE: Dose-related nausea, reduced by dosing with food • Decreased WBC counts (5/9 volunteers 2400mg/day) and increased reticulocyte counts (1600-2400mg/day) were observed • Transient myalgias noted for 3/9 volunteers @ 2400mg/day (no CPK elevation) • No clinically significant ECG findings.

8. AZD5847: Carboxylic acid metabolite • Exposure • Metabolite was identified during analysis of pooled plasma samples from healthy subjects in the MAD study • Total AUC approximately 50% of the parent compound (free is <10%) • Exposure of metabolite in rat and dog did not provide in vivo toxicology qualification • Activity • Metabolite is equipotent to AZD5847 against TB in vitro and has nearly identical PK profile • Safety • No structural alerts for genetic toxicity and negative in Ames assay • Active against mitochondrial protein synthesis, however less potent than the parent molecule (30 µM IC50 versus 13 µM IC50) • Secondary pharmacology panel (including hERG and cardiac channels) • Some differences from parent, but no risks identified • No change to risk - benefit ratio.

9. Phase 2a: EBA Study (Sponsored by NIAID) Short duration (14 days) monotherapy with AZD5847 in patients with drug sensitive TB • To be conducted in South Africa (TASK, Andreas Diacon) • Scheduled start in late October Inclusions/exclusions; HAINE test to for sensitivity to rifampin and isoniazid; Baseline safety labs Treatment: 14 days Daily quantitative sputum culture for M.tb Days 0-2 = early bactericidal activity Days 3-14 = sterilizing activity 1 2 Active pulmonary tuberculosis documented by positive sputum smear x 2 Initiate SOC for DS-pulmonary TB Randomization 3 4 PK sampling days 1 and 14, trough levels days 5 and 10 Safety labs on days 7 and 14 5 Treatment groups (total enrollment ~75: 15 per arm) • AZD5847 500mg qd • AZD5847 500mg bid • AZD5847 1200mg qd • AZD5847 800mg bid • Rifafour 1 tab PO qd (weight based) Endpoint: Rate of change in sputum colony forming unit (CFU) counts (bactericidal activity) during the entire 14 days of study drug administration (EBA0-14) 9

10. Summary Next steps • Preparation for potential Ph2b • 90 day chronic toxicology studies in mouse and dog (currently setting up) • DDI studies as appropriate for specific design and population • Pharmaceutical development • Oxazolidinones offer a promising (clinically validated) addition to future novel combination regimens (MDR/XDR treatment or simplification/reduced duration) • AZD5847 has potential to differentiate in the clinic: • Active against slowly dividing TB • Active against intracellular TB • Has reduced potency against human mitochondrial protein synthesis • AZD5847 is safe and well tolerated at predicted efficacious doses • Phase 2a trial to start October/November 2012