1. Challenges in Antibacterial Drug Development Francis P. Tally M.D. Cubist Pharmaceuticals, Inc.

2. Francis P. Tally M.D. Background Tufts/New England Medical Center 1975-1986 –Infectious Disease, Senior Physician –Principal Investigator – 7 New Antimicrobials Lederle/Wyeth 1987-1995 –Executive Director, Infectious Disease Research –Registered Zosyn (piperacillin sodium & tazobacam sodium) – 1993 –Involved with discovery of tigecycline Cubist Pharmaceuticals, Inc. 1995 – present –Currently working to develop daptomycin

3. Challenges in Antibacterial Drug Development Characteristics of the Drug Broad Spectrum vs. Narrow Spectrum Oral and/or IV Modification of Existing Class vs. Novel Class EXISTING CLASSNOVEL CLASS Quinopristin/dalfopristinLinezolid TigecyclineDaptomycin Dalbavancin, OritavancinTelithromycin Ertapenem

4. Challenges in Antibacterial Drug Development

5. Challenges in Antibacterial Drug Development Characteristics to Justify Development Microbiological Superiority –Inhibit resistant organisms Pharmacological Advantage –Frequency of dosing –Ease of administration Safety Advantage

6. Challenges in Antibacterial Drug Development Classification of New Antibacterial Drugs Broad Spectrum – Existing Classes –Carbapenem – oral; qd –Penicillin / ß-lactamase inhibitor –Cephalosporin – MRSA activity Narrow Spectrum – Gram+ Susceptible and Resistant Organisms New Drug Class – Covers Resistant Organisms

7. Challenges in Antibacterial Clinical Protocol Development Spectrum and Drug Distribution Defines the Clinical Indications to Be Studied PK/PD Guide to Dose Selection Preclinical Safety Profile Influences Patient Selection Clinical Trial Design –Superiority –Noninferiority

8. Challenges in Antibacterial Drug Development Trial Design Clinical Indications and Organisms Encountered –Monomicrobial – S. aureus – cSST –Mixed infection – intra-abdominal Potential Pathogens Dictate Selection of Comparative Agents –Narrow – UTI, SST –Divergent – CAP, nosocomial pneumonia, intraabdominal infection

9. Bacterial Causes of Pneumonia Microbial Agent Community- Acquired Nosocomial Streptococcus pneumoniae20-6010-20 Haemophilus influenzae3-1010-20 Staphylococcus aureus3-515-30 Gram-negative bacilli3-1050-70 Miscellaneous agents3-5 Legionella sp.2-84 Mycoplasma pneumoniae1-6 Chlamydia pneumoniae4-6 Aspiration pneumonia6-10

10. Challenges in Antibacterial Drug Development Trial Design Type of Controlled Trial to Prove Noninferiority –Blinded »double or investigator »open label – microbiology endpoint Sample Size –“delta” –95% Confidence Interval –projected efficacy rate End Points – Clinical vs. Microbiological

11. Challenges in Antibacterial Drug Development Challenges of Selecting Delta for Clinical Trial Is Drug Therapy Better Than Placebo – Superiority –Placebo controlled requires monitoring board Seriousness of the Infection – Affects Delta –Mild: Impetigo, UTI, gonorrhea –Moderate: Bacteremia/Nosocomial pneumonia –Severe (rare): Endocarditis/Meningitis Is Drug Equal to Standard of Care –“Biocreep” in mild infections –Serious infection – select best therapy

12. Challenges in Antibacterial Drug Development “Biocreep” Historically, drugs with lower efficacy rates than standard of care can be approved with wider deltas Theoretically, one could sequentially compare and approve slightly inferior products relative to an approved standard of care “Biocreep” – over time a product could be approved as noninferior that would not be better than placebo

13. Challenges in Antibacterial Drug Development Delta – Related to Efficacy Rates in 1992 Predicted Cure Rate (%)Delta (%) 9010 80-8915 <8020

14. Challenges in Antibacterial Drug Development Impact of Small Delta Number of Patients to Be Enrolled is Greatly Increased Time to Complete Enrollment Measured in Years Enrollment Outside U.S. –Patient population differs –Control for study variables Cost of Drug Development –Big Pharma –Biotech / Specialty Pharma

15. Challenges in Antibacterial Drug Development Opinion “Biocreep” Should Be Stopped –Selection of comparative agent in collaboration with academic societies’ cited guidelines »Infectious Disease Society of America »American College of Pediatrics »Society for Critical Care Medicine »American College of Surgeons

16. Challenges in Antibacterial Drug Development Opinion Oral Drugs for Common Community Diseases –Skin and skin structure –Sinusitis –Otitis media –Bronchitis –Urinary tract infection –Gonorrhea 10% Delta Appropriate

17. Challenges in Antibacterial Drug Development Opinion IV Drug for Serious Infections Diagnosis Expected Cure Rate (%) Nosocomial Pneumonia75-85 Hospitalized CAP85-90 Intra-abdominal infection85 cSST80-88 Delta Should be Based on Clinical Knowledge of the Infection

18. Challenges in Antibacterial Drug Development Problems With IV Only Drugs Serious Infections – Limited Subjects for Enrollment – cSST, Pneumonia, Intraabdominal Selection of Comparative Agent (Stop Biocreep) Inpatient Hospital Requirement vs. Home IV Therapy Criteria for oral switch – small delta magnifies the challenges to perform adequate studies

19. Challenges in Antibacterial Drug Development Opinion – Paradox of Higher Mortality Infections Widest Delta in Severe Disease such as Meningitis and Bacterial Endocarditis – because sterilization of blood or CSF are hard end points IndicationMortality Meningitis10-28% Bacterial Endocarditis Viridans Strep Enterococcus S. aureus 4-16 15-25 24-47%

20. Challenges in Antibacterial Drug Development Overall Conclusions on Delta Community-acquired common infections are where the most “Biocreep” has occurred. Therefore a small delta is appropriate and the best comparative agent should be selected. Intravenous therapy for serious infections are the main problem in clinical development where physicians will select the best therapy. The delta should be based on statistical and clinical considerations and comparative therapy should represent the standard of care.

21. Challenges in Antibacterial Drug Development Overall Conclusions on Delta Severe infections (e.g. meningitis and bacterial endocarditis) require the widest deltas because microbiology end points are firm and incidence of infection is low.