Challenges in Antibacterial Drug Development

1. Challenges in AntibacterialDrug 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 AntibacterialDrug DevelopmentCharacteristics of the Drug • Broad Spectrum vs. Narrow Spectrum • Oral and/or IV • Modification of Existing Class vs. Novel Class

4. Challenges in AntibacterialDrug Development

5. Challenges in AntibacterialDrug DevelopmentCharacteristics to Justify Development • Microbiological Superiority • Inhibit resistant organisms • Pharmacological Advantage • Frequency of dosing • Ease of administration • Safety Advantage

6. Challenges in AntibacterialDrug DevelopmentClassification 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 AntibacterialClinical 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 AntibacterialDrug DevelopmentTrial 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

10. Challenges in AntibacterialDrug DevelopmentTrial 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 AntibacterialDrug DevelopmentChallenges 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 DevelopmentDelta – Related to Efficacy Rates in 1992

14. Challenges in AntibacterialDrug DevelopmentImpact 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 AntibacterialDrug DevelopmentOpinion • “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 AntibacterialDrug DevelopmentOpinion • Oral Drugs for Common Community Diseases • Skin and skin structure • Sinusitis • Otitis media • Bronchitis • Urinary tract infection • Gonorrhea • 10% Delta Appropriate

17. Challenges in AntibacterialDrug DevelopmentOpinion • IV Drug for Serious Infections Delta Should be Based on Clinical Knowledge of the Infection

18. Challenges in Antibacterial Drug DevelopmentProblems 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 AntibacterialDrug DevelopmentOpinion – 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

20. Challenges in Antibacterial Drug DevelopmentOverall 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 DevelopmentOverall 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.