1. Development of Drugs for Resistant Pathogens Francis P. Tally M.D. Cubist Pharmaceuticals, Inc.

2. Synthetic MoleculesNatural Products Sulfonamides Trimethoprim Quinolones Nitroimidazoles Nitrofurans Oxazolidinones ß-lactams –Penicillins –Cephalosporins –Carbapenems –ß-lactamase inhibitors Tetracyclines Chloramphenicol Aminoglyosides Glycopeptides Lincosamides Macrolides Streptogramins Polymyxins Rifampicins Lipopeptides Mupirocin Development of Drugs for Resistant Pathogens Antimicrobials Developed

3. Development of Drugs for Resistant Pathogens Characteristics to Justify Development Microbiological Superiority –Inhibit resistant organisms Pharmacological Advantage –Frequency of dosing –Ease of administration Safety Advantage

4. Development of Drugs for Resistant Pathogens Preclinical IND Criteria Potency –therapeutic potency vs. drug resistant pathogens –novel MOA, cidality, low induction of resistance Efficacy –Competitive efficacy vs. key pathogens in salient models Pharmacokinetics –IV required for serious infections –Oral bioavailability desired to facilitate registration study Safety –balance risk/benefit with infection –mild, reversible, easily monitored safety profile

5. Development of Drugs for Resistant Pathogens Problems With IV Only Drugs Serious Infections – limited Subjects for enrollment – cSST, pneumonia intraabdominal infections 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

6. Antimicrobial Resistance in Nosocomial Pathogens Drug/PathogenResistance (%) Vancomycin/enterococci24.7 Methicillin/S. aureus53.5 Methicillin/CNS88.2 3 rd Ceph/E. coli3.9 3 rd Ceph/K. pneumoniae10.4 Imipenem/P. aeruginosa16.4 Quinolone/P. aeruginosa23.0 3 rd Ceph/P. aeruginosa20.6 3 rd Ceph/Enterobacter spp.33.1

7. Drug Resistance in the USA Cubist SECURE surveillance study, 50 Centers *multi-drug resistance

8. Penicillinase-Producing Staphylococcus aureus H. Chambers (personal communication)

9. Nosocomial Methicillin-Resistant Staphylococcus aureus (MRSA) Infections Fridkin et al. Clin Chest Med.1999;20:303.

10. Methicillin-Resistant Staphylococcus aureus: SFGH Charlebois et al. EPI Center Data.

11. MRSA in Bay Area Communities H. Chambers (personal communication)

12. Reports of Community-Acquired MRSA H. Chambers (personal communication)

13. Resistant Pathogens Nosocomial Enterococci Infections Resistant to Vancomycin * 0 5 10 15 20 25 198919901991199219931994199519961997 Year % Resistance ICU Non-ICU *NNIS 1989-1997. Fridkin SK, Gaynes RP. Clinics in Chest Medicine. 1999.

14. Antibacterial Drugs in Development

15. Development of New Chemical Entity Efficacy – type of infection –Mild - UTI, Otitis Media –Serious – pneumonia, intraabdominal infections –Severe – meningitis, endocarditis Two well-controlled trials with appropriate “delta” are required Safety - over 1,000 patients required will result in study of 2,500-3,000 patients Cost of each patient enrolled $30,182 in Cubist studies in 2002

16. Development of Drugs for Resistant Pathogens Cost of Clinical Studies with per patient cost of $30,182: Number of Patients Total Cost 2500$75,455,000 3500$105,637,700 5000$150,910,000

17. Action Item 82 Streamline the regulatory process to bring AR products to market efficiently while assuring safety and efficacy Subpart E –Surrogate endpoints – not appropriate in bacterial infections – resistant pathogen is endpoint –Potential surrogate is susceptible pathogen –Animal model surrogates are only guides to the clinical study

18. Action Item 82 AR for life threatening infections focus development – selected infections –MRSA – incidence high enough in U.S. clinical studies »cSST »BE/bacteremia »Nosocomial pneumonia –VRE – incidence low in different infections drives need to obtain microbiology claim »cUTI »Wound »Bacteremia - in ICU, transplant and immunocompromised patients

19. Action Item 80 To promote development and appropriate use of priority AR products Restrictive labeling to antibiotic resistant organism –MRSA - empiric therapy worth developing –VRE - niche product not worth developing Products with safety issues and activity vs. resistant pathogens will be restricted based on the physicians creed to do no harm

20. Development of Drugs for Resistant Pathogens Drug Categories Broad range of indications requires large clinical program with two well controlled and sized studies to support claims. Two potential sources: –New classes of drugs –Analog of an approved drug with novel activity versus resistant pathogens Conclusion: Both types need full development to determine appropriate use –Adequate dose to retard resistance development –Appropriate indications for use

21. Development of Drugs for Resistant Pathogens Drug Categories Narrow range e.g. gram positive for serious infections requires IV New agents vs. old agents approved previously for susceptible pathogens. Learn from vancomycin use tracts with increasing frequency of MRSA

22. Vancomycin Use in the US Kirst. AAC. 1998;42:1303. ICU MRSA rate > 30% VISA reported

23. Development of Drugs for Resistant Pathogens Opinion What is the “problem” in focused drug development for Antimicrobial Resistant Organisms? –Very limited drugs in pipeline –The promise that genomic sequencing of pathogens and combinatory chemistry would yield new antimicrobial drugs has failed –To realize the potential of genomics in antimicrobial development will require substantial funding for new approaches

24. Development of Drugs for Resistant Pathogens Opinion What is the “problem” in focused drug development for Antimicrobial Resistant Organisms? (continued) –FDA clearly indicate the number of patients with resistant infections required in efficacy trials »Is it absolute number or »A percentage of the dominant pathogen e.g. MRSA/MSSE; VRE/Enterococci –Cost to prove clinical efficacy and safety of known novel compound ~$75M-$150M –To restrict novel new drugs for antibiotic resistant isolates only would limit market return to levels that would not justify development

25. Development of Drugs for Resistant Pathogens Cubist Path with IV Only Narrow Spectrum Drug Efficacy – selected indication with high incidence of Gram positive pathogens –cSST – Staphylococcus aureus, MRSA –CAP – Streptococcus pneumoniae –Bacterial endocarditis – S. aureus –cUTI – Enterococci, VRE Safety – new classes of drugs –Two well-controlled trials for each indication Special antibiotic resistant pathogens –MRSA – efficacy proven in selected indications –VRE – design pathogen-based clinical trial

26. Development of Drugs for Resistant Pathogens What is the answer? – Frank Tally Antimicrobial resistance is a complex issue without simple solutions Reserving novel new antimicrobial agents for antimicrobial resistant pathogens will –Limit the economic return –Result in decreased research in both big pharma and biotech sectors –Doesn’t solve the problem

27. Development of Drugs for Resistant Pathogens What is the answer? – Frank Tally To justify the high investment to develop novel drugs, the drug’s use should be determined based upon the safety and effectiveness of the agent in focused, well- designed clinical studies Industry and Regulatory Agencies should have frequent dialog in the design of clinical studies to develop novel agents for antimicrobial resistant pathogens

28. Development of Drugs for Resistant Pathogens What is the answer? – Frank Tally In order to restrict a safe novel antimicrobial agent to the shelf for only antimicrobial resistant pathogens, the government would have to develop a large funded program similar to the efforts for AIDS and cancer