Ketek ™ (Telithromycin) NDA 21-144 Efficacy Review

1. Ketek™ (Telithromycin) NDA 21-144 Efficacy Review John Alexander, M.D., M.P.H. Medical Team Leader Division of Anti-Infective Drug Products

2. Outline • Indications • Original NDA Studies • Resubmission Studies • Drug-Resistant Streptococcus pneumoniae • Penicillin Resistance • Erythromycin Resistance

3. Indications • Acute Exacerbation of Chronic Bronchitis • Acute Sinusitis • Community-Acquired Pneumonia • Tonsillitis/Pharyngitis

4. Acute Exacerbation of Chronic Bronchitis • Two Studies with the Original NDA • Study 3003 • Telithromycin for 5 days • Amox/Clav 500mg/125mg TID for 10 days • Study 3007 • Telithromycin for 5 days • Cefuroxime Axetil 500 mg BID for 10 days • One Study in the Resubmission • Study 3013 • Telithromycin for 5 days • Clarithromycin 500 mg BID for 10 days

5. Acute Exacerbation of Chronic Bronchitis

6. Acute Exacerbation of Chronic Bronchitis

7. Acute Exacerbation of Chronic Bronchitis

8. Acute Sinusitis • Three Studies with 1st Review Cycle • Study 3002 • Telithromycin for 5 days or 10 days, uncontrolled • Study 3005 • Telithromycin for 5 days or 10 days • Amox/Clav 500mg/125mg TID for 10 days • Study 3011 • Telithromycin for 5 days • Cefuroxime Axetil 250 mg BID for 10 days • No New Studies in the Resubmission

9. Acute Sinusitis

10. Acute Sinusitis

11. Community-Acquired Pneumonia • Original NDA Studies • Study 3001 • Telithromycin for 10 days • Amoxicillin 1g TID for 10 days • Study 3006 • Telithromycin for 10 days • Clarithromycin 500 mg BID for 10 days • Study 3009 • Telithromycin for 7-10 days • Trovafloxacin 200 mg QD for 7-10 days • Open-Label Studies 3000, 3009OL, 3010

12. Community-Acquired Pneumonia

13. Community-Acquired Pneumonia

14. Community-Acquired Pneumonia

15. Community-Acquired Pneumonia • New Studies in the Resubmission • Study 4003 • Telithromycin for 5 days or 7 days • Clarithromycin 500 mg BID for 10 days • Study 3012 • Open-label, Telithromycin for 7 days • Japanese Studies • Study 3107 and Study 2105

16. Drug-Resistant S. pneumoniae • Clinical Cases with DRSP Collected from CAP and AS Studies • Penicillin Resistance (MIC  2g/mL) • Erythromycin Resistance (MIC  1g/mL)

17. CAP: Drug-Resistant S. pneumoniaeTelithromycin MIC

18. CAP: Drug-Resistant S. pneumoniae • A Total of 49 Cases of CAP due to DRSP from Western Studies • Subset of Bacteremic Cases • Additional Cases from Japanese Trials

19. CAP: Drug-Resistant S. pneumoniae

20. CAP: Drug-Resistant S. pneumoniae • Non-evaluable Patients • 5 Successes • 2 Failures • 5 Indeterminate • Withdrawn for Elevated BUN/CR on Day 6 • Bronchitis at TOC visit, Aspiration on Day 5, New Antibiotics on Day 3 (AE and baseline bacteremia), Withdrawal for Personal Reasons

21. CAP: Drug-Resistant S. pneumoniae • All PRSP: • 19/27 (70.4%) in MITT, 1 Indeterminate • All ERSP: • 29/37 (78.4%) in MITT • 7 Comparator Patients with DRSP • 2 Isolates Susceptible to Comparator Agent • 3/5 in Clarithromycin Patients with ERSP

22. CAP: Drug-Resistant S. pneumoniaeBacteremia Patients

23. CAP: Drug-Resistant S. pneumoniaeCases from Japanese Studies

24. AS: Drug-Resistant S. pneumoniae • A Total of 29 Cases of Acute Sinusitis due to DRSP • Includes both 5-day and 10-day Duration • All cases from Studies in Original NDA

25. AS: Drug-Resistant S. pneumoniae

26. Acknowledgments • Statistical • Thamban Valappil, Ph. D. • George Rochester, Ph. D. • Clinical • Alma Davidson, M. D. • Janice Soreth, M. D. • Project Management • Judit Milstein • Ketek Review Team