Factive ® (gemifloxacin) NDA 21-158

1. Factive® (gemifloxacin)NDA 21-158 March 4, 2003 Anti Infective Drugs Advisory Committee Meeting Edward Cox, M.D., M.P.H. Deputy Director, Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. FDA Presentations • Microbiology Peter Dionne, MS • Community-Acquired Pneumonia Regina Alivisatos, MD • Acute Bacterial Exacerbation of Chronic Bronchitis Eileen Navarro, MD • Safety Maureen Tierney, MD, MSc • Summary Edward Cox, MD, MPH

3. MICROBIOLOGY OF FACTIVE ® GEMIFLOXACIN MESYLATE NDA 21-158 Peter A. Dionne Microbiologist DSPIDP

4. OVERVIEW • Activity compared to other Quinolones • Activity against Resistant S. pneumoniae • Activity against S. pneumoniae Mutants • Efficacy against S. pneumoniae in Rat Pneumonia model

5. In vitro Activity of Gemifloxacin and Comparators {MIC90s}

6. Comparative PK Data for Quinolones

7. Gemi MICs are Lower against Gram positive bacteria compared to other quinolones • Gemi MICs are about equal to other quinolones against Gram negative bacteria • Gemi PK parameters weaken the significance of lower MICs against Gram + • Gemi PK parameters may affect efficacy against Enterobacteriaceae

8. ActivityAgainst PEN-R S. pneumoniae

9. Activity Against Quinolone-RS. pneumoniae

10. MICs of Selected S. pneumoniaeMutants

11. Susceptibility of Cipro-RS. pneumoniae

12. Activity Against 44 S. pneumoniaeSecond Step Mutants [# at each MIC]

13. S. pneumoniae MICs against Pen-R = MICs against Pen-S as with all quinolones • Gemi MICs against Quin-R S. pneumoniae are in the range of 0.25-1 mcg/mL; Moxi MICs about 4 mcg/mL • S. pneumoniae double-mutants have Gemi MICs 0.25 mcg/mL; Moxi ~ 2 mcg/mL; Levo ~32 mcg/mL • Gemi PK values about 6 times lower than Moxi PK

14. Efficacy of Gemifloxacin Compared toLevofloxacin in RTI in Rats (Gemi MIC < 0.03 mcg/mL]

15. Efficacy of Gemifloxacin Compared to Levofloxacin in RTI in Rats [Gemi MICs > 0.125 mcg/mL]

16. Efficacy of Gemifloxacin Compared to Moxifloxacin and Gatifloxacin in RTI in Rats

17. In rat S. pneumoniae RTI infection model • Isolates with Gemi MICs < 0.03 mcg/mL once daily dosing is effective and CFU/lung reaches close to level of detection (< 1.7 CFU/lung] • Isolates with Gemi MICs > 0.125 mcg/mL must be dosed BID for efficacy and CFU/lung is > level of detection • Gemi better than Levo; Gemi about same as Moxi and Gati

18. Summary GEMI ~ MOXI > LEVO

19. Community Acquired PneumoniaFactive (gemifloxacin)NDA 21-158 Regina Alivisatos, MD

20. Sponsor’s Proposed Indication • Community-acquired pneumonia caused by Streptococcus pneumoniae (including penicillin-, clarithromycin- and cefuroxime-resistant strains), Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella catarrhalis; Mycoplasma pneumoniae; Chlamydia pneumoniae;Legionella pneumophila; Staphylococcus aureus • Proposed Dose: One 320 mg tablet daily for 7 days

21. Overview Efficacy in relation to • Duration of Treatment • Severity of disease • Streptococcus pneumoniae Penicillin-resistant Macrolide-resistant Cefuroxime-resistant Quinolone-resistant

22. Clinical Studies

23. FDA Analyses - Duration of Treatment Statistical issues with the combining of all 7 day patients because • 1 controlled study (011) and 2 uncontrolled were of 7 days duration a priori • in studies 061, 049, and 185, the duration of treatment was determined at the on-therapy visit and was investigator-driven • FDA performed additional analyses based on a stricter division of studies into those with a priori duration of 7 days and those where duration could vary

24. Patient Disposition- CAP

25. FDA Analysis of Clinical Response by Duration of Treatment

26. Severity • Severity was determined by retrospective application of Fine criteria with the exception of study 287 where the Fine criteria were applied prospectively • Patients assigned to a risk class (I - V) according to demographic, clinical and laboratory characteristics that stratified them by risk of mortality within 30 days • Based on assigned risk class, patients were classified as having mild (I, II), moderate (III) or severe (IV, V) disease • Patients in risk classes I, II and III can often be managed as outpatients, whereas those in classes IV and V are at higher risk of death and often require hospitalization* *mortality risk class IV = 9 - 12%, class V = 30%

27. Severity DemographicsGemifloxacin ITT

28. FDA Analysis of Clinical Response by Severity

29. Clinical Response in Hospitalized Patients • Hospitalization used as a criterion to assess the effectiveness of gemifloxacin in severe cases CAP • Questions regarding appropriateness of using hospitalization as a sole determinant of severity • Decision to hospitalize was investigator-driven and may have varied according to geographic location • Only in study 185 were all patients hospitalized as per protocol for at least 24 hours • Comparable efficacy between treatment arms

30. FDA Analysis of Clinical Response in Bacteremic Patients

31. Severity and Mortality

32. Severity and Precedents • Two quinolones, levofloxacin and moxifloxacin have a severe disease claim; both with PO and IV formulations • Criteria for determining severity differed but were applied at the time of randomization in both applications that received an approval. • Criteria were used to determine mode of treatment as well as duration. • Most of the severe patients in the levofloxacin NDA received IV treatment. • Moxifloxacin claim was granted after FDA review of the IV formulation.

33. Streptococcus pneumoniae • Sponsor is requesting approval for penicillin, macrolide, and cefuroxime resistant S. pneumoniae Data also submitted on quinolone-resistant S. pneumoniae • Levofloxacin and moxifloxacin have the indication of PRSP • No antimicrobial currently has an MRSP indication • PRSP and MRSP discussed at January 2003 AIDAC • No previous claims for cefuroxime-resistant PRSP • What is the clinical relevance of Macrolide- and Cefuroxime-resistant S. pneumoniae in the setting of penicillin resistance?

34. Penicillin Resistant Streptococcus pneumoniae Agency and sponsor in agreement that: • 12 BPP gemifloxacin-treated patients had Streptococcus pneumoniae isolates with penicillin MICs of  2mcg/mL (3 of these had MICs of 4 mcg/mL) • Clinical success and bacteriological eradication rates in the PP patients with PRSP were 100% • Four (4) comparator arm patients had PRSP with 100% clinical success and bacteriological eradication rates

35. Macrolide Resistant Streptococcus pneumoniae 25 gemifloxacin-treated PP patients with Streptococcus pneumoniae had macrolide resistant isolates (clarithromycin MIC  1mcg/mL) • Clinical success and bacteriologic eradication rates were 22/25 (88%) PP • 10 isolates (40%) were also penicillin-resistant 12 comparator-treated PP patients had macrolide resistant Streptococcus pneumoniae • Clinical success and bacteriologic eradication rates were 11/12 (91.6%) PP • 3 isolates (25%) were also penicillin-resistant

36. Cefuroxime-resistant Streptococcus pneumoniae • 18 patients had cefuroxime -resistant Streptococcus pneumoniae isolates (MIC  4 mcg/mL) • Clinical success and bacteriological eradication rates at follow-up were 17/18 (94.4%) • 12 out of the 18 cefuroxime-resistant isolates were also PRSP (67%) • 15 of the 18 cefuroxime-resistant isolates were also clarithromycin resistant (83%) • On the comparators arm there were 7 patients with Streptococcus pneumoniae isolates (PP) resistant to cefuroxime that were all successfully treated (ITT 8)

37. Quinolone-resistant Streptococcus pneumoniae • In the gemifloxacin group of the combined studies population, there were no pathogens resistant to ofloxacin and levofloxacin • 1 resistant isolate on the all comparators arm (failure) • In the gemifloxacin group there were 4 isolates of Streptococcus pneumoniae with an MIC against ciprofloxacin of 4 mcg/mL (clinical success and bacteriological eradication rate: 100%)

38. Acute Bacterial Exacerbation of Chronic BronchitisFactive (gemifloxacin) NDA 21-158 Eileen Navarro, MD

39. ABECBApplicant’s Proposed Label Indication and Claim “FACTIVE is effective for the treatment of acute exacerbations of chronic bronchitis due to H. influenzae, M. catarrhalis, S. pneumoniae, H. parainfluenzae and S. aureus.” “earlier eradication of H. influenzae from the sputum”

40. Issues in Applicant’s Additional Findings : • “Superior clinical efficacy” • “Prolonged exacerbation-free intervals” • “Efficacy in hospitalized severe ABECB” • “no requirement for an IV to oral switch” • results in earlier time to hospital discharge • reduces RTI related hospitalization LIMITATIONS: • Study design issues • Adjustments for multiple comparisons • Clinical relevance

41. Efficacy in Principal Studies

42. Early BacterialEradication in ABECB • Patients with H. influenzae represent only a small • proportion of patients with ABECB in the clinical • studies • In patients with H. influenzae, no clear correlation • of early eradication with clinical benefit • Early eradication related to pharmacokinetics • Eradication favored comparators in some pivotal • studies

43. Clinical Success - ITT AnalysisSupportive Studies

44. Applicant’s Finding: Superiority over Comparators ITT - Considerations • A finding limited to the ITT population of Supportive Studies 069 and 207 • Primary analysis of clinical efficacy (PP) - non-inferiority • Similar response rates in the secondary analyses of Bacterial Efficacy in the BPP and BITT • Pivotal ABECB studies do not show superiority for Clinical Efficacy in ITT and PP population.

45. Efficacy in Severe ABECBStudy 207- Considerations • Non-inferior to parenteral therapy in hospitalized ABECB • open label, non-US study • hospitalized patients able to tolerate oral therapy limits applicability to ALL hospitalised patients requiring parenteral therapy • Earlier time to discharge (mean difference of 0.5 days) • clinical significance of a 0.5 day difference • multiple secondary endpoints • no difference in primary outcome • no difference in other related outcomes (time to resolution, indirect costs)

46. Prolonged Time to Next Exacerbation & Reduced Respiratory Tract Related Hospitalization - Considerations Prolonged Time to Next Exacerbation • 3 studies - contradictory outcomes • one showed a trend favoring FACTIVE (Study 139), one favored the comparator (Study 105) • Study 112 -primary analysis showed no difference Reduced Respiratory Tract Related Hospitalization • Analyses not adjusted for multiple comparisons • No difference in other related outcomes (e.g. indirect costs)

47. Quinolone: levofloxacin ofloxacin moxifloxacin ciprofloxacin gatifloxacin Macrolide: clarithromycin azithromycin Beta lactam: amoxicillin/clavulanate cefaclor ceftibuten cefuroxime axetil cefdinir cefditoren pivoxil cefixime cefpodoxime loracarbef Partial List of Approved Products for ABECB

48. Anti-infective Use in ABECB- Considerations

49. Summary • FACTIVE clinical efficacy non-inferior to comparators in ABECB • Unresolved questions regarding clinical relevance or applicability of other findings • Limited evidence supporting other findings • Potential impact of broader use in the community

50. Safety of Factive(gemifloxacin)NDA 21-158 Maureen R. Tierney, MD, MSc. Medical Officer FDA