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AVELOX  (moxifloxacin HCl) NDA # 21-085

AVELOX  (moxifloxacin HCl) NDA # 21-085. Introduction Carl E. Calcagni, R.Ph. Vice President, Regulatory Affairs Bayer Corporation, Pharmaceutical Division. AVELOX  (moxifloxacin HCl) NDA # 21-085. Bayer Corporation - a global leader in the development of quinolones and anti-infectives

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AVELOX  (moxifloxacin HCl) NDA # 21-085

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  1. AVELOX (moxifloxacin HCl)NDA # 21-085 Introduction Carl E. Calcagni, R.Ph. Vice President, Regulatory Affairs Bayer Corporation, Pharmaceutical Division

  2. AVELOX (moxifloxacin HCl)NDA # 21-085 Bayer Corporation - a global leader in the development of quinolones and anti-infectives • Cipro Tablets approved in 1987 • 12 years of marketed clinical experience in the USA • Over 200 million patients treated worldwide

  3. AVELOX (moxifloxacin HCl)NDA # 21-085 Advanced generation quinolone (1994 Bayer AG, Leverkusen, Germany) Synthesized and developed: • to cover respiratory tract pathogens by enhancing Gram positive and atypical activity • to provide longer half-life to ensure QD dosing • to improve compliance by shorter course of therapy and good tolerability • to potentially minimize antibiotic resistance • to provide new alternative for community RTI treatment

  4. AVELOX (moxifloxacin HCl)NDA # 21-085 • Current Approval Status • Mexico (December 1998) • Germany (July 1999) • Argentina (August 1999) • Switzerland (August 1999) • Vietnam (August 1999) • Colombia (September 1999) • EU Mutual Recognition Procedure in Final Stages

  5. AVELOX (moxifloxacin HCl)NDA # 21-085 Objectives • To demonstrate that moxifloxacin is safe and effective for: • Acute Bacterial Exacerbations of Chronic Bronchitis • Acute Sinusitis • Community Acquired Pneumonia • Uncomplicated Skin/Skin Structure Infections • To review the observation of QTc prolongation with moxifloxacin, assess relative risk factors and present submitted labeling that is appropriate and responsible

  6. AVELOX (moxifloxacin HCl)NDA # 21-085 Dosage Administration and Proposed Indications Indication Duration Acute Bacterial Exacerbation of Chronic 5 Days Bronchitis Uncomplicated Skin and Skin Structure 7 Days Infections Acute Sinusitis 10 Days Community Acquired Pneumonia 10 Days One 400 mg tablet taken once daily

  7. Agenda Introduction: Carl E. Calcagni, R.Ph. Vice President, Regulatory Affairs, Bayer Efficacy/Safety: Deborah Church, M.D. Director Anti-Infectives, Medical, Bayer QTc Background: Joel Morganroth, M.D. Clinical Professor of Medicine, University of Pennsylvania QTc Data: Alan Hollister, M.D., Ph.D., FACP Deputy Director, Clinical Pharmacology, Bayer Risk/Benefit & Stephen H. Zinner, M.D. Conclusion: Charles S. Davidson Professor of Medicine, Harvard Medical School Chair, Department of Medicine, Mount Auburn Hospital

  8. Experts John DiMarco, M.D., Ph.D. Director, Clinical Electrophysiology Laboratory Associate Division Head, Cardivascular Division University of Virginia Gerald Faich, M.D., M.Ph. President Pharmaceutical Safety Assessments, Inc. Lance Peterson, M.D. Professor of Pathology and Medicine Director, Clinical Microbiology Laboratory Northwestern University David Talan, M.D., F.A.C.E.P., Professor of Medicine, UCLA F.I.D.S.A Chair, Faculty of Infectious Diseases Olive View-UCLA Medical Center Lowell Young, M.D. Clinical Professor of Medicine University of California, San Francisco Chief, Division of Infectious Diseases California Pacific Medical Center

  9. FDA Advisory Committee Moxifloxacin Efficacy & Safety Deborah A. Church, M.D. Director, Anti-Infectives Medical Department Bayer Corporation

  10. Efficacy Rationale for Development Microbiology Drug resistance PK/PD Clinical / bacteriologic results for AS, AECB, CAP and SSSI Outcomes Analysis Safety Dosing and Metabolism Drug Interactions Extent of Exposure Adverse Events Premature Discontinuations Serious Adverse Events Deaths Selected quinolone-related events Overview

  11. Moxifloxacin: Rationale for Development

  12. Rationale for Development • Respiratory tract infections still account for significant morbidity and mortality • Drug resistance has increased over time, underscoring evolutionary adaptiveness of microorganisms • New antibiotics and a change in selection/use may be needed to alter these trends • Potent, new fluoroquinolones should have an important place in the management of infectious diseases

  13. Decreasing Penicillin/Macrolide Susceptibility of S. pneumoniae in the US % Susceptible Spika et al. Doern et al. MRL RTI Surveillance Study, 1997-1998, Data on File

  14. Rationale for the Design of Moxifloxacin Increased knowledge of quinolone structure-activity relationship facilitates rational design, providing for: • Excellent Gram-negative coverage plus enhanced Gram-positive, atypical and anaerobe activity • Innovative approach to resistance in terms of efflux and mechanisms of action • Optimal pharmacokinetics and pharmacodynamics (i.e., selection of appropriate dose) • Favorable safety profile

  15. Chemical Structure of Moxifloxacin • Minimizes efflux (S. pneumoniae, S. aureus) • Enhances gram-positive activity OH O F 4 5 O 3 6 2 H 7 N 1 8 N *HCI NH O H3C H • Minimizes development of resistance • Enhances anaerobic activity Petersen et al 1996 Domagala, JM 1994

  16. Microbiology of Moxifloxacin

  17. In Vitro Activity of Moxifloxacin Against Key RTI Pathogens Pathogen(# of isolates) MIC90 (g/mL) 0.250.250.25 0.060.06 0.060.06 0.12510.06 Strain Penicillin-SusceptiblePenicillin-IntermediatePenicillin-Resistant  -Lactamase negative -Lactamase positive  -Lactamase negative -Lactamase positive Legionella spp. (149)Chlamydia pneumoniae (19)Mycoplasma pneumoniae (131) S. pneumoniae(6636) H. influenzae(1892) M. catarrhalis(1203) Atypicals NDA Data on File

  18. In Vitro Activity of Moxifloxacin Against Other RTI Pathogens Pathogen (# of isolates) MIC90 (g/mL) 0.25 1 0.125 (MS*)4 (MR*) 0.25 H. parainfluenzae(81) K. pneumoniae(138) S. aureus(835) S. pyogenes(1607) MS* = Methicillin Susceptible, MR* = Methicillin Resistant

  19. Moxifloxacin is active against: A wide variety of clinically important anaerobic species BacteroidesPeptostreptococcus (MIC90 2 g/mL) (MIC90 0.25 g/mL) MIC90 value is less than 2 mg/mL for the majority of anaerobes Active against M. tuberculosis (MIC90 0.5 g/mL) In Vitro Activity of Moxifloxacin Against Other Pathogens

  20. Moxifloxacin MIC90 for S. pneumoniae is Unaffected by Resistance to Penicillin MIC: g/mL MRL RTI Surveillance Study, 1997-1998. MRL Pharmaceutical Services MXF, moxifloxacin; LEV, levofloxacin; CIP, ciprofloxacin; CLR, clarithromycin; AZM, azithromycin; AMC, amox/clav; CXM cefuroxime.

  21. Moxifloxacin and Drug Resistance

  22. Mechanisms of Resistance and Quinolones Mutations in the norA gene that upregulate membrane-associated drug efflux pump • Despite increased antibiotic efflux from norA-containing S. pneumoniae and S. aureus, moxifloxacin MICs remain identical to wild type Mutations in topoisomerase IV (grlA and grlB) and DNA gyrase (gyrA and gyrB) • Simultaneous independent mutations in both grlA and gyrA are required to increase moxifloxacin MICs; even when this occurs, MICs are still near clinically observed Cmin

  23. 0 2 4 6 8 Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin (S. pneumoniae 4241) 100 10 Slow development of resistance to MXF and to a lesser extent than LEV. MIC: g/mL 1.0 0.1 100 Number of Passages from serial exposure at 0.5 x MIC = LEV = MXF Data on File

  24. 0 2 4 6 8 Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin(S. aureus 133) 100 10 Slow development of resistance to MXF and to a lesser extent than LEV. MIC: g/mL 1.0 0.1 100 Number of Passages from serial exposure at 0.5 x MIC = LEV = MXF Data on File

  25. No Development of Moxifloxacin Resistance in Rat Granuloma Pouch Model Dalhoff. Moxifloxacin in Practice. P 81, 1999. Dosing regimens: 100 mg/kg/day starting 1 h postinfect; 100 mg/kg/day, starting 24 h postinfection; 50 mg/kg/day, starting 24 h postinfection. MICs for each dosing regimenwere the same.

  26. Moxifloxacin: Minimization of the Emergence of Resistance Summary • Targeting of both DNA gyrase and topoisomerase IV has been achieved • Minimization of resistance has been demonstrated in: • in vitro: minimal changes in MIC under selective pressure, in contrast to levofloxacin. • animal studies: no emergence of resistance in rat granuloma pouch model. • These important results are achieved via the methoxy at C-8 (significantly delays the selection of resistance), and the bicyclic amine at C-7 (minimizes drug efflux)

  27. Moxifloxacin Pharmacokinetics and Pharmacodynamics

  28. VariableDay 1 Day 10 AUC (mg·h/L) 30.2 48 Cmax (mg/L) 3.36 4.52 Cmin (mg/L) 0.52 0.94 T1/2 (h) 9.3 12 6 5 4 Sullivan et al. ECCMID, 1997 3 2 1 0 0 4 8 12 16 20 24 28 Pharmacokinetics of Moxifloxacin Support Once Daily Oral Dosing of 400 mg Steady-State Plasma Concentrations of Moxifloxacin Obtained With Once Daily Dosing of 400 mg (mean;SD) (n=10) Plasma Concentration (mg/L) MIC90 0.25 (S. pneumoniae) 0.125 (S. aureus) 0.06 (H. influenzae) (M. catarrhalis) Time (hours)

  29. MXF Tissue: Plasma Ratio* LEV Tissue: Plasma Ratio** 21.2 + 10.0 1.7 + 0.3 8.7 + 6.1 7.3 / 6.8 1.3 / 1.8 0.8 / 3.0 2.0 + 0.3 ND Moxifloxacin and Levofloxacin Concentrations in Plasma and Respiratory Tissue Tissue or Fluid Plasma Concentration* (mg/ml) Tissue or FluidConcentration* (mg/mlor mg/g) Respiratory • Alveolar Macrophages • Bronchial Mucosa • Epithelial Lining Fluid 3.3 + 0.7 3.3 + 0.7 3.3 + 0.7 61.8 + 27.3 5.5 + 1.3 24.4 + 14.7 Sinus • Maxillary Sinus Mucosa 3.7 + 1.1 7.6 + 1.7 NDA Data on File *Mean ± SD measured 3H after dosing with 400 mg Andrews, et al. JAC 40:573-577, 1997 **Measured 2 and 4H after dosing with 500 mg

  30. Moxifloxacin Pharmacokinetics/Pharmacodynamics PK/PD Parameters that best correlate with Quinolone Efficacy* • Cmax / MIC90 > 8-10 • AUC / MIC90 > 100 *for review, see Craig, 1998

  31. Cmax/MIC90* Data for SelectedQuinolones^ * For optimal antibiotic effect and to minimize development of resistance, the Cmax/MIC90 ratio should be at least 8-10 (for review, see Craig 1998) ^ Clinical correlation not confirmed MXF PK data based on NDA Data on File; Levofloxacin, Ciprofloxacin (750 mg), Sparfloxacin, Grepafloxacin Data from PDR. RTI isolates from 1997-1998 Surveillance Study, MRL Pharmaceutical Sciences

  32. AUC/MIC90* Data for Selected Quinolones^ * For optimal antimicrobial effect and to minimize resistance, AUC/MIC90 should be > 100 (for review, see Craig 1998) ^ Clinical correlation not confirmed MXF PK data based on NDA Data on File; Levofloxacin, Ciprofloxacin (750 mg), Sparfloxacin, Grepafloxacin Data from PDR. RTI isolates from 1997-1998 Surveillance Study, MRL Pharmaceutical Sciences.

  33. Summary of Moxifloxacin PK/PD Attributes • Moxifloxacin PK supports qd dosing and provides plasma and tissue levels above the MIC90 for relevant respiratory pathogens for the entire 24 hour dosing interval • A 400 mg qd dose of moxifloxacin provides optimal PK/PD • Moxifloxacin PK results in optimal overall PD characteristics (Cmax/MIC;AUC/MIC) compared with other fluoroquinolones

  34. Moxifloxacin Clinical Development

  35. Phase II/Phase III Clinical Development Program • Phase II/III studies were performed in acute sinusitis, AECB, CAP and SSSI indications • FDA/IDSA guidelines were implemented • Primary efficacy variable was clinical outcome assessed at the test-of-cure • Secondary variables included bacteriological response and safety

  36. Phase II/Phase III Clinical Development Program (continued) • Treatment groups were tested for equivalence Definition: Lower limits of the two-sided 95% CI for the difference between groups [moxifloxacin - control] greater than - 10% • ITT safety population included all patients who took at least one documented dose ofstudy drug

  37. Phase II/III Studies* of Moxifloxacin in Patients with Infectious Diseases *NDA Data - # Valid for Safety (Intent-to-treat)

  38. Moxifloxacin NDA Phase III Acute Sinusitis Clinical Program

  39. Study Design Acute Sinusitis (North America) Clinical Resolution at Test-of-Cure 7 Days 10 Days 10 Days Total # Pts. - 191 336 % Cure - 81 80 Total # Pts. 223 - - % Cure 90 - - Total # Pts. 234 193 - % Cure 89 91 -

  40. 116 161 Acute Sinusitis (Ex-North America) Clinical Response at Test-of-Cure 7 Days 10 Days 10 Days Total # Pts. 195 - % Cure 90 - Total # Pts. - 217 % Cure - 94 Total # Pts. 212 222 % Cure 84 95

  41. S. pneumoniae H. influenzae M. catarrhalis Acute Sinusitis: Pathogen Eradication Rates at Test-of-Cure Visit* Moxifloxacin 400 mg Cefuroxime 250 mg BID 10 Days 7 Days #isolates %erad #isolates %erad 95 46 98 20 42 86 85 13 25 88 67 3 * Eradication + presumed eradication, Pathogens isolated by needle aspiration

  42. Conclusions for Acute Sinusitis • Both North American and Ex-North American studies demonstrate equivalence between 10 days of moxifloxacin and 10 days of cefuroxime • Microbiologic efficacy of 7 day moxifloxacin was demonstrated against the 3 target pathogens • Moxifloxacin given for 10 days is clinically and bacteriologically effective for the treatment of acute maxillary sinusitis

  43. Moxifloxacin NDAPhase IIIAcute Exacerbation ofChronic Bronchitis (AECB)Clinical Program

  44. Control* Moxifloxacin Study# Study Design (Location) 400 mg x 5 days 400 mg x 10 days D96-027 (NA) 124 (Ex-NA) Double-Blind Prospective Multi-center Double-Blind Prospective Multi-national AECB: (North America and Ex-North America) Clinical Resolution at Test-of-Cure # pts % cure # pts % cure # pts % cure 250 322 89 89 256 - 91 - 251 327 89 88 *D96-027 – Clarithromycin 500 mg BID x 10 days 124 – Clarithromycin 500 mg BID x 7 days

  45. Moxifloxacin 400 mg x 5 Days Clarithromycin 500 mg BID** Pathogen H. influenzae S. pneumoniae M. catarrhalis S. aureus K. pneumoniae H. parainfluenzae AECB: Overall Pathogen Eradication Rates* at Test-of-Cure (All studies pooled) #isolates 81 54 50 17 20 25 %erad 90 89 86 94 85 84 #isolates 84 59 48 19 11 18 %erad 64 95 98 84 91 100 *includes eradication + presumed eradication **10 day regimen for D96-027, 7 day regimen for 124

  46. Conclusions for Acute Exacerbation of Chronic Bronchitis • Moxifloxacin consistently demonstrated equivalence to comparator • Moxifloxacin is effective against the major pathogens associated with AECB • A five day treatment course is recommended based on the favorable clinical and bacteriologic results; the shorter duration may increase compliance and facilitate patient convenience

  47. Moxifloxacin NDA Phase IIIin Community-Acquired Pneumonia (CAP)

  48. Moxifloxacin Comparator* Study Study Design (Location) 400 mg x 10 days D96-026 (NA) D96-025 (NA) 119(Ex-NA) 0140(Ex-NA) Double-Blind Prospective Multi-center Open, Non- comparative Double-Blind Prospective Multinational Double-Blind Prospective Multinational CAP: (North America and Ex-North America) Clinical Resolution at Test-of-Cure # pts % cure # pts % cure 194 196 152 160 95 93 93 89 188 - 153 178 95 - 92 89 *119 and D96-026 – Clarithromycin 500 mg bid x 10 days 0140 - Amoxicillin 1 gm tid x 10 days

  49. Community-Acquired Pneumonia: Pathogen Eradication Rates* by Culture at Test-of-Cure * Eradication + presumed eradication ^by culture and/or serology ** Clarithromycin 500 mg BID X 10 days or Amoxicillin 1 gm tid X 10 days

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