FDA Advisory Committee April 26, 2001

1
FDA Advisory CommitteeApril 26, 2001

• KETEK (telithromycin)

2
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• VP, Clinical Development, Anti-Infectives,
  Aventis
• Microbiology André Bryskier, MD
• Human Pharmacology Vijay Bhargava, PhD
• Clinical Efficacy and Safety Bruno Leroy, MD
• ECG Analysis Claude Benedict, MD
• Conclusions Mindell Seidlin, MD

3
Need for New Antibiotics in Respiratory Tract
Infections

• Driven by the emergence of multi-resistant
  strains
• Availability of a new class reduces resistance
  pressure on any existing classes
• Maintain coverage of all key RTI pathogens
• Simple, short course of therapy
• Recent Policy statements recommend NEW drug
  development
• WHO
• HHS

4
Pathogens of Community RTIs in 2001

• Most significant
• S. pneumoniae
• multidrug resistance
• Other bacterial
• H. influenzae
• beta-lactamase ve
• M. catarrhalis
• beta-lactamase ve
• S. pyogenes

• Atypical / Intracellular
• C. pneumoniae
• M. pneumoniae
• L. pneumophila

Importance ofintracellular levels
Importance of plasmaand ECF levels
5
Recognition of Clinical Relevance of Penicillin
Resistance

• Impact of penicillin G nonsusceptibility was
  readily demonstrated in meningitis
• Recent outcome studies show impact for
  high-level resistance in pneumonia
• Turett et al., Feikin et al. showed associated
  mortality
• Metlay et al. showed association with increased
  suppurative complications
• PRSP relevant for pneumonia at MIC ?2
  µg/mL,Heffelfinger et al.
• gt60 of PRSP are multidrug resistant

6
Recognition of Clinical Relevance of
Erythromycin-Resistant S. pneumoniae

• 6 cases reported through 1992 (Lonks and
  Medeiros, Infect Med 199411415-424)
• Reports of failure are increasing
• Fogarty et al (3 azithromycin failures)
• Kelley et al (1 clarithromycin and 3 azithromycin
  failures)
• Waterer (azithromycin failure)
• All recently reported failures had S. pneumoniae
  with MIC ?8 µg/mL to erythromycin A

7
Evolution of Resistance of S. pneumoniae to
Erythromycin in the US
All resistant isolates MIC ?1 µg/mL
Resistant isolates with MIC ?8 µg/mL
M Phenotype
MLSB Phenotype
Resistant Isolates
Resistant Isolates
N2508
N3147
N3110
N3303
N3435
N2508
N3147
N3435
N3110
N3303
Source CDC Active Bacterial Core Surveillance
(ABCs)/Emerging Infections Program Network,
published and unpublished data.
8
Therapy of RTI

• Community-Acquired Pneumonia

Bacterial Infection
Risk DRSP Fluoroquinolone
Known DRSP Fluoroquinolone
No risk DRSP Macrolide Doxycycline Fluoroquinolone
9
Telithromycin

• Novel mechanism of action
• Excellent antipneumococcal activity
• Activity against Ery-R and Pen-R S. pneumoniae
• Activity against other common, intracellular, and
  atypical pathogens
• Short, simple course of treatment

10
Telithromycin Proposed Indications

• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis due to Group A
  beta-hemolytic streptococci (GABHS)

11
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• Microbiology André Bryskier, MD
• Senior Director, Clinical Microbiology,
  Aventis
• Human Pharmacology Vijay Bhargava, PhD
• Clinical Efficacy and Safety Bruno Leroy, MD
• ECG Analysis Claude Benedict, MD
• Conclusions Mindell Seidlin, MD

12
Telithromycin

• Telithromycin, the first ketolide, is designed to
  overcome erythromycin A resistance within
  gram-positive cocci

O
R
OCH3
9
N
6
O
D - desosamine
11
O
12
O
3
O
New chemical class (3keto)
Innovation(C11C12 carbamate)
O
O
13
Benefits of the 3Keto Function

• High stability in acidic environment
• Antibacterial activity against erm-containing
  gram-positive cocci
• Inability to induce MLSB resistance

3
O cladinose
3keto function
14
Benefits of Carbamate Residue and Side Chain at
Position C11 C12
N

• Reduced impact of efflux mechanism of resistance
• Enhanced antibacterial activity against
  gram-positive bacteria
• Governs intracellular accumulation and efflux in
  phagocytes

N
N
Butyl imidazolyl-pyridinylside chain
O
N
O
11
12
15
Telithromycin Mode of Action

• Inhibition of protein synthesis
• Depletion of ribosomes in bacterial cell

16
Inhibition of Protein Synthesis (1)

• Bacterial ribosome

30S
Target of erythromycin A and telithromycin is the
peptidyl transferase site located in 23S rRNA
50S subunit
17
Inhibition of Protein Synthesis (2)

• Inhibition of peptidyl transferase activity

Domain V
5S rRNA
30S
Domain II
Pocket peptidyl transferase site
50S
Erythromycin A
Telithromycin
V
V
2058
2058
5S rRNA
O
5S rRNA
-cladinose
O
O
II
II
752
752
18
Ribosomal Depletion

• Inhibition of ribosomal subunit formation

30S
50S
50S
30S
Erythromycin A
30S
Depletion of ribosome in the bacterial cells
Telithromycin
19
Consequence of Double Binding to 23S rRNA
Erythromycin A
Telithromycin
V
V
2058
2058
(methylation)
(methylation)
x
x
O
O
5S rRNA
5S rRNA
-cladinose
O
O
O
O
II
II
752
752
No link with domain V
Link with domain II
Resistance to erythromycin A,azithromycin,
clarithromycin
Telithromycin retains activity against
erythromycin A- resistant organisms
20
Telithromycin Activity Against Erythromycin
A-Resistant S. pneumoniae
Erythromycin A Telithromycin
Methylation (erm) Efflux (mef, msr,
mre) Mutation (ribosomal protein L4)
21
Telithromycin Antipneumococcal Activity (1)

• Cumulative susceptibility of 400 strains of S.
  pneumoniae

100
80
60
Cumulative susceptible
40
20
0
2
8
32
0.5
Source G Doern, 1999
0.03
0.12
0.008
MIC (µg/mL)
22
Telithromycin Antipneumococcal Activity (2)

• Potent antipneumococcal activity, including
  erythromycin A-resistant S. pneumoniae strains
• in vitro activity vs clarithromycin

MIC (µg/mL)
Telithromycin Clarithromycin
Phenotype N 50 90 50 90
Ery-S 537 0.01 0.03 0.03 0.06 Ery-R
(efflux) 47 0.25 0.5 2.0 4.0 Ery-R
(MLSB) 24 0.03 0.25 32.0 32.0
Source A Barry et al., 1997
23
Telithromycin Antipneumococcal Activity Against
Resistant Isolates
MIC (µg/mL)
N 50 90 Reference
Cefotaxime S 102 ? 0.008 0.25 1 I 168 0.06 0.5 1
R 148 0.06 1.0 1 Penicillin G S 1495 0.004 -
0.06 0.004 - 0.12 2 I 365 0.01 - 0.03 0.03 -
0.25 2 R 867 0.004 - 0.12 0.01 -
2.0 2 Tetracycline R 15 0.01 0.01 3 Cotrimoxazole
R 20 0.003 0.007 4 Ofloxacin R 15 0.001 -
0.03 0.001 - 0.03 3, 4
(1) A Barry et al, 2000 (2) Data from 14
laboratories (3) K Klugman et al, 1997 (4) R
Reinert et al, 1997
24
Telithromycin Bactericidal Activity

• Telithromycin exhibits bactericidal activity
  against S. pneumoniae resistant to erythromycin
  A and penicillin G (ermB)

9
8
7
6
Log10 cfu/mL
5
4
3
2
0
2
4
6
12
24
Time (hours)
Source P Appelbaum, 2000
25
Telithromycin In VivoAntipneumococcal Activity

• Efficacy confirmed in animal models
• disseminated infections in mice
• lung infections in mice
• using
• erythromycin Asusceptible strains
• erm and mefcontaining strains

26
Antipneumococcal Activity in North American
Isolates of S. pneumoniae Resistant to
Penicillin G and Erythromycin A
Resistance in 1999
USA a Canada
b n/N () n/N ()
Penicillin G 203/576 (35) 185/1333 (14) Erythromyc
in A 117/576 (20) 131/1333 (10) Telithromycin
c 0/576 1/1333
a Barry et al., 1999 b Hoban et al., 1999
c MIC of ?4.0 µg/mL
27
Telithromycin Main Respiratory Pathogens (North
America)
MIC range (µg/mL)
Number of centers
Number of strains
50
90
S. pneumoniae 8 2467 ?0.008 - 0.12 ?0.008 -
0.25 S. pyogenes 6 519 ?0.008 - 0.03 0.015 -
0.06 H. influenzae 5 1071 1.0 - 2.0 2.0 - 4.0 M.
catarrhalis 4 728 0.06 0.12 L. pneumophila 2 76 0.
015 - 0.06 0.03 - 0.12 C. pneumoniae a 1 15 0.03
- 2.0 0.03 - 2.0 M. pneumoniae 1 49 0.12 0.25
a MIC / MCC
28
Intracellular Concentration of Telithromycin in
Neutrophils
500
Intracellular concentration(neutrophils) - efflux
Intracellular accumulation
100
400
75
300
Roxithromycin
Uptake
Efflux
50
200
25
100
Roxithromycin
0
0
0
180
30
60
120
0
5
30
60
Time (min)
Time (min)

• Intracellular bioactivity demonstrated with C.
  pneumoniae, L. pneumophila, S. pneumoniae, and
  other intracellular pathogens

29
Microbiology of Telithromycin Summary (1)

• Telithromycin, the first ketolide, has a novel
  antibacterial mechanism of action
• Telithromycin exhibits antibacterial activity
  against common, atypical, and intracellular
  pathogens involved in community-acquired
  respiratory tract infections
• Telithromycin overcomes erythromycin A resistance

30
Microbiology of Telithromycin Summary (2)

• Telithromycin has rapid bactericidal activity
  against S.pneumoniae
• Does not induce MLSB resistance
• Low frequency of selection of resistant mutants
• Active against S. pneumoniae strains resistantto
  erythromycin A, penicillin G, tetracycline,
  cotrimoxazole, fluoroquinolones and cefotaxime

31
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• Microbiology André Bryskier, MD
• Human Pharmacology Vijay Bhargava, PhD Senior
  Director, Drug Metabolism and Pharmacokinetics
  , Aventis
• Clinical Efficacy and Safety Bruno Leroy, MD
• ECG Analysis Claude Benedict, MD
• Conclusions Mindell Seidlin, MD

32
Clinical Pharmacology Program

• Clinical pharmacology, bioavailability, and drug
  metabolism of telithromycin
• plasma and tissue pharmacokinetic characteristics
• multiple pathways of disposition and exposure in
  special populations
• pharmacokinetic/pharmacodynamic rationale for
  doses used in Phase III clinical efficacy program

33
Pharmacokinetics of Oral Telithromycin in
Healthy Subjects
800 mg single dose
800 mg multiple dose (7 d)
tmax (h)
1.0 a
1.0 a
0.5-4
0.5-3
Cmax (µg/mL)
1.9
2.3
(42)
(31)
C24h (µg/mL)
0.03
(72)
(45)
0.07
AUC(0-24h) (µg.h/mL)
8.3
(43)
(31)
12.5
7.2
(20)
t½,?z (h)
(19)
9.8
Data are mean (CV) Min-Max, N 18 a Median
34
Tissue and Fluid Penetration of Telithromycin in
Patients
Mean (CV) telithromycin concentration after 800
mg dose (µg/mL)
Tissue
2-3h
24h
12h
Epithelial lining fluid a
14.9
0.8
3.3
(76)
(62)
(51)
Alveolar macrophages a
69.3
161.6
318.1
(60)
(59)
(73)
Tonsils (µg/g) b
4.0
0.7
0.9
(13)
(40)
(56)
a Data from Honeybourne and Wise, N 5-7 b Data
from Gehanno, N 6-8
35
Other Key Pharmacokinetic Features

• Absolute bioavailability 60
• Serum protein binding 70
• Similar pharmacokinetics in men and women
• Similar pharmacokinetics with or without food

36
Pathways of Telithromycin Disposition
Oral administration (? 90 absorbed, lt10
unabsorbed)
Metabolism in liver and GI tract
First pass effect
(33)
Systemic bioavailability (57)
Renal excretion
GI tract/biliary
Hepatic excretion
(13)
(37)
(7)
Unchanged drug in feces
Unchanged drug in urine
Metabolized drug
½
½
CYP3A4-mediated
Non-P450 mediated
Telithromycin is not metabolized by CYP2D6
37
Effect of CYP3A4 Inhibition
First pass effect
Metabolism in liver and GI tract
Systemic bioavailability
Hepatic excretion
Metabolites
½
½
CYP3A4-mediated
Telithromycin ketoconazole N11
Telithromycin N11
AUC(0-24 h) (µg.h/mL) 14.4 (39) 28.6 (31) Cmax
(µg/mL) 2.0 (38) 3.1 (36)
t½,?z (h)
11.2 (26)
12.6 (27)
Data are mean (CV) telithromycin 800 mg qd (5
days), ketoconazole 400 mg qd (7 days)

• Itraconazole less interaction, grapefruit juice
  no interaction

38
Effect of Hepatic Impairment
Metabolism in liver and GI tract
First pass effect
Systemic bioavailability
Hepatic excretion
Renal excretion
Metabolites
Hepatic impairment N12
Healthy N12
Data are mean (CV) Mild impairment N 2
Moderate impairment N 5 Severe impairment N
5
39
Effect of Hepatic Impairment (Multiple Dose)
Metabolism in liver and GI tract
First pass effect
Systemic bioavailability
Hepatic excretion
Renal excretion
Metabolites
Hepatic impairment N12
Healthy N10
Day 1
Day 7
Day 1
Day 7
AUC(0-24h) (µg.h/mL)
9.5 (32)
12.3 (21)
9.0 (35)
13.8 (28)
Cmax (µg/mL)
1.6 (26)
1.8 (23)
1.7 (26)
2.0 (32)
t1/2, ?z (h)
12.5 (26)

10.6 (18)

CLR (L/h)
14.5 (50)
14.9 (47)
10.3 (20)
11.3 (16)
Data are mean (CV) Mild impairment N 4
Moderate impairment N 6 Severe impairment N
2
40
Effect of Renal Impairment
Systemic bioavailability
Renal excretion
Unchanged drug in urine
Renal function
gt80 N10
41 to 80 N10
11 to 40 N10
Creatinine clearance (mL/min)
Data are mean (CV)
41
Exposure in CAP Patients Elderly and
Non-Elderly (Phase III/Study 3000)
lt65 years N142
?65 years N20
AUC(0-24 h) (µg.h/mL) 18.1 (63) 25.9 (70) Cmax
(µg/mL) 2.8 (50) 3.5 (63)
Data are mean (CV)
42
Selection of Telithromycin Dose Regimen (Mouse
Thigh Infection Model - Craig)

• Effective dose was similar, irrespective of
  dosing frequency (3, 6, 12, 24 hours)
• Efficacy of telithromycin is concentration-depende
  nt rather than time-dependent
• AUC/MIC and Cmax/MIC are better predictors of
  efficacy than time above MIC

43
Selection of Telithromycin Dose Regimen Based on
PK/PD Model

• Dose in humans was chosen to give unbound AUC/MIC
  values similar to, or higher than, AUC/MIC values
  at effective dose in mice
• 800 mg once-daily dose regimen is supported by
  high tissue levels in humans

44
Dose Selection H. influenzae

• No well-validated animal model of lower RTI
• ELF peak levels (up to 14.9 µg/mL) exceed MIC90
  of H. influenzae
• Plasma and extracellular (ELF) levels for
  telithromycin (Cmax ELF/MIC 3.6 to 7.2) are
  well above those reported for azithromycin

45
Summary of Human Pharmacology

• Telithromycin rapidly achieved targeted plasma
  and respiratory tissue concentrations
• Telithromycin has a well-characterized and
  reproducible PK profile
• Multiple elimination pathways limit the potential
  for increased exposure in special populations
• The PK/PD profile of telithromycin supports an
  800 mg once-daily regimen

46
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• Microbiology André Bryskier, MD
• Human Pharmacology Vijay Bhargava, PhD
• Clinical Efficacy and Safety Bruno Leroy, MD
• Senior Director, Clinical Development, Anti-In
  fectives, Aventis
• ECG Analysis Claude Benedict, MD
• Conclusions Mindell Seidlin, MD

47
Clinical Efficacy of Telithromycin

• Study design across indications
• Clinical efficacy by indication
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis

48
Telithromycin Dosage Regimens in Phase III
Studies
Indication Dosage Duration

• CAP 800 mg qd 7-10 days
• AECB 800 mg qd 5 days
• Acute sinusitis 800 mg qd 5 days
• 800 mg qd 10 days
• Tonsillitis/Pharyngitis 800 mg qd 5 days

49
Generalized Study Design
50
Main Analysis Populations

• Population Definition

mITT All subjects with disease who received at
least one dose PPc All mITT subjects excluding
major protocol violators (clinically
evaluable) PPb All PPc subjects with a causative
pathogen isolated at pretherapy/ entry
(microbiologically evaluable)
51
Clinical Efficacy of Telithromycin

• Study design across indications
• Clinical efficacy by indication
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis

52
CAP Phase III Controlled Studies

• 3 randomized, controlled, double-blind,
  comparative trials (Western countries)

Study No.
Treatment
N (mITT)
3001
TEL
10 d
800 mg qd
199
AMX
10 d
1000 mg tid
205
3006
TEL
10 d
800 mg qd
204
CLA
10 d
500 mg bid
212
3009
TEL
7-10 d
800 mg qd
100
TVA
7-10 d
200 mg qd
104
TEL Telithromycin AMX Amoxicillin CLA
Clarithromycin TVA Trovafloxacin
53
CAP Other Studies

• 3 Phase III open-label studies (Western countries)

Study No.
Treatment
N (mITT)
3000
TEL
7-10 d
800 mg qd
240
3009 OL
TEL
7-10 d
800 mg qd
212
3010
TEL
7 d
800 mg qd
418

• 1 Phase II dose-comparison study (Japan)

2105
TEL
7 d
600 mg qd
46
TEL
7 d
800 mg qd
50
54
CAP Key Subject Background Characteristics, mITT
(Western Studies)
All CAP studies
Controlled studies
TEL Comparator TEL Subjects ()
with N503 N521 N1373
?65 years old 83 (17) 87 (17) 196 (14) Pneumococc
al 22 (4) 18 (4) 56 (4) bacteremia Fine
score ?III 84 (17) 105 (20) 220 (16) Consolidati
on 187 (37) 190 (36) 791 (58) Multiple
lobes 41 (9) 35 (7) 161 (12)
55
CAP Clinical Cure at TOC, PPc (Controlled
Studies, Western Countries)
2.1 11.1 a
7.9 7.5 a
13.6 5.2 a
100
94
95
90
90
89
88
80
60
40
20
143162
138156
141149
137152
7280
8186
0
3001 vs AMX
3006 vs CLA
3009 vs TVA
a 95 confidence intervals
56
CAP Clinical Cure at TOC, PPc(Uncontrolled
Studies, Western Countries)
TEL
n/N ()
Study
3000 183/197 (93) 3009 OL 175/187 (94) 3010 332/35
7 (93)
57
CAP Clinical Cure by Pathogen(All Western
Studies)
PPb population at TOC
TEL Comparator a
All Cultures n/N () n/N ()
S. pneumoniae 165/174 (95) 40/44 (91) H.
influenzae 95/105 (91) 27/27 (100) M.
catarrhalis 26/30 (87) 4/5 (80)
a Study 3001 Amoxicillin Study 3006
Clarithromycin Study 3009 Trovafloxacin
58
CAP Clinical Cure for Atypical Pneumonia in
Telithromycin Subjects (All Western Studies)
PPc population, subjects without other causative
pathogens
TOC LPTV a
n/N () n/N ()
Mycoplasma 30/31 (97) 24/26 (92)pneumoniae Ch
lamydia 32/34 (94) 27/29 (93)pneumoniae
Legionella 12/12 (100) 7/7 (100)pneumophila
a Late posttherapy visit (Day 31-45)
59
CAP Clinical Cure by Risk Factors for Morbidity
(Western Studies)
PPc population at TOC
All CAP studies
Controlled studies
TEL Comparator a TEL
n/N () n/N () n/N ()
Total population 356/391 (91) 356/394 (90)
1046/1132 (92) ?65 years old
53/60 (88) 56/66 (85) 139/154 (90)
Pneumococcal 15/15 (100) 11/13 (85) 43/47 (91)
bacteremia b Fine score
?III 56/61 (92) 65/78 (83) 161/175 (92)
a Study 3001 Amoxicillin Study 3006
Clarithromycin Study 3009 Trovafloxacin b PPb
population
60
CAP Clinical Cure forS. pneumoniae-Resistant
Isolates in Subjects Treated with Telithromycin
PPb population at TOC
n/N Subjects
All Western Japanese studies studies study
Single and multiple pathogens
Pen-R 16/19 13/16 3/3 Ery-R 21/25 13/16 8/9 Sing
le pathogens Pen-R 11/12 8/9 3/3
Ery-R 15/17 8/9 7/8
Pen-R Penicillin G-resistant (MIC ?2.0 µg/mL)
Ery-R Erythromycin A-resistant (MIC ?1.0 µg/mL)
61
CAP Clinical Cure for Subjects with
Pneumococcal Bacteremia (Treatment with
Telithromycin, All Western Studies)
PPb population at TOC
n/N Subjects
Single Single and pathogens multiple pathogens
All S. pneumoniae 38/40 43/47 Pen-R 4/5 4/6 Ery
-R a 2/3 4/6 Pen-R and/or Ery-R 5/6 7/9
Pen-R Penicillin G-resistant (MIC ?2.0 µg/mL)
Ery-R Erythromycin A-resistant (MIC ?1.0
µg/mL) a MIC to erythromycin A ranged from 4.0 to
32.0 for strains eradicated
62
Summary of Efficacy in CAP

• Treatment with telithromycin 800 mg once daily
  for 7 to 10 days is effective in CAP due to

• Common pathogens
• S. pneumoniae
• Pen-R strains
• Ery-R strains
• H. influenzae
• M. catarrhalis

• Atypical pathogens
• M. pneumoniae
• C. pneumoniae
• L. pneumophila

• Effective in outpatients at risk for
  complications (elderly, pneumococcal bacteremia,
  Legionella)

63
Clinical Efficacy of Telithromycin

• Study design across indications
• Clinical efficacy by indication
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis

64
AECB Phase III Studies
Study No.
Treatment
N (mITT)
3003 a
TEL
5 d
800 mg qd
160
AMC
10 d
500/125 mg tid
160
3007
TEL
800 mg qd
5 d
182
500 mg bid
10 d
191
CXM
AMC Amoxicillin/clavulanic acid CXM
Cefuroxime axetil
a Documented COPD
65
AECB Clinical Cure at TOC, PPc
6.4 14.3 a
5.8 12.4 a
100
87
86
83
82
80
60
40
20
99115
92112
121140
118142
0
3003 vs AMC
3007 vs CXM
a 95 confidence intervals
66
AECB Clinical Cure by Pathogen (Both Studies)
PPb population at TOC
TEL Comparator a 5 d 10 d
n/N () n/N ()
S. pneumoniae 12/14 (86) 8/12 (67) H.
influenzae 17/25 (68) 13/17 (76) M.
catarrhalis 10/10 (100) 14/16 (88) S.
aureus 2/2 (100) 3/3 (100)
a Study 3003 Amoxicillin/clavulanic acid, Study
3007 Cefuroxime axetil
67
AECB Clinical Cure for Atypical Pathogens (Both
Studies)
PPc population at TOC, subjects without other
causative pathogens
n/N ()
Chlamydia pneumoniae 10/11 (91) Mycoplasma
pneumoniae 1/1 (100)
68
AECB Clinical Cure by Baseline Characteristics
(Both Studies)
PPc population at TOC
TEL Comparator
n/N () n/N ()
Total Population 220/255 (86) 210/254 (83) ? 65
years old 79/90 (88) 90/114 (79) Morbidity
risk factors a At least 1 128/148 (87) 116/142
(82) At least 2 59/70 (84) 63/76 (83) FEV1/FVC
lt60 56/68 (82) 64/81 (79)
a COPD, pulmonary insufficiency, coronary
atherosclerosis, history of inhaled steroids,
diabetes mellitus, etc.
69
Summary of Efficacy in AECB

• Treatment with telithromycin 800 mg once daily
  for 5 days is effective in AECB due to
• S. pneumoniae
• H. influenzae
• M. catarrhalis
• S. aureus
• C. pneumoniae
• Effective in outpatients at risk for
  complications (elderly, significant obstruction)

70
Clinical Efficacy of Telithromycin

• Study design across indications
• Clinical efficacy by indication
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis

71
Acute Sinusitis Phase III Studies
Study No.
Treatment
N (mITT)
3002
TEL
5 d
800 mg qd
167
TEL
10 d
800 mg qd
168
3005
TEL
5 d
800 mg qd
201
TEL
10 d
800 mg qd
204
AMC
10 d
500/125 mg tid
202
3011
TEL
240
5 d
800 mg qd
CXM
116
10 d
250 mg bid
AMC Amoxicillin/clavulanic acid CXM
Cefuroxime axetil
72
Acute Sinusitis Clinical Cure at TOC, PPc
7.7 7.9 a
12.7 9.5 a
7.1 13.4 a
100
91
91
9.9 11.7 a
85
82
80
75
75
73
60
40
121133
102137
7389
112123
110146
102140
161189
20
0
3002
3005 vs AMC
3011 vs CXM
a 95 confidence intervals
73
Acute Sinusitis Clinical Cureby Pathogen (All
Studies)
PPb population at TOC
TEL 5 d TEL10 d
n/N () n/N ()
S. pneumoniae 55/61 (90) 27/30 (90) H.
influenzae 42/48 (88) 15/16 (94) M.
catarrhalis 13/14 (93) 3/4 (75) S.
aureus 18/19 (95) 4/4 (100)
74
Acute Sinusitis Clinical Cure for S.
pneumoniae-Resistant Isolates in Subjects Treated
with Telithromycin (All Studies)
PPb population at TOC, according to treatment
duration
n/N Subjects
5 and 5 days 10 days 10 days
Single and multiple pathogens
Pen-R 8/10 3/3 11/13 Ery-R 12/14 6/7 18/21 Singl
e pathogens Pen-R 6/8 3/3 9/11
Ery-R 8/10 5/6 13/16
Pen-R Penicillin G-resistant (MIC ?2.0 µg/mL)
Ery-R Erythromycin A-resistant (MIC ?1.0 µg/mL)
75
Summary of Efficacy in Acute Sinusitis

• Treatment with telithromycin 800 mg once daily
  for 5 days is equivalent to 10 days of standard
  treatment given 2 to 3 times daily
  (amoxicillin/clavulanic acid, cefuroxime axetil)
• Telithromycin 800 mg once daily for 5 days is
  effective in acute sinusitis due to
• S. pneumoniae
• Pen-R strains
• Ery-R strains
• H. influenzae
• M. catarrhalis
• S. aureus

76
Clinical Efficacy of Telithromycin

• Study design across indications
• Clinical efficacy by indication
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis (AECB)
• Acute sinusitis
• Tonsillitis/Pharyngitis

77
Tonsillitis/Pharyngitis Phase III Studies
Study No.
Treatment
N (mITT)
3004
TEL
5 d
800 mg qd
198
PEN
10 d
500 mg tid
197
3008
TEL
5 d
800 mg qd
232
CLA
10 d
250 mg bid
231
PEN Penicillin VK CLA Clarithromycin
78
Tonsillitis/Pharyngitis Bacterial Eradication
by Subject at TOC, PPb (Both Studies)
14.3 4.8 a
4.6 11.0 a
100
91
89
88
84
80
60
40
20
97115
106119
137150
119135
0
3004 vs PEN
3008 vs CLA
a 95 confidence intervals
79
Summary of Efficacy in Tonsillitis/Pharyngitis

• Treatment with telithromycin 800 mg once daily
  for 5 days is effective in GABHStonsillitis/phary
  ngitis
• Equivalence demonstrated between 5-day
  telithromycin treatment and 10-day standard
  treatment (penicillin VK 500 mg tid or
  clarithromycin 250 mg bid)

80
Summary of Efficacy in RTIs (1)

• Efficacy results consistent across analysis
  populations in 13 studies in 4 indications
• 5-day treatment effective in AECB, acute
  sinusitis and tonsillitis/pharyngitis vs 10-day
  treatment with comparators
• 7 to 10-day treatment effective in CAP

81
Summary of Efficacy in RTIs (2)

• Effective in subjects at risk for complications
  
• CAP elderly, pneumococcal bacteremia, Legionella
  infection
• AECB elderly, significant obstruction (FEV1/FVC
  lt 60)
• Effective in infections (CAP, acute sinusitis)
  due to S. pneumoniae resistant to penicillin G
  and erythromycin A

82
Safety Results

• Phase III
• general adverse event profile
• serious adverse events
• laboratory abnormalities
• ECG analysis

83
Subjects () in Phase III Safety Population
Total Controlled Uncontrolled TEL TEL TEL
N3265 N2045 N1220
Men 1631 (50.0) 949 (46.4) 682 (55.9) Women 1634
(50.0) 1096 (53.6) 538 (44.1) 13-18 years 95
(2.9) 68 (3.3) 27 (2.2) ?65 years 372
(11.4) 257 (12.6) 115 (9.4)
Subjects who received ?1 dose and safety
assessment following randomization
84
Subjects () with Treatment-Related Adverse
Events (? 2) (Controlled Phase III Studies)
TEL Comparator N2045 N1672
All Treatment-rel. AEs 712 (34.8) 465 (27.8) Dia
rrhea 272 (13.3) 158 (9.4) Nausea 166 (8.1) 64 (3
.8) Dizziness 73 (3.6) 26 (1.6) Vomiting 57 (2.8
) 24 (1.4) Headache 45 (2.2) 51 (3.1) Taste
perversion 34 (1.7) 35 (2.1) Blurred
vision 10 (0.5) 0 (0)
85
Subjects () with Discontinuations Due to Adverse
Events (Controlled Phase III Studies)
TEL Comparator N2045 N1672
All adverse events 98 (4.8) 73 (4.4) Treatment-rel
ated AEs 76 (3.7) 51 (3.1) GI related events 54
(2.6) 33 (2.0) Diarrhea 19 (0.9) 13
(0.8) Nausea 18 (0.9) 9 (0.5)
Vomiting 19 (0.9) 6 (0.4) Other events 25
(1.2) 18 (1.1)
86
Prevalence of Diarrhea for Telithromycin vs
Comparator Drugs (Controlled Phase III Studies)
Subjects
Clarithromycin
Amoxicillin/ clavulanic acid
Cefuroxime axetil
Day
Prevalence included for each day from onset
through last day of occurrence.
87
Treatment-Related Adverse Eventsby Age
(Controlled Phase III Studies)
Subjects
100
TEL
Comparator
80
60
36
40
28
29
27
26
19
20
1968
1369
6231720
385 1343
70 257
67260
0
13-18 yr
?18 ?65 yr
?65 yr
Age
88
Summary of Mortality(All Phase III Studies)

• Controlled studies Telithromycin 2 Comparator
  4
• Uncontrolled studies Telithromycin 5
• No treatment-related deaths
• Deaths occurred in CAP subjects(telithromycin
  7/1415 0.5)

89
Serious Adverse Events(Controlled Phase III
Studies)
N () Subjects
TEL Comparator N2045 N1672
All serious adverse events 40 (2.0) 41 (2.5) All
treatment-related serious AEs 8 (0.4) 4 (0.2) A
llergic reaction 2 (0.1) 1 (0.06) Asymptomatic
transaminase elevation 2 (0.1) 0 (0) Pseudo
mem colitis a 1 (0.05) 1 (0.06) Erythema
multiforme 1 (0.05) 0 (0) Gastroenteritis 1 (0.0
5) 1 (0.06) Vomiting 1 (0.05) 0 (0) Dyspnea 0
(0) 1 (0.06)
a Toxin C. difficile negative
90
Subject 0502/1069

• 53 year-old man with CAP and baseline elevated
  transaminases,
• eosinophilia, history of diabetes, asthma, 3
  recent courses
• of macrolides
• Episode 1 four days after completing
  telithromycin, new onset of fever and diarrhea
  peak ALT 1529 U/L 8 days later
• Biopsy (6 days after peak transaminase)
  centrilobular necrosis, granulomas,
  eosinophil/plasma cell infiltration
• Resolved with return to baseline levels 8 weeks
  after starting therapy
• Episode 2 asymptomatic transaminase increase
  (1331 U/L ALT) 9 months after telithromycin
  therapy, with normalization 10 weeks later
• Second biopsy (7 weeks after peak transaminase)
  centrilobular hepatic cell depletion without
  frank necrosis, plasma cell infiltration,
  bridging fibrosis

91
Hepatic Adverse Events(Controlled Phase III
Studies)
N () Subjects
TEL Comparator N2045 N1672
All hepatic adverse events 56 (2.7) 48 (2.9) Trea
tment-related hepatic AEs 40 (2.0) 33 (2.0) Hepat
ic AEs leading to 10 (0.5) 8 (0.5)
discontinuation
92
Frequency of Subjects with ALT ?3x ULN During
Treatment (Controlled Phase III Studies)
n/N () Subjects
ALT status at baseline Telithromycin Comparator
Normal 8/1646 (0.5) 5/1324 (0.4) ?
ULN 24/283 (8.5) 25/226 (11.1)
93
Distribution of ALT Values During Treatment in
Subjects with Normal ALT at Baseline (Controlled
Phase III Studies)
CAP Studies
Non-CAP Studies
90.0
89.3
81.7
78.2
Subjects
Subjects
18.2
16.5
9.8
9.4
2.5
1.0
0.8
0.3
0.5
0.3
0.4
0.6
0.2
0.2
0.1
0
0
0
0
0
?1
?2
?3
?5
? 8
ULN
ULN
ULN Upper limit of normal
94
Summary of Phase III Safety

• Well tolerated
• pattern of adverse events similar to macrolides
• GI events in the range seen with other
  antibiotics
• adverse event profile similar in different age
  groups
• rates of transaminase elevation similar to
  comparators
• Low incidence of serious adverse events and
  discontinuations, similar to comparators

95
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• Microbiology André Bryskier, MD
• Human Pharmacology Vijay Bhargava, PhD
• Clinical Efficacy and Safety Bruno Leroy, MD
• ECG Analysis Claude Benedict, MD Senior
  VP, Preclinical and Early Clinical
  Development, Aventis
• Conclusions Mindell Seidlin, MD

96
Background

• Macrolides have been associated with changes in
  cardiac repolarization
• Telithromycin is structurally derived from
  macrolides
• Extensive preclinical and prospective clinical
  investigation of potential effect of
  telithromycin on cardiac repolarization and
  comparison to macrolides and non-macrolides
• Program was designed in accordance with EU
  guidelines and FDA recommendations

97
Telithromycin Preclinical Studies

• Binding to membrane ionic channels (KATP,
  Kvoltage-dependent, KCa, Na, L-type Ca)
• Interaction with cloned channels(Ikr (HERG),
  Kv1.5, IKS)
• Studies on isolated human atrial cells(Ito,
  Ikur, AP duration)
• Rabbit Purkinje fibers
• bradycardia, hypokalemia
• interaction with sotalol and quinidine
• Studies in awake dogs

98
Plasma Levels and HERG Affinity of Selected
Antibiotics

• Peak free
• Oral dose plasma HERG IC50 Ratio
• Drug (mg) µM µM IC50/ plasma

Sparfloxacin 400 1.8 17.9 10 Moxifloxacin 400 5.9
129 22 Clarithromycin 500 1.9 54.5 29 Telithromyci
n 800 0.84 42.5 51 Erythromycin 1000 0.9 50.7 56 L
evofloxacin 500 12 915 76
Investigations on HERG were all conducted at the
same laboratory using the same methodology (CHO
cells).
99
ECG Phase III Analysis

• ECGs performed pre- and on-therapy (Day 3 to 5)
  and read by a single central reader in 10 Phase
  III studies (N1872 patients)
• 625 patients at risk for QT prolongation (33.4)
  included in Phase III program
• 1512 patients with a PK sample drawn within one
  hour of ECG
• QT measured as mean of longest and shortest QT
  intervals, corrected for heart rate by Bazett
  Formula (QTc)

100
QTc Values at Baseline and On-Therapy for
Telithromycin-treated Subjects
450
Baseline
On-Therapy
400
350
300
?QTc 1.0 21.1 ms
Number of Subjects
250
200
150
100
50
0
?310
330
350
370
390
410
430
450
470
490
510
530
QTc (ms)
101
?QTc from Baseline and QT Dispersion
Mean SD
?QTc QT dispersion Treatment N (ms) (ms)
Telithromycin (all studies) 1872 1.0 ? 21.1
21.0 ? 9.8 Telithromycin (controlled studies)
1368 2.3 ? 20.2 21.8 ? 9.2 All comparators
1234 -0.8 ? 20.6 22.3 ? 9.4 Beta-lactams
721 -3.2 ? 22.0 21.5 ? 9.6 Clarithromycin 414 2.
3 ? 18.1 23.7 ? 9.5 Trovafloxacin 99 1.4 ?
23.0 21.0 ? 8.5
102
?QTc vs Telithromycin Plasma Concentration
120
80
40
0
?QTc (ms)
-40
-80
N1512 patients Slope0.88 ms/µg/mL r20.0025,
p?0.05
-120
-160
0
2
4
6
8
10
12
Concentration (µg/mL)
103
?QTc vs Telithromycin Plasma Concentration
Concs ? 5µg/mL
Conc QTc ?QTc 5.2 410 -7.4 5.2 364 -24.5 5.2 4
11 13.1 5.2 409 -3.3 5.3 428 -0.9 5.8 431 17.0
6.2 425 1.5 6.2 410 10.1 6.4 391 -38.8 6.4 381
-5.1 6.4 393 -6.0 6.7 435 18.0 7.2 408 17.8 7
.8 396 0.1 9.9 427 8.7
120
80
40
0
?QTc (ms)
-40
-80
N1512 patients Slope0.88 ms/µg/mL r20.0025,
p?0.05
-120
-160
0
2
4
6
8
10
12
Concentration (µg/mL)
104
Frequency of QTc Outliers (Telithromycin vs
Clarithromycin)
n/N () Subjects
Telithromycin Clarithromycin
QTc increase ?30 and lt60 ms 30/393 (7.6) 29/414
(7.0) ?60 ms 0/393 (0) 0/414 (0) QTc
value ?450 ms, men 1/175 (0.6) 1/190 (0.5) ?470
ms, women 0/219 (0) 0/231 (0) ?500 ms, men or
women 0/394 (0) 0/421 (0)

• No telithromycin subjects had both QTc increase
  ?60 ms and QTc value ?450 ms (men) / ?470 ms
  (women)

105
Frequency of QTc Outliers (Telithromycin vs
Non-macrolides)
n/N () Subjects
Telithromycin Non-macrolidesa
QTc increase ?30 and lt60 ms 73/975 (7.5) 52/820
(6.3) ?60 ms 3/975 (0.3) 2/820 (0.2) QTc
value ?450 ms, men 17/480 (3.5) 10/417 (2.4) ?4
70 ms, women 4/508 (0.8) 1/427 (0.2) ?500 ms,
men or women 2/988 (0.2) 1/844 (0.1)
a Trovafloxacin, amoxicillin, cefuroxime axetil,
amoxicillin/clavulanic acid, penicillin VK

• No telithromycin subjects had both QTc increase
  ?60 ms and QTc value ?450 ms (men) / ?470 ms
  (women)

106
Clinical Risk Factors for QTc Prolongation (1)
?QTc (ms) N Mean SD
Gender Men 906 0.4 ? 22.9 Women 966 1.6 ?
19.3 Age lt 65 years 1653 1.1 ? 21.1 ? 65
years 219 0.0 ? 21.7 Hepatic Present 29 -2.4 ?
36.9Impairment Absent 1843 1.1 ? 20.8 Renal
CLCRlt 50 mL/min 40 0.8 ? 20.6Impairment CLCR?
50 mL/min 1832 1.0 ? 21.2 Concomitant Taking 154
3.2 ? 19.7CYP3A4 inhibitors Not taking 1718 0.8
? 21.3
107
Clinical Risk Factors for QTc Prolongation (2)
?QTc (ms) N Mean SD
Drugs metabolized Taking 251 1.0 ? 23.4by
CYP2D6 Not taking 1621 1.0 ? 20.8 QT-prolonging Ta
king 57 3.0 ? 18.7 drugs Not taking 1815 0.9 ?
21.2 Hypokalemia Present 103 -0.2 ? 20.4 or
diuretics Absent 1769 1.1 ? 21.2 Cardiovascular
Present 358 0.9 ? 21.1Disease Absent 1514 1.0 ?
21.2 Prolonged QTc Present 127 -18.0 ? 24.2at
baseline Absent 1745 2.4 ? 20.2
108
Association Between Baseline QTc and ?QTc
N 2 18 86 292 634 606 179 39 11 3 2
80
60
40
20
Mean ?QTc (ms)
0
20
40
60
Error bars show std deviation
80
?310
?350
?390
?430
?470
?510
Baseline QTc Interval (ms)
109
Incidence of Treatment-Related Adverse Events of
Special Interest in QT Interval Assessment
Number () Subjects
Telithromycin Comparators Adverse Event (N
2045) (N 1672)
Dizziness 73 (3.6) 26 (1.6) Vertigo 4 (0.2) 2 (0.1
) Palpitation 1 (0.05) 1 (0.1) Hypotension 1 (0.05
) 0 (0) Arrhythmia 0 (0) 2 (0.1) Ventricular
arrhythmia 0 (0) 0 (0) Torsades de pointes
0 (0) 0 (0) Syncope 0 (0) 0 (0)
110
Further Characterization of Telithromycin Effect
on Cardiac Repolarization

• Evaluation of concentration vs ?QT at up to 4
  times the therapeutic dose
• Evaluation of heart rate correction formulas for
  QT

111
Comparison between Correction Formulas for Heart
Rate Effects Using Data Obtained at Baseline
(Phase I Data)
QTc
QTf
QTn
QTc QT / (RR 0.5)
QTf QT / (RR 0.33)
QTn QT / (RR 0.284)
112
Relationship Between ?QTn and Concentration for
Telithromycin Doses from 800 to 3200 mg (Phase I
Data)
113
Drug Interactions of Special Interest

• Ketoconazole (potent CYP3A4 inhibitor)
• Cisapride (exclusively metabolized by CYP3A4)
• Sotalol (class III antiarrhythmic drug)

114
Effect of Telithromycin and Ketoconazole on ?QTn
?QTn Mean SD (ms)
Placebo
3 10
Telithromycin
3 11
Ketoconazole
10 9
Telithromycin Ketoconazole
9 8
N16
115
Drug Interaction Between Telithromycin and
Cisapride
Placebo N14
Cisapride 20 mg single dose N14
50
Telithromycin 800 mg once daily for 5 days, N14
40
Telithromycin 800 mg once daily for 6 days
cisapride 20 mg single dose, N14
30
20
Mean ?QTn SD (ms)
10
0
-10
-20
1
1.5
2
2.5
3
6
12
Time (hours)
116
Effect of Telithromycin on Sotalol-Induced
Prolongation of QTn
Placebo Telithromycin Sotalol Sotalol
Sotalol Cmax (µg/mL) 1.49 0.26 1.0 0.23 QTn
(ms) 469 4 451 4 ?QTn (ms) 76 5 58
5 Slope (ms/µg/mL) 45 48
Mean SD, N24

• Holter monitoring No rhythm disorders

117
Study in Subjects with CV Disease
Design/Population

• Single-dose, double-blind, randomized,
  placebo-controlled, 4-way crossover study
• Telithromycin 800 and 1600 mg, clarithromycin
  500 mg x2, placebo
• 24 high-risk subjects with underlying
  cardiovascular disease
• ECG and 24-hour Holter recording before and after
  dosing

118
Subjects with CV Disease Mean Changes in ?QTn
and ?QTc
Mean SD
TEL TEL CLA 800 mg 1600 mg 500 mg
Cmax (µg/mL) 1.8 0.9 3.1 1.0 2.5 1.2 ?QTn
(ms) -0.8 10 1.0 9.0 2.0 9.0 ?QTc (ms) 3.0
13 6.5 13.5 3.2 15
Data corrected for placebo

• Holter No arrhythmias recorded

119
Subjects with CV Disease ?QTn vs Telithromycin
Plasma Concentration
100
50
0
?QTn (ms)
-50
N 24 subjects (800mg 1600 mg TEL) Slope
1.53 ms/µg/mL
-100

0
2
4
6
Concentration (µg/mL)
120
?QTc vs Telithromycin Plasma Concentration in
RTI Patients with Cardiovascular Disease (Phase
III)
120
80
40
0
DQTc (ms)
-40
N 284 subjects Slope -0.42 ms/µg/mL r2
0.00069, p 0.65
-80
-120
-160
0
1
2
3
4
5
6
7
8
9
10
11
12
Concentration (µg/mL)
121
Summary of ECG Analysis (1)

• Telithromycin has a weak effect on IKr channels
• In patients with respiratory infections, the mean
  change in QTc observed was small (1 ms)
• Shallow relationship between QTc and plasma
  telithromycin concentrations over a wide range of
  concentrations
• No difference in the frequency of QTc outliers
  between telithromycin and macrolide and
  non-macrolide antibiotics

122
Summary of ECG Analysis (2)

• Analysis of at-risk subpopulations did not
  reveal a propensity for enhanced effect on
  cardiac repolarization
• No increase in the incidence of cardiovascular
  adverse events, including no torsades de pointes,
  no ventricular tachycardias, and no syncope
  associated with QT prolongation
• Limited risk due to brief duration of treatment
  and multiple pathways of elimination that limit
  exposure

123
Telithromycin Presentation Agenda

• Introduction Mindell Seidlin, MD
• Microbiology André Bryskier, MD
• Human Pharmacology Vijay Bhargava, PhD
• Clinical Efficacy and Safety Bruno Leroy, MD
• ECG Analysis Claude Benedict, MD
• Conclusions Mindell Seidlin, MD VP, Clinical
  Development, Anti-Infectives, Aventis

124
Medical Need for New Antibiotics

• Resistance in respiratory tract pathogens is
  increasing
• S. pneumoniae High level penicillin or macrolide
  resistance in gt15 strains
• threat of multi-drug resistance
• beta-lactamase strains of M. catarrhalis and
  H. influenzae
• increasing importance of atypical pathogens
• Respiratory infections are associated with
  significant morbidity and mortality
• more patients with underlying illness are being
  treated in the community

125
Microbiological and PK Features

• Telithromycin, the first ketolide, has
• two sites of interaction with 50S
  ribosomalsubunit also interferes with assembly
  of both ribosomal subunits
• potent in vitro antipneumococcal activity
• activity against erythromycin-resistant strains
• activity against common, intracellular, and
  atypical respiratory pathogens
• Well-characterized pharmacokinetic profile, with
  therapeutic plasma and sustained tissue levels

126
Summary of Efficacy in Respiratory Tract
Infections

• Consistently effective in all analyses in 13
  Phase III trials
• CAP
• elderly cure rate 90
• pneumococcal bacteremia cure rate 91
• atypical infections (including Legionella cure
  rate 100)
• AECB, Acute Sinusitis, Tonsillitis/Pharyngitis
• 5-day once-daily telithromycin treatment was
  equivalent to 10-day, 2-3 doses per day
  comparator treatment
• Efficacy in resistant S. pneumoniae infections in
  CAP and Acute Sinusitis

127
Summary of Safety

• Safety studied in a broad spectrum of patients
• incidence of GI events comparable to other widely
  used antibiotics
• hepatic events and transaminase elevation similar
  to comparators
• discontinuations and serious events equivalent to
  comparators
• small effect on QTc (1 ms mean increase) in
  patients with RTIs

128
The Advantages that Telithromycin Brings

• Highly effective in pneumococcal infections
• No cross-resistance in pneumococci to macrolides,
  beta-lactams, quinolones
• Effective against common, atypical, and
  intracellular RTI pathogens
• 5-day once-daily regimen for common infections
• Expands the options for outpatient management of
  RTIs