mm-1 fda advisory committee april 26, 2001 ketek ™ (telithromycin)

MM-1

FDA Advisory CommitteeFDA Advisory CommitteeApril 26, 2001April 26, 2001

KETEKKETEK™™ (telithromycin) (telithromycin)

MM-2

Telithromycin – Presentation Agenda

Introduction Mindell Seidlin, MDVP, 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

MM-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

MM-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

MM-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.

• >60% of PRSP are multidrug resistant

MM-6

Recognition of Clinical Relevance of Erythromycin-Resistant S. pneumoniae

• 6 cases reported through 1992 (Lonks and Medeiros, Infect Med 1994;11:415-424)

• 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

MM-7

Evolution of Resistance of S. pneumoniae to Erythromycin in the US

Source: CDC Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, published and unpublished data.

% R

esis

tan

t Is

ola

tes

0

10

20

30

1995 1996 1997 1998 1999

M Phenotype

MLSB Phenotype

All resistant isolatesMIC 1 µg/mL

N=2508 N=3147 N=3110 N=3303 N=3435

0

10

20

30

1995 1996 1997 1998 1999N=2508

% R

esis

tan

t Is

ola

tes

N=3147 N=3435

Resistant isolates withMIC 8 µg/mL

N=3110 N=3303

MM-8

Therapy of RTI

Community-Acquired Pneumonia

Bacterial Infection

Risk DRSPFluoroquinolone

Known DRSPFluoroquinolone

No risk DRSPMacrolide

DoxycyclineFluoroquinolone

MM-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

MM-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)

MM-11


Introduction Mindell Seidlin, MD

Microbiology André Bryskier, MDSenior Director, Clinical Microbiology, Aventis





MM-12

Telithromycin

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

O

O

O

OOCH3

O

9

6N

R

3

OO D - desosamine

New chemical class (3–keto)

Innovation(C11–C12 carbamate)

11

12

MM-13

Benefits of the 3–Keto Function

• High stability in acidic environment

• Antibacterial activity against erm-containing gram-positive cocci

• Inability to induce MLSB resistance

3O – cladinose

3–keto function

3O

MM-14

Benefits of Carbamate Residue and Side Chain at Position C11 – C12

• Reduced impact of efflux mechanism of resistance

• Enhanced antibacterial activity against gram-positive bacteria

• Governs intracellular accumulation and efflux in phagocytes

N

N

N

N

O

O

1211

Butyl imidazolyl-pyridinyl

side chain

MM-15

Telithromycin: Mode of Action

• Inhibition of protein synthesis

• Depletion of ribosomes in bacterial cell

MM-16

Inhibition of Protein Synthesis (1)

• Bacterial ribosome

30S

50Ssubunit

Target of erythromycin A and telithromycin is the peptidyl transferase site located in 23S rRNA

MM-17

Inhibition of Protein Synthesis (2)

• Inhibition of peptidyl transferase activity

5S rRNADomain V

Domain II

Pocket: peptidyl transferase site

5S rRNA5S rRNA

2058

752

V

II

V

II

Erythromycin A Telithromycin

2058

752

30S

50S

O O

O

OO

O

-cladinose

MM-18

Ribosomal Depletion

30S 50S

30S

50S

30S

Depletion ofribosome in thebacterial cells

Erythromycin A

Telithromycin

• Inhibition of ribosomal subunit formation

MM-19

Consequence of Double Binding to 23S rRNA

2058

752

V

II

V

II


2058

752

No link withdomain V

Resistance to erythromycin A,azithromycin, clarithromycin

Link withdomain II

Telithromycin retains activityagainst erythromycin A-

resistant organisms

5S rRNA5S rRNA-cladinoseOO

O

O O

O(methylation) (methylation)x x

MM-20

Telithromycin Activity Against Erythromycin A-Resistant S. pneumoniae


Methylation (erm) – +

Efflux (mef, msr, mre) – +

Mutation (ribosomal protein L4) – +

MM-21

Telithromycin: Antipneumococcal Activity (1)

• Cumulative susceptibility of 400 strains of S. pneumoniae

0

20

40

60

80

100

0.00

80.

030.

12 0.5 2 8 32

MIC (µg/mL)

Cu

mu

lati

ve%

su

scep

tib

le Telithromycin

Levofloxacin

Erythromycin A

Clarithromycin

Azithromycin

Linezolid

Source: G Doern, 1999

MM-22

Telithromycin ClarithromycinPhenotype N 50 90 50

90Ery-S 537 0.01 0.03 0.030.06

Ery-R (efflux) 47 0.25 0.5 2.04.0

Ery-R (MLSB) 24 0.03 0.25 32.032.0

Source: A Barry et al., 1997

MIC (µg/mL)

Telithromycin: Antipneumococcal Activity (2)

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

MM-23

Telithromycin: Antipneumococcal Activity Against Resistant Isolates

N 50 90 Reference

Cefotaxime S 102 0.008 0.25 1I 168 0.06 0.5 1R 148 0.06 1.0 1

Penicillin G S 1495 0.004 - 0.06 0.004 - 0.12 2I 365 0.01 - 0.03 0.03 - 0.25 2R 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

MIC (µg/mL)

MM-24

Telithromycin: Bactericidal Activity

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

2

3

4

5

6

7

8

9

0 2 4 6 12 24Time (hours)

Lo

g1

0 cf

u/m

L

8X MIC

4X MIC

2X MIC

MIC

0.5X MIC

0.25X MIC

Growth Control

Threshold

Source: P Appelbaum, 2000

MM-25

Telithromycin: In VivoAntipneumococcal Activity

• Efficacy confirmed in animal models:– disseminated infections in mice– lung infections in mice

using:• erythromycin A–susceptible strains• erm– and mef–containing strains

MM-26

Antipneumococcal Activity in North American Isolates of S. pneumoniae

Resistant to Penicillin G and Erythromycin A

a Barry et al., 1999; b Hoban et al., 1999

USA a Canada b

n/N (%) n/N (%)

Penicillin G 203/576 (35) 185/1333(14)

Erythromycin A 117/576 (20) 131/1333(10)

Telithromycin c 0/576 1/1333c MIC of 4.0 µg/mL

Resistance in 1999

MM-27

Telithromycin: Main Respiratory Pathogens (North America)

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

Number of centers

Number of strains 50 90

MIC range (µg/mL)

a MIC / MCC

MM-28

Intracellular Concentration of Telithromycin in Neutrophils

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

500

0

100

200

300

0 18030 60

Time (min)

% U

pta

ke

400

120

Intracellular accumulation

100

0

25

50

75

0 5 30 60

Time (min)

% E

fflu

x

Intracellular concentration(neutrophils) - efflux

Telithromycin

Azithromycin

Roxithromycin

Telithromycin

Azithromycin

Roxithromycin

MM-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

MM-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

MM-31




Human Pharmacology Vijay Bhargava, PhD Senior Director,

Drug Metabolism and Pharmacokinetics, Aventis




MM-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

MM-33

Pharmacokinetics of Oral Telithromycin in Healthy Subjects

800 mg single dose

800 mg multiple dose (7 d)

C24h (µg/mL) 0.03 (72)

AUC(0-24h) (µg.h/mL) 8.3 (43)

7.2 (20)t½,z (h)

Data are mean (CV%) [Min-Max], N = 18a Median

(19)

(31)

(45)

Cmax (µg/mL) 1.9 2.3(42) (31)

tmax (h) 1.0 a 1.0 a [0.5-4] [0.5-3]

0.07

12.5

9.8

MM-34

Tissue and Fluid Penetration of Telithromycin in Patients

Tissue

Mean (CV%) telithromycin concentration after 800 mg dose (µg/mL)

2-3h 24h

Alveolar macrophages a 69.3 161.6

Tonsils (µg/g) b 4.0 0.7

a Data from Honeybourne and Wise, N = 5-7b Data from Gehanno, N = 6-8

Epithelial lining fluid a

12h

0.9

14.9 0.83.3

318.1

(76) (62)(51)

(60) (59)(73)

(13) (40)(56)

MM-35

Other Key Pharmacokinetic Features

• Absolute bioavailability ~60%

• Serum protein binding ~70%

• Similar pharmacokinetics in men and women

• Similar pharmacokinetics with or without food

MM-36

Oral administration ( 90% absorbed, <10% unabsorbed)

Systemic bioavailability (57%)

Renal excretion

Unchanged drug in urine

GI tract/biliary Hepatic excretion

Unchanged drugin feces

Metabolized drug *

Metabolism in liver and GI tract First pass effect

Pathways of Telithromycin Disposition

(13%) (37%)(7%)

(33%)

Non-P450 mediated

CYP3A4-mediated

½ ½

* Telithromycin is not metabolized by CYP2D6

MM-37

First First pass effectpass effect

Telithromycin

N=11

Telithromycin +

ketoconazoleN=11

AUC(0-24 h) (µg.h/mL) 14.4 (39) 28.6 (31)

Cmax (µg/mL) 2.0 (38) 3.1 (36)

Data are mean (CV%): telithromycin 800 mg qd (5 days), ketoconazole 400 mg qd (7 days)

• Itraconazole: less interaction, grapefruit juice: no interaction

Effect of CYP3A4 Inhibition

Systemic Systemic bioavailabilitybioavailability

Hepatic Hepatic excretionexcretion

MetabolitesMetabolites

Metabolism in Metabolism in liver and GI tract liver and GI tract

CYP3A4-mediatedCYP3A4-mediated

½½½½

t½,z (h) 11.2 (26) 12.6 (27)

MM-38

Hepatic impairment

N=12HealthyN=12

Data are mean (CV%)Mild impairment: N = 2; Moderate impairment: N = 5; Severe impairment: N = 5

Effect of Hepatic Impairment

Cmax (µg/mL) (52) (43)2.0 2.3

AUC(0-z) (µg.h/mL) (37) (30)11.3 9.8

CLR (L/h) (43) (16)17.3 10.8

Systemic bioavailability

Renal excretion

Hepatic excretion

Metabolites

Metabolism in liver and GI tract

First pass effect

t½,z (h) 14.2 (14) 10.3 (27)

MM-39

Hepatic impairmentN=12

HealthyN=10

Day 1 Day 7 Day 1 Day 7

t1/2, z (h) 12.5 (26) – 10.6 (18)

CLR (L/h)

Cmax (µg/mL) 1.6 (26) 1.8 (23) 1.7 (26) 2.0 (32)

AUC(0-24h)

(µg.h/mL)9.5 (32) 12.3 (21) 9.0 (35) 13.8 (28)

–

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

Effect of Hepatic Impairment

(Multiple Dose)


Renal excretion

Hepatic excretion

Metabolites

Metabolism in liver and GI tract

First pass effect

MM-40

>80

N=10

41 to 80

N=10

11 to 40

N=10

Creatinine clearance(mL/min)

Data are mean (CV%)

Effect of Renal Impairment


Renal excretion

Unchanged drug in urine

Renal function

Cmax (µg/mL) 2.3 3.0 3.3(38) (26) (43)

AUC(0-z) (µg.h/mL) 10.0 14.2 15.8(35) (41) (46)

t½,z (h) 10.7 11.4 12.6(25) (13) (27)

MM-41

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%)

<65 yearsN=142

65 yearsN=20

Exposure in CAP Patients: Elderly and Non-Elderly (Phase III/Study 3000)

MM-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-dependent rather than time-dependent:– AUC/MIC and Cmax/MIC are better predictors of

efficacy than time above MIC

MM-43

• 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

Selection of Telithromycin Dose Regimen Based on PK/PD Model

MM-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

MM-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

MM-46





Clinical Efficacy and Safety Bruno Leroy, MDSenior Director, Clinical Development,Anti-Infectives, Aventis



MM-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

MM-48

Telithromycin Dosage Regimens in Phase III Studies

CAP 800 mg qd7-10 days

AECB 800 mg qd5 days

Acute sinusitis 800 mg qd5 days

800 mg qd10 days

Tonsillitis/Pharyngitis 800 mg qd

5 days

Indication Dosage Duration

MM-49

Generalized Study Design

Pretherapy/Entry

Comparator: 10 days

TEL:5 days

Placebo: 5 days

Posttherapy/TOC

Late Posttherapy

Telithromycin: 10 days

Visit 5(Day 31 to 36)

End ofTherapy

Visit 1(Day 1)

Visit 2(Day 3 to 5)



On Therapy Off Therapy

MM-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)

MM-51



• Clinical efficacy by indication:– Community-acquired pneumonia (CAP)


– Acute sinusitis


MM-52

CAP: Phase III Controlled Studies

Study No. Treatment

3001 TEL 10 d 800 mg qd

AMX 10 d 1000 mg tid

3006 TEL 10 d 800 mg qd

CLA 10 d 500 mg bid

TEL = Telithromycin; AMX = Amoxicillin; CLA = Clarithromycin; TVA = Trovafloxacin

3009 TEL 7-10 d 800 mg qd

TVA 7-10 d 200 mg qd

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

N (mITT)

199

205

204

212

100

104

MM-53

CAP: Other Studies

Study No. Treatment

3000 TEL 7-10 d 800 mg qd

3009 OL TEL 7-10 d 800 mg qd

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

N (mITT)

240

212

• 1 Phase II dose-comparison study (Japan)

3010 TEL 7 d 800 mg qd 418

2105 TEL 7 d 600 mg qd

TEL 7 d 800 mg qd

46

50

MM-54

CAP: Key Subject Background Characteristics, mITT (Western Studies)

65 years old 83 (17) 87 (17) 196 (14)

Pneumococcal 22 (4) 18 (4) 56 (4) bacteremia

Fine score:III 84 (17) 105 (20) 220 (16)

Consolidation 187 (37) 190 (36) 791 (58)

Multiple lobes 41 (9) 35 (7) 161 (12)

Controlled studies

TEL Comparator TELSubjects (%) with N=503 N=521 N=1373

All CAPstudies

MM-55

CAP: Clinical Cure at TOC, PPc (Controlled Studies, Western Countries)

95%88%

94%90%89%90%

0%

20%

40%

60%

80%

100%

3001 vs AMX 3006 vs CLA 3009 vs TVA

TEL (7-10 d) Comparator (10 d)

[–2.1; 11.1] a

143162

138156

141149

137152

7280

8186

a 95% confidence intervals

[–7.9; 7.5] a [–13.6; 5.2] a

MM-56

CAP: Clinical Cure at TOC, PPc(Uncontrolled Studies, Western Countries)

3000 183/197 (93)

3009 OL 175/187 (94)

3010 332/357 (93)

TEL

n/N (%)Study

MM-57

S. pneumoniae 165/174 (95) 40/44 (91)

H. influenzae 95/105 (91) 27/27 (100)

M. catarrhalis 26/30 (87) 4/5 (80)

TEL Comparator a

All Cultures: n/N (%) n/N (%)

CAP: Clinical Cure by Pathogen(All Western Studies)

a Study 3001: Amoxicillin; Study 3006: Clarithromycin; Study 3009: Trovafloxacin

PPb population at TOC

MM-58

Mycoplasma 30/31 (97) 24/26 (92)pneumoniae

Chlamydia 32/34 (94) 27/29 (93)pneumoniae

Legionella 12/12 (100) 7/7 (100)pneumophila

TOC LPTV a

n/N (%) n/N (%)

CAP: Clinical Cure for Atypical Pneumonia in Telithromycin Subjects

(All Western Studies)

a Late posttherapy visit (Day 31-45)

PPc population, subjects without other causative pathogens

MM-59

CAP: Clinical Cure by Risk Factors for Morbidity (Western Studies)

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)

Controlled studies

n/N (%) n/N (%) n/N (%)

All CAPstudies

PPc population at TOC

TEL Comparator a TEL

a Study 3001: Amoxicillin; Study 3006: Clarithromycin; Study 3009: Trovafloxacin b PPb population

MM-60

CAP: Clinical Cure forS. pneumoniae-Resistant Isolates

in Subjects Treated with Telithromycin

Single and multiple pathogens

Pen-R 16/19 13/16 3/3

Ery-R 21/25 13/16 8/9

Single pathogens

Pen-R 11/12 8/9 3/3

Ery-R 15/17 8/9 7/8

n/N SubjectsPPb population at TOC

All Western Japanesestudies studies study

Pen-R = Penicillin G-resistant (MIC 2.0 µg/mL); Ery-R = Erythromycin A-resistant (MIC 1.0 µg/mL)

MM-61

CAP: Clinical Cure for Subjects with Pneumococcal Bacteremia

(Treatment with Telithromycin, All Western Studies)

All S. pneumoniae 38/40 43/47

Pen-R 4/5 4/6Ery-R a 2/3 4/6Pen-R and/or Ery-R 5/6 7/9


Single Single andpathogens multiple

pathogens

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

n/N Subjects

MM-62

Summary of Efficacy in CAP

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

Common pathogens– S. pneumoniae

• Pen-R strains• Ery-R strains

– H. influenzae– M. catarrhalis

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

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

MM-63





– Acute sinusitis


MM-64

AECB: Phase III Studies

3003 a TEL 5 d 800 mg qd

AMC 10 d 500/125 mg tid

3007 TEL 5 d 800 mg qd

CXM 10 d 500 mg bid

AMC = Amoxicillin/clavulanic acid; CXM = Cefuroxime axetil

Study No. Treatment N (mITT)

160

160

182

191

a Documented COPD

MM-65

AECB: Clinical Cure at TOC, PPc

86% 87% 83%82%

0%

20%

40%

60%

80%

100%

3003 vs AMC 3007 vs CXM

TEL (5 d) Comparator (10 d)

99115

92112

121140

118142

[–6.4; 14.3] a


[–5.8; 12.4] a

MM-66

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)

TEL Comparator a 5 d 10 d

n/N (%) n/N (%)

AECB: Clinical Cure by Pathogen (Both Studies)


a Study 3003: Amoxicillin/clavulanic acid, Study 3007: Cefuroxime axetil

MM-67

Chlamydia pneumoniae 10/11 (91)

Mycoplasma pneumoniae 1/1 (100)

n/N (%)

AECB: Clinical Cure for Atypical Pathogens (Both Studies)

PPc population at TOC, subjects without other causative pathogens

MM-68

AECB: Clinical Cure by Baseline Characteristics (Both Studies)

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 <60% 56/68 (82) 64/81 (79)

TEL Comparator

n/N (%) n/N (%)

a COPD, pulmonary insufficiency, coronary atherosclerosis, history of inhaled steroids, diabetes mellitus, etc.

PPc population at TOC

MM-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)

MM-70





– Acute sinusitis


MM-71

Acute Sinusitis: Phase III Studies

3002 TEL 5 d 800 mg qd

TEL 10 d 800 mg qd

AMC 10 d 500/125 mg tid

3005 TEL 5 d 800 mg qd

TEL 10 d 800 mg qd

AMC = Amoxicillin/clavulanic acid; CXM = Cefuroxime axetil


3011 TEL

202

240

167

168

201

204

CXM 116

5 d

10 d 250 mg bid

800 mg qd

MM-72

Acute Sinusitis: Clinical Cure at TOC, PPc

0%

20%

40%

60%

80%

100%

TEL (5 d) TEL (10 d) Comparator (10 d)

91% 91%

3002

112123

121133

[–7.7; 7.9] a

75% 73% 75%

3005 vs AMC

110146

102137

102140

[–12.7; 9.5] a

[–9.9; 11.7] a


85% 82%

3011 vs CXM

161189

7389

[–7.1; 13.4] a

MM-73

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)

TEL 5 d TEL10 d

n/N (%) n/N (%)

Acute Sinusitis: Clinical Cureby Pathogen (All Studies)


MM-74

Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects

Treated with Telithromycin (All Studies)

Single and multiple pathogens

Pen-R 8/10 3/3 11/13

Ery-R 12/14 6/7 18/21

Single pathogens

Pen-R 6/8 3/3 9/11

Ery-R 8/10 5/6 13/16

n/N Subjects

PPb population at TOC, according to treatment duration

5 and5 days 10 days 10 days

Pen-R = Penicillin G-resistant (MIC 2.0 µg/mL); Ery-R = Erythromycin A-resistant (MIC 1.0 µg/mL)

MM-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

MM-76





– Acute sinusitis


MM-77

Tonsillitis/Pharyngitis: Phase III Studies

3004 TEL 5 d 800 mg qd

PEN 10 d 500 mg tid

3008 TEL 5 d 800 mg qd

CLA 10 d 250 mg bid

PEN = Penicillin VK; CLA = Clarithromycin


198

197

232

231

MM-78

Tonsillitis/Pharyngitis: Bacterial Eradication by Subject at TOC, PPb (Both Studies)

84%91% 88%89%

0%

20%

40%

60%

80%

100%

3004 vs PEN 3008 vs CLA

TEL (5 d) Comparator (10 d)

97115

106119

137150

119135

[–14.3; 4.8] a


[–4.6; 11.0] a

MM-79

Summary of Efficacy in Tonsillitis/Pharyngitis

• Treatment with telithromycin 800 mg once daily for 5 days is effective in GABHStonsillitis/pharyngitis

• Equivalence demonstrated between 5-day telithromycin treatment and 10-day standard treatment (penicillin VK 500 mg tid or clarithromycin 250 mg bid)

MM-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

MM-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 < 60%)

• Effective in infections (CAP, acute sinusitis) due to S. pneumoniae resistant to penicillin G and erythromycin A

MM-82

Safety Results

• Phase III:– general adverse event profile

– serious adverse events

– laboratory abnormalities

• ECG analysis

MM-83

Total Controlled Uncontrolled

TEL TEL TEL N=3265 N=2045 N=1220

Subjects (%) in Phase III Safety Population

Subjects who received 1 dose and safety assessment following randomization

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)

MM-84

Subjects (%) with Treatment-Related Adverse Events ( 2%) (Controlled Phase III Studies)

TEL Comparator N=2045 N=1672

All Treatment-rel. AEs 712 (34.8) 465 (27.8)

Diarrhea 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)

MM-85

All adverse events 98 (4.8)73 (4.4)

Treatment-related 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)

Subjects (%) with Discontinuations Due to Adverse Events (Controlled Phase III Studies)

TEL Comparator N=2045 N=1672

MM-86

0

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10

TEL 5-day

TEL 7-10 day

Clarithromycin

Amoxicillin/clavulanic acid

Day

% Subjects

Prevalence of Diarrhea for Telithromycin vs Comparator Drugs (Controlled Phase III Studies)

Prevalence included for each day from onset through last day of occurrence.

Cefuroximeaxetil

MM-87

Treatment-Related Adverse Eventsby Age (Controlled Phase III Studies)

28%36%

27%19%

29% 26%

0

20

40

60

80

100

13-18 yr 18 65 yr 65 yr

TEL Comparator

1968

1369

6231720

3851343

70257

67260

Age

% Subjects

MM-88

Summary of Mortality(All Phase III Studies)

• Controlled studies: Telithromycin = 2Comparator = 4

• Uncontrolled studies: Telithromycin = 5

• No treatment-related deaths

• Deaths occurred in CAP subjects(telithromycin 7/1415; 0.5%)

MM-89

All serious adverse events 40 (2.0) 41 (2.5)

All treatment-related serious AEs 8 (0.4) 4 (0.2)

Allergic reaction 2 (0.1) 1 (0.06)

Asymptomatic transaminase elevation 2 (0.1) 0 (0)

Pseudomem colitis a 1 (0.05) 1 (0.06)

Erythema multiforme 1 (0.05) 0 (0)

Gastroenteritis 1 (0.05) 1 (0.06)

Vomiting 1 (0.05) 0 (0)

Dyspnea 0 (0) 1 (0.06)

Serious Adverse Events(Controlled Phase III Studies)

TEL ComparatorN=2045 N=1672

N (%) Subjects

a Toxin C. difficile negative

MM-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

MM-91

All hepatic adverse events 56 (2.7) 48 (2.9)

Treatment-related hepatic AEs 40 (2.0) 33 (2.0)

Hepatic AEs leading to 10 (0.5) 8 (0.5) discontinuation

Hepatic Adverse Events(Controlled Phase III Studies)

TEL ComparatorN=2045 N=1672

N (%) Subjects

MM-92

Frequency of Subjects with ALT 3x ULN During Treatment

(Controlled Phase III Studies)

n/N (%) SubjectsALT statusat baseline Telithromycin Comparator

Normal 8/1646 (0.5) 5/1324 (0.4)

ULN 24/283 (8.5) 25/226 (11.1)

MM-93

0

20

40

60

80

100

0

20

40

60

80

100

Distribution of ALT Values During Treatment in Subjects with Normal ALT at Baseline

(Controlled Phase III Studies)

CAP Studies Non-CAP Studies

ULN ULN

% S

ub

ject

s

% S

ub

ject

s

ULN = Upper limit of normal

TEL (N=1251)

Comparator (N=936)

TEL (N=395)

Comparator (N=388)

1 2 3 5 8 ULN ULN 1 2 3 5 8

2.5

1.0

0.8

0.5

0.3

0.3

0 0 0.4

0.6

0.2

0.2

0 0 0.1

0

18.2

16.5

78.2 81.7

9.4 9.8

90.0

89.3

MM-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

MM-95






ECG Analysis Claude Benedict, MDSenior VP,Preclinical and Early Clinical Development, Aventis


MM-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

MM-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

MM-98

Plasma Levels and HERG Affinity of Selected Antibiotics

Peak free Oral dose [plasma] HERG IC50 Ratio

Drug (mg) µM µM IC50/ [plasma]

Investigations on HERG were all conducted at the same laboratory using the same methodology (CHO cells).

Sparfloxacin 400 1.8 17.9 10

Moxifloxacin 400 5.9 129 22

Clarithromycin 500 1.9 54.5 29

Telithromycin 800 0.84 42.5 51

Erythromycin 1000 0.9 50.7 56

Levofloxacin 500 12 915 76

MM-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 (N=1872 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)

MM-100

QTc Values at Baseline and On-Therapy for Telithromycin-treated Subjects

Baseline On-Therapy

Nu

mb

er

of

Su

bje

cts

QTc = 1.0 ± 21.1 ms

0

50

100

150

200

250

300

350

400

450

310 330 350 370 390 410 430 450 470 490 510 530

QTc (ms)

MM-101

QTc QT dispersionTreatment N (ms) (ms)

QTc from Baseline and QT Dispersion

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 9.4Beta-lactams 721 -3.2 22.0 21.5 9.6Clarithromycin 414 2.3 18.1 23.7 9.5Trovafloxacin 99 1.4 23.0 21.0 8.5

Mean ± SD

MM-102

QTc vs Telithromycin Plasma Concentration

Concentration (µg/mL)

QT

c (

ms)

0 2 4 6 8 10 12-160

-120

-80

-40

0

40

80

120

N=1512 patientsSlope=0.88 ms/µg/mLr2=0.0025, p0.05

MM-103

QTc vs Telithromycin Plasma Concentration


QT

c (

ms)

0 2 4 6 8 10 12-160

-120

-80

-40

0

40

80

120

Concs 5µg/mL

Conc QTc QTc

5.2 410 -7.45.2 364 -24.55.2 411 13.15.2 409 -3.35.3 428 -0.95.8 431 17.06.2 425 1.56.2 410 10.16.4 391 -38.86.4 381 -5.16.4 393 -6.06.7 435 18.07.2 408 17.87.8 396 0.19.9 427 8.7

N=1512 patientsSlope=0.88 ms/µg/mLr2=0.0025, p0.05

MM-104

Telithromycin Clarithromycin

Frequency of QTc Outliers (Telithromycin vs Clarithromycin)

n/N (%) Subjects

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

QTc increase:30 and <60 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)

MM-105

Telithromycin Non-macrolidesa

Frequency of QTc Outliers (Telithromycin vs Non-macrolides)

a Trovafloxacin, amoxicillin, cefuroxime axetil, amoxicillin/clavulanic acid, penicillin VK

n/N (%) Subjects

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

QTc increase:30 and <60 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)470 ms, women 4/508 (0.8) 1/427

(0.2)500 ms, men or women 2/988 (0.2) 1/844

(0.1)

MM-106

Gender Men 906 0.4 22.9Women 966 1.6 19.3

Age < 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 CLCR< 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

Clinical Risk Factors for QTc Prolongation (1)

QTc (ms) N Mean ± SD

MM-107

Drugs metabolized Taking 251 1.0 23.4by CYP2D6 Not taking 1621 1.0 20.8

QT-prolonging Taking 57 3.0 18.7drugs Not taking 1815 0.9 21.2

Hypokalemia Present 103 -0.2 20.4or 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

QTc (ms) N Mean ± SD

Clinical Risk Factors for QTc Prolongation (2)

MM-108

Association Between Baseline QTc and QTc

Baseline QTc Interval (ms)

Mea

n Q

Tc

(ms)

–60

–40

–20

0

20

40

60

310 350 390 430 470 510

+

–

Error bars show ± std deviation

N = 2 18 86 292 634 606 179 39 11 3 2

–80

80

MM-109

Telithromycin Comparators

Adverse Event (N = 2045) (N = 1672)

Incidence of Treatment-Related Adverse Events of Special Interest

in QT Interval AssessmentNumber (%) Subjects

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)

MM-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

MM-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)

-500 -300 -100 100 300 500RR (msec)

-100

-50

0

50

100

QTc

(mse

c )

corrected by Bazett's formula

-500 -300 -100 100 300 500RR (msec)

-100

-50

0

50

100

QTf

(mse

c )

corrected by Fridericia's formula

-500 -300 -100 100 300 500RR (msec)

-100

-50

0

50

100

QTn

(mse

c)

corrected by the New formula

MM-112

Relationship Between QTn and Concentration for Telithromycin Doses

from 800 to 3200 mg (Phase I Data)

0 2 4 6 8Concentration (mg/L)

-100

-50

0

50

100

QTn

(m

sec)

Slope=1.01 msec/mg/Ln=4945 observations

0 2 4 6 8

-100

-50

0

50

100

N = 4 9 4 5 o b se rv a tio n s

S lo p e = 1 .0 1 m s /µ g /m L

C o n c e n tr a tio n (µ g /m L )

QT

n (

ms)

MM-113

Drug Interactions of Special Interest

• Ketoconazole (potent CYP3A4 inhibitor)

• Cisapride (exclusively metabolized by CYP3A4)

• Sotalol (class III antiarrhythmic drug)

MM-114

Effect of Telithromycin and Ketoconazole on QTn

QTn Mean ± SD (ms)

Telithromycin 3 ± 11

Ketoconazole 10 ± 9

Telithromycin + Ketoconazole 9 ± 8

Placebo 3 ± 10

N=16

MM-115

Drug Interaction Between Telithromycin and CisaprideM

ea

n

QT

n ±

SD

(m

s)

-20

-10

0

10

20

30

40

50

1 1.5 2 2.5 3 6 12

Telithromycin 800 mg once daily for 6 days + cisapride 20 mg single dose, N=14

Telithromycin 800 mg once daily for 5 days, N=14

Cisapride 20 mg single dose N=14

Placebo N=14

Time (hours)

MM-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, N=24

Holter monitoring: No rhythm disorders

MM-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

MM-118

Subjects with CV Disease: Mean Changes in QTn and QTc

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• Holter: No arrhythmias recorded

Mean ± SD

Data corrected for placebo

MM-119

Subjects with CV Disease: QTn vs Telithromycin Plasma Concentration


QT

n (

ms

)

0 2 4 6

-100

-50

0

50

100

N = 24 subjects (800mg + 1600 mg TEL)

Slope = 1.53 ms/µg/mL

MM-120

QTc vs Telithromycin Plasma Concentration in RTI Patients with Cardiovascular Disease (Phase III)

QT

c (

ms

)

0 1 2 3 4 5 6 7 8 9 10 11 12-160

-120

-80

-40

0

40

80

120

N = 284 subjects

Slope = -0.42 ms/µg/mL

r2 = 0.00069, p = 0.65


MM-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

MM-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

MM-123







Conclusions Mindell Seidlin, MDVP, Clinical Development, Anti-Infectives, Aventis

MM-124

Medical Need for New Antibiotics

• Resistance in respiratory tract pathogens is increasing– S. pneumoniae: High level penicillin or macrolide resistance in >15%

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

MM-125

Microbiological and PK Features

• Telithromycin, the first ketolide, has:– two sites of interaction with 50S ribosomal

subunit; 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

MM-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

MM-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

MM-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

mm-1 fda advisory committee april 26, 2001 ketek ™ (telithromycin)

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