why another antibiotic for respiratory tract infections ?

AFRT 8 nov 2002 A3-1

Why Another Antibiotic for Why Another Antibiotic for Respiratory Tract InfectionsRespiratory Tract Infections??

Why Another Antibiotic for Why Another Antibiotic for Respiratory Tract InfectionsRespiratory Tract Infections??

C. CouturierC. CouturierC. CouturierC. Couturier


Community Acquired Pneumonia

Bartlett et al. Clin Infect Dis 1998;26:811–38

Incidence 2–3 millions

Hospitalisations 500 000 (env. 1/5)

Mortalité 45 000 (env. 1/50)

No./an USA


Incidence increases with age

0 20 40 60 80 100 120 140

70–79

60–69

50–59

40–49

30–39

20–29

16–19

MacFarlane et al. Lancet 1993;341:511–14

Age (years)

Cases per 1000 population/year

AFRT 8 nov 2002 A3-4LaForce. Clin Infect Dis 1992;14 (Suppl. 2):S233–7

Mycoplasma (6.7%)

Other bacteria (12.5%) Viral (12.6%)

H. influenzae(14.3%)

S. pneumoniae(44.9%)

Chlamydia (3.7%)

Legionella (5.2%)

Analysis of 16 studies of >3300 hospitalized patients (1960–1987)

Community Acquired Pneumopathy Etiology


Why Another Antibiotic for RTI S. pneumoniae Resistance Rates

Penicillin G 24.2 22.3Erythromycin A 31.7 30.7Azithromycin 31.5 30.9Clarithromycin 31.3 30.6Clindamycin 13.6 8.6Cotrimoxazole 31.1 33.9Tetracycline 22.1 15.9Levofloxacin 0.9 0.8

Antimicrobial US Worldwideagent (N=10,103) (N=16,672)

% Resistance

Source: PROTEKT US


Penicillin-resistant S. pneumoniae tend to be resistant to other -lactams

Goldstein et al. J Antimicrob Chemother 1996;38(Suppl. A):71–84

MIC distribution for ceftriaxone against S. pneumoniae

MIC (mg/L)

0

10

20

30

40

50

60

70

80

0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 80.004

% isolates

Penicillin-sensitive(MIC 0.06 mg/L)

Penicillin-intermediate(MIC 0.12–1 mg/L)

Penicillin-resistant(MIC 2 mg/L)


Telithromycin – R&D Target

•Tailored activity against pathogens from community RTIs: common & atypicals

•Excellent antipneumococcal activity SPN is the leading organism in frequency and morbidity

•includes activity against ERSP and PRSP

Ketolides are developed in response to Bacterial Resistance


Macrolides Target the 50S Subunit of the Bacterial Ribosome

• Macrolide binding inhibits protein synthesis by interfering with elongation of peptide synthesis and preventing 50S subunit assembly

Exit site for the growing peptide

30S Subunit16S rRNA + 20 proteins

50S Subunit23S and 5S rRNA +32 proteins

mRNA

AA-tRNA PeptidyltRNA

J. Zhu, et al., J Struct Biol. 1997 118:197-219


Telithromycin Mechanism of Action

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

23S rRNA

AFRT 8 nov 2002 A3-10

Consequence of Double Binding to 23S rRNA

2058

752

V

II

V

II

Erythromycin A Telithromycin

2058

752

No link withdomain V

Resistance to erythromycin A

Link withdomain II

Telithromycin retains activityagainst erythromycin A-

resistant organisms

5S rRNA5S rRNA-cladinoseOO

O

O O

O(methylation) (methylation)x x

AFRT 8 nov 2002 A3-11

Ribosomal Depletion

30S 50S

30S

50S

30S

Depletion ofribosome in thebacterial cells

Erythromycin A

Telithromycin

• Inhibition of ribosomal subunit formation

AFRT 8 nov 2002 A3-12

Macrolide Resistance

• Inactivating Enzymes– Staphylococci

– Gram Negative Rods

• Efflux – Wildly distributed

– Multi drug activity

• Target modification– 23S Methylases

– 23 S Mutations

– r-Proteins Mutations

AFRT 8 nov 2002 A3-13

erm(A) S. pneumoniae are Inducibly Resistant to ML Antibiotics

Telithromycin activity is not altered by inducible methylases in S.pneumoniae

Strain no. erm ERYa CLR AZM JOS TYL SPI TEL LIN CLI STB PEN357 (A) 1.56 0.78 6.25 0.39 3.12 0.39 0.006 3.12 0.10 1.56 0.012

357 + ERY 6.25 3.12 50 12.5 100 25 0.012 >100 >100 3.12 0.012

1255 (B) 3.12 1.56 50 0.78 25 3.12 0.006 >100 0.39 0.78 0.01

1255 + ERY >100 >100 >100 >100 >100 >100 0.012 >100 >100 >100 0.01

ATCC 49619 (None) 0.02 0.02 0.10 0.20 0.78 0.39 0.006 0.78 0.10 3.12 0.39a 14-membered macrolides: ERY = erythromycin, CLR = clarithromycin; 15-membered macrolide: AZM =

azithromycin; 16-membered macrolides: JOS = josamycin, TYL = tylosin, SPI = spiramycin; Ketolide: TEL =

telithromycin; lincosamides: LIN = lincomycin, CLI= clindamycin; STB = streptogramin B; PEN = Penicillin G.

erm(A)

AFRT 8 nov 2002 A3-14

Resistance Phenotype (N) MIC50 MIC90 Range

Macrolide-susceptible (11,384) 0.015 0.015 0.004 - 1

Macrolide-resistant (5,288) 0.12 1.0 0.008 - 8

erm(B) (657) 0.06 0.5 0.008 - 8

mef(A) (436) 0.12 0.5 0.008 - 1

mef(A)+erm(B) (71) 0.5 0.5 0.06 - 1

Penicillin-resistant (4,027) 0.12 1.0 0.004 - 8

Levofloxacin-resistant (154) 0.03 0.5 0.004 - 1

Multi-drug resistant (1,500) a 0.12 1.0 0.008 - 8

In vitro Activity of Telithromycin Against S. pneumoniae

a resistant to the macrolides, penicillin, cotrimoxazole, and tetracycline Data from PROTEKT Worldwide, N = 16,672

MIC (µg/mL)

AFRT 8 nov 2002 A3-15

Activities of Telithromycin and Macrolides Erythromycin-Resistant S. pneumoniae (N=3,131)

0

500

1000

1500

2000

2500

Nu

mb

er o

f Is

ola

tes

0.01

50.

030.

060.

120.

25 0.5 1 2 4 8

16

MIC (µg/mL)

Telithromycin

Erythromycin

Clarithromycin

Azithromycin

Data from PROTEKT US 2000/2001

AFRT 8 nov 2002 A3-16

Bactericidal activity of telithromycin in vitro

Felmingham et al. 38th ICAAC 1998

Counts (log10 CFU/mL)

Time (hours)

-5 0 5 10 15 20 25 30 -5

ControlTEL at 2x MIC (0–0.6 mg/L)TEL at 4x MIC (0–12 mg/L)TEL at 8x MIC (0–25 mg/L)AZI at 2x MIC (0–25 mg/L)AZI at 4x MIC (0–5 mg/L)AZI at 8x MIC (1 mg/L)

Starting inoculum 105 CFU/mL

01

2

3

4

5

6

7

8

9

10

S. pneumoniaePenS EryS

AFRT 8 nov 2002 A3-17

Bactericidal Activity of telithromycin Against Macrolide-Resistant S. pneumoniae

S. pneumoniae Strain 5467 mef(A)

S. pneumoniae Strain 5991 erm(B)

Hours

0 µg/mL

0.06

0.125

0.25

0.5

1

2

4

8

16

2

4

6

8

10

0 2 4 6 8 12

LO

G10

cfu

/mL

0 2 4 6 8 122

4

6

8

10

LO

G10

cfu

/mL

Hours

AFRT 8 nov 2002 A3-18

In vitro Activity of Telithromycin

Data from PROTEKT US; a PROTEKT Worldwide, 2000-2001

Organism (N) MIC50 MIC90 Range

S. pneumoniae (10,103) 0.015 0.5 0.015 - 8

H. influenzae (2,706) 2.0 4.0 0.12 - 32

(-lactamase positive; 769) 2.0 4.0 0.12 - 16

M. catarrhalis (1,896) a 0.06 0.12 0.004 - 0.5

S. pyogenes (3,918) 0.03 0.03 0.015 - 16

MIC (µg/mL)

AFRT 8 nov 2002 A3-19

Telithromycin Selection of Antibiotic Resistance

• Telithromycin does not induce MLSB resistance in pneumococci

• In serial passage experiments, telithromycin was less efficient in selecting resistant mutants of pneumococci than azithromycin, clarithromycin, erythromycin, or clindamycin

• Selection of resistant strains of viridans group streptococci and other usual oropharyngeal flora less efficient with telithromycin than azithromycin

• Selection of resistant strains of viridans group streptococci and intestinal enterococci less efficient with telithromycin than clarithromycin

AFRT 8 nov 2002 A3-20

Telithromycin

• Ketolide antibiotic, derived from macrolides

• Novel mechanism of action

• Tailored activity against pathogens from community RTIs: common & atypicals

• Excellent antipneumococcal activity: – leading organism in frequency and morbidity– includes activity against ERSP and PRSP

• Short, simple course of treatment

AFRT 8 nov 2002 A3-21

Telithromycin – Development Strategy

•Global development ( +Japan specificities)

•Sharing indications

•Only one Database

•Resulting in 2 dossiers FDA & EMEA

AFRT 8 nov 2002 A3-22

Telithromycin – Development Strategy

•In vitro studies•PK•PK/PD animal

Dose Ranging Phase II study was not performed

Short duration treatment choosen

AFRT 8 nov 2002 A3-23

Indications

• Community-acquired pneumonia (CAP)

• Acute exacerbation of chronic bronchitis (AECB)

• Acute sinusitis (AS)

AFRT 8 nov 2002 A3-24

Antibacterial studies difficulties

• Bacteriological End Point difficult to monitor

• Strains are fastidious

• Efficacy results in absence of sputum

AFRT 8 nov 2002 A3-25

Large number of Patients >> few Strains

• mITT

• PPc

• S. pneumoniae

• ERSP

• PRSP

2511

1925

318

5027

CAP Studies

AFRT 8 nov 2002 A3-26

Human Pharmacology Program

• Clinical pharmacokinetics of telithromycin have been studied extensively:– studies on plasma PK, studies on tissue

penetration– interaction studies– special population studies (elderly;

renal, hepatic, and multiple impairment)

AFRT 8 nov 2002 A3-27

Pharmacokinetics of Oral Telithromycin in Healthy Subjects

800 mg single dose

800 mg multiple dose (7 d)

C24h (mg/L) 0.03 (72)

AUC(0-24h) (mg.h/L) 8.3 (43)

7.2 (20)t½,z (h)

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

(19)

(31)

(45)

Cmax (mg/L) 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

AFRT 8 nov 2002 A3-28

Tissue and Fluid Penetration of Telithromycin in Patients

Tissue

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

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)

AFRT 8 nov 2002 A3-29

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

AFRT 8 nov 2002 A3-30

PK Modifications Under Various Conditions Comparisons with Healthy Control Subjects

Cmax AUC

Renal impairment CLCR <30 mL/min 1.5 x 2.0 x

30-80 1.1 x 1.2 x

CYP3A4 inhibition Ketoconazole 1.5 x 2 x Itraconazole 1.2 x 1.5 x

Grapefruit juice

Hepatic impairment

Renal impairment+ ketoconazole

CLCR <30 mL/min 3.4 x 4.5 x 30-80 1.7 x 2.7 x

AFRT 8 nov 2002 A3-31

30-80

N=6

30-80

N=10

<30

N=2

Creatinine clearance(mL/min)

Data are mean (CV%).

Effects of Multiple Impairments (Elderly, Renal, +Ketoconazole)

Clarithromycin

AUC(0-24) (mg.h/L) 112.2 33.4 51.7, 61.6(41) (31)

Cmax,ss (mg/mL) 6.2 3.6 5.4, 8.8(36) (22)

Telithromycin

AFRT 8 nov 2002 A3-32

Telithromycin Interaction with CYP3A4 Substrate: Midazolam

Dose of iv midazolam was 2 mg for TEL and KET and 0.05 mg/kg for CLADose of oral midazolam was 6 mg for TEL and KET and 4 mg for CLA

TEL = Telithromycin; CLA = Clarithromycin; KET = Ketoconazole

Midazolam Parameter TEL CLA KET

Intravenous AUC 2.2 x 2.7 x 5 x

Oral AUC 6.1 x 7 x 16 x

Change in exposure

AFRT 8 nov 2002 A3-33

Summary of Human Pharmacology

• PK of telithromycin have been well characterized, and are reproducible or predictable under various conditions

• Telithromycin rapidly achieved targeted plasma and respiratory tissue concentrations

• Multiple elimination pathways limit the potential for increased exposure in special populations. CYP3A4 metabolism accounts for a small fraction of total drug clearance

• Similar inhibition of CYP3A4 to clarithromycin and erythromycin but for less time because of the short treatment duration

AFRT 8 nov 2002 A3-34

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

Indication Dosage Duration

AFRT 8 nov 2002 A3-35

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

AFRT 8 nov 2002 A3-36

Clinical Efficacy of Telithromycin

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

– acute exacerbation of chronic bronchitis (AECB)

– acute sinusitis

AFRT 8 nov 2002 A3-37

CAP: Phase III Controlled Studies

Study No. Treatment

3001 TEL 10 d 800 mg qdAMX 10 d 1000 mg tid

3006 TEL 10 d 800 mg qdCLA 10 d 500 mg bid

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

3009 TEL 7-10 d 800 mg qdTVA 7-10 d 200 mg qd

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

N (mITT)

199205

204212

100104

4003 TEL 5 d 800 mg qdTEL 7 d 800 mg qd

187191

CLA 10 d 500 mg qd 181

AFRT 8 nov 2002 A3-38

CAP: Other Studies

Study No. Treatment

3000 TEL 7-10 d 800 mg qd

3009 OL TEL 7-10 d 800 mg qd

• 4 Phase III open-label studies (Western countries)N (mITT)

240

212

• 2 Phase II/III comparative studies (Japan)

3010 TEL 7 d 800 mg qd 418

2105 TEL 7 d 600 mg qd

TEL 7 d 800 mg qd

46

50

3012 TEL 7 d 800 mg qd 538

3107 TEL 7 d 600 mg qd

LVX 7 d 100 mg tid

126

111 LVX = Levofloxacin

AFRT 8 nov 2002 A3-39

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

95%88%

94%90%89%90%

0%

20%

40%

60%

80%

100%

3001 vs AMX 3006 vs CLA 3009 vs TVA

[–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

4003 vs CLA

89%89% 92%

142159

143161

134146

TEL (7-10 d) Comparator (10 d)TEL (5 d)

[–9.7; 4.7] a,b

[–10.2; 4.3] a,c

b TEL (5 d) vs CLA c TEL (7 d) vs CLA

AFRT 8 nov 2002 A3-40

CAP: Clinical Cure at Test Of Cure, PerProtocol(clinical)

(Uncontrolled Western Studies)

3000 183/197 (93)

3009 OL 175/187 (94)

3010 332/357 (93)

3012 424/473 (90)

TEL

n/N (%)Study

AFRT 8 nov 2002 A3-41

Key pathogens (PPb at TOC)S. pneumoniae 300/318 (94) 63/70 (90)H. influenzae 206/229 (90) 42/44 (95)M. catarrhalis 44/50 (88) 7/9 (78)

Atypical pathogens (PPc at TOC)M. pneumoniae 36/37 (97) 20/22 (91)C. pneumoniae 34/36 (94) 18/19 (95)L. pneumophila 13/13 (100) 2/3 (67)

TEL Comparators a

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

CAP: Clinical Cure by Pathogen(All Western Studies)

a Study 3001: Amoxicillin; Studies 3006 and 4003: Clarithromycin; Study 3009: Trovafloxacin

AFRT 8 nov 2002 A3-42

CAP: Clinical Cure for Resistant S. pneumoniae Isolates

Single and multiple pathogensPRSP 24/27 (89)

ERSP 44/50 (88)PRSP and ERSP 16/19 (84)

Single pathogens PRSP 15/16 (94) ERSP 29/32 (91)

PRSP and ERSP 9/10 (90)

n/N (%) SubjectsTEL: PPb population at TOC (Western + Japanese studies)

PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL) a Excludes strains that are both PRSP and ERSP

AFRT 8 nov 2002 A3-43

CAP: Clinical Cure for Erythromycin-Resistant S. pneumoniae by genotype

Single and multiple pathogensERSP 44/50 (88)

erm(B) 24/28 (86)mef(A) 16/18 (89)erm(B)/mef(A) 3/3 (100)Negative for erm(B) and mef(A) 1/1 (100)

n/N (%) Subjects

TEL: PPb population at TOC (Western + Japanese studies)

PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL)

AFRT 8 nov 2002 A3-44

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:

AFRT 8 nov 2002 A3-45

Summary of Efficacy in RTIs (1)

• Efficacy of telithromycin demonstrated in 14 studies in 3 indications: – 5-day treatment for AECB and acute sinusitis

– 7- to 10-day treatment for CAP

• Effective in subjects at risk for complications: – CAP: elderly, pneumococcal bacteremia

– AECB: elderly, significant obstruction (FEV1/FVC < 60%)

AFRT 8 nov 2002 A3-46

Summary of Efficacy in RTIs (2)

• Effective against S. pneumoniae resistant to penicillin G and macrolides (erythromycin A)

• Effective against atypical and intracllular organisms:– C. pneumoniae– M. pneumoniae

– L. pneumophila

AFRT 8 nov 2002 A3-47

Clinical Safety of Telithromycin

• Phase III clinical efficacy studies

• Large study in usual care setting (Study 3014)

• Post-marketing experience

AFRT 8 nov 2002 A3-48

Current Extent of Exposure

• Significant global exposure to TEL:– 4,472 subjects in 16 Phase III clinical efficacy

studies– 12,159 subjects in large comparative study in

usual care setting (Study 3014)– >24,000 patients in post-marketing survey

– >750 000 global post-marketing exposures*

* based upon Aventis internal sales data to retail and outpatient pharmacies as of 09 July 2002 (PSUR n°2 submitted September 9, 2002)

AFRT 8 nov 2002 A3-49

Subjects (%) with Treatment-Emergent Adverse Events (2%) (Controlled Efficacy Studies)

TEL Comparator N=2702 N=2139

Subjects with TEAEs 1348 (49.9) 1035 (48.4)

Diarrhea 292 (10.8) 184 (8.6)Nausea 213 (7.9) 99 (4.6)Dizziness (excl vertigo) 99 (3.7) 57 (2.7)Vomiting 79 (2.9) 48 (2.2)Loose stools 63 (2.3) 33 (1.5)

Headache 148 (5.5) 125 (5.5) Dysguesia 43 (1.6) 77 (3.6)

AFRT 8 nov 2002 A3-50

Deaths in Clinical Efficacy Studies

• Reports of deaths balanced between TEL and comparators:– TEL: 7 (0.3%), comparators: 9 (0.4%)– (uncontrolled studies: 10; 0.6%)

• No treatment related deaths

AFRT 8 nov 2002 A3-51

Serious Adverse Events(Controlled Efficacy Studies)

All serious adverse events 59 (2.2) 61 (2.9)

All treatment-related serious AEs 9 (0.3) 6 (0.3)

TEL ComparatorN=2702 N=2139

N (%) Subjects

Most SAEs were in the infections and respiratory SOCs, and were related to the underlying infection

AFRT 8 nov 2002 A3-52

Subjects (%) with Discontinuations due to Adverse Events (Controlled Efficacy Studies)

Subjects with D/C 119 (4.4)92 (4.3)

GI related events 58 (2.1)37 (1.7)

– Diarrhea 23 (0.9)13 (0.6)

– Nausea 19 (0.7)10 (0.5)

– Vomiting 21 (0.8)10 (0.5)

TEL Comparator N=2702 N=2139

AFRT 8 nov 2002 A3-53


• Phase III clinical efficacy studies



AFRT 8 nov 2002 A3-54

Study 3014: Key Design features

• Designed in consultation with the FDA:– randomized, open-label comparative safety study

– Telithromycin vs Augmentin

– 24,000 subjects

– treatment: 5 days for AS, 7-10 days for AECB and CAP

• Usual care setting:– primary care physicians

– minimal exclusion criteria

• Targeted subjects with comorbidities: – 35% subjects 50 years or older

– 40% with CAP or AECB

AFRT 8 nov 2002 A3-55

Study 3014: Collection of Safety Data

• Clinic visits at Visit 1 (Day 1) and Visit 2 (Day 17-22); late follow-up contact at Visit 3 (up to Day 30-35)

• Hepatic laboratory analytes collected at Visits 1 and 2

• Investigators monitored for all AEs, with particular focus on adverse events of special interest (AESIs)

AFRT 8 nov 2002 A3-56

Study 3014: AESI definitions

• Hepatic: hepatitis, jaundice, any worsening of a pre-existing hepatic condition, alanine aminotransferase (ALT) values 3x ULN

• Cardiac: torsades de pointes, ventricular arrhythmias, syncope as defined by total loss of consciousness, cardiac arrest, or unwitnessed or unexplained death

• Visual: blurred vision

• Vasculitic: purpura or other signs of vasculitis

AFRT 8 nov 2002 A3-57

Study 3014: Investigation of AESIs

• AESIs followed up using standardized questionnaires and clinical work-up

• All adverse events and laboratory values reviewed regularly to ensure collection of all AESIs

• All predefined safety endpoints adjudicated by clinical events committees (CECs)

• Final adjudication data used for primary endpoint incidence rates

AFRT 8 nov 2002 A3-58

Subjects (%) with Treatment-Emergent Adverse Events (1%) (Study 3014)

TEL Comparator N=12,159 N=11,978

Subjects with TEAEs 2807 (23.1) 2745 (22.9)

Diarrhea 423 (3.5) 813 (6.8)Nausea 382 (3.1) 286 (2.4)Headache 230 (1.9) 144 (1.2)Dizziness (excl vertigo) 192 (1.6) 59 (0.5)Abdominal pain 106 (0.9) 100 (0.8)Vomiting 102 (0.8) 115 (1.0)Vaginosis fungal 58 (0.5) 162 (1.4)

AFRT 8 nov 2002 A3-59


• Phase III efficacy studies



AFRT 8 nov 2002 A3-60

Safety in Post-Marketing Experience

• >750 000 global post-marketing exposures* to TEL since first approval in Europe in July 2001– Germany, Italy, Spain, Mexico, Brazil and France

• Overall safety profile in first year of post-marketing experience confirms findings in clinical development– no new or unanticipated safety signals identified

*As of July 9, 2002

AFRT 8 nov 2002 A3-61

Summary of Telithromycin Safety (1)

• Extensive patient safety data available to date:– including 16,000 subjects in controlled clinical trials and

>1 million post-marketing exposures

• Well-characterized and well-tolerated safety profile:– pattern of adverse events similar to variety of marketed

antibiotics– no excess toxicity in at-risk populations – low incidence of serious adverse events and

discontinuations, similar to comparators

AFRT 8 nov 2002 A3-62


• Acceptable hepatic safety profile:– tendency toward slightly more frequent and

predominantly minimal transaminase elevations, with no increase in clinically significant events

– no severe hepatotoxicity in >1 million exposures

• Acceptable cardiac safety profile– small mean change in QTc Bazett (~1.5 msec), of no

detectible clinical significance– no excess in cardiac mortality or arrhythmia

AFRT 8 nov 2002 A3-63


• Well-characterized and consistent visual effects:– uncommon, generally mild, transient, and reversible

events most consistent with a slight delay in accommodation

• No signal for severe vasculitis detected

AFRT 8 nov 2002 A3-64

Telithromycin Registration Status

• Around 20 European countries including all EU countries

•17 south American countries

•14 other countries (i.e. NZ, Singapore, Hongkong, Egypt, Vietnam)

•Approved in the USA

•Awaited in Canada, Australia and Japan

AFRT 8 nov 2002 A3-65

Telithromycin – Marketing Status

•Marketed in the following major countries– France, Germany, Spain, Italy– Brazil, Mexico

•More than 1 Million subjects were treated with Ketek•Expected to increase sharply during the coming winter

why another antibiotic for respiratory tract infections ?

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