MM-1 FDA Advisory Committee April 26, 2001 KETEK ™ (telithromycin)

MM-2 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD VP, Clinical Development, Anti-Infectives, Aventis MicrobiologyAndré Bryskier, MD Human PharmacologyVijay Bhargava, PhD Clinical Efficacy and SafetyBruno Leroy, MD ECG AnalysisClaude 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 of intracellular levels Importance of plasma and 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: ) 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in the US Source: CDC Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, published and unpublished data. % Resistant Isolates M Phenotype MLS B Phenotype All resistant isolates MIC  1 µg/mL N=2508N=3147N=3110N=3303N=3435N=2508 % Resistant Isolates N=3147N=3435 Resistant isolates with MIC  8 µg/mL N=3110N=3303

MM-8 Therapy of RTI Community-Acquired Pneumonia Bacterial Infection Risk DRSP Fluoroquinolone Known DRSP Fluoroquinolone No risk DRSP Macrolide Doxycycline Fluoroquinolone

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 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD MicrobiologyAndré Bryskier, MD Senior Director, Clinical Microbiology, Aventis Human PharmacologyVijay Bhargava, PhD Clinical Efficacy and SafetyBruno Leroy, MD ECG AnalysisClaude Benedict, MD Conclusions Mindell Seidlin, MD

MM-12 Telithromycin Telithromycin, the first ketolide, is designed to overcome erythromycin A resistance within gram-positive cocci O O O O OCH 3 O 9 6 N R 3 O OD - desosamine New chemical class (3–keto) Innovation (C 11 –C 12 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 MLS B resistance 3 O – cladinose 3–keto function 3 O

MM-14 Benefits of Carbamate Residue and Side Chain at Position C 11 – C 12 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 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 50S subunit 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 rRNA Domain V Domain II Pocket: peptidyl transferase site 5S rRNA V II V Erythromycin ATelithromycin S 50S O O O O O O -cladinose

MM-18 Ribosomal Depletion 30S 50S 30S 50S 30S Depletion of ribosome in the bacterial cells Erythromycin A Telithromycin Inhibition of ribosomal subunit formation

MM-19 Consequence of Double Binding to 23S rRNA V II V Erythromycin ATelithromycin No link with domain V Resistance to erythromycin A, azithromycin, clarithromycin Link with domain II Telithromycin retains activity against erythromycin A- resistant organisms 5S rRNA -cladinose O O O O O O (methylation) xx

MM-20 Telithromycin Activity Against Erythromycin A-Resistant S. pneumoniae Erythromycin ATelithromycin Methylation (erm)–+ Efflux (mef, msr, mre)–+ Mutation (ribosomal protein L 4 )–+

MM-21 Telithromycin: Antipneumococcal Activity (1) Cumulative susceptibility of 400 strains of S. pneumoniae MIC (µg/mL) Cumulative % susceptible Telithromycin Levofloxacin Erythromycin A Clarithromycin Azithromycin Linezolid Source: G Doern, 1999

MM-22 TelithromycinClarithromycin PhenotypeN Ery-S Ery-R (efflux) Ery-R (MLS B ) 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 N5090Reference CefotaximeS102  I R Penicillin GS I R TetracyclineR CotrimoxazoleR OfloxacinR , 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) Time (hours) Log 10 cfu/mL 8X MIC 4X MIC 2X MIC MIC 0.5X MIC 0.25X MIC Growth Control Threshold Source: P Appelbaum, 2000

MM-25 Telithromycin: In Vivo Antipneumococcal 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 G203/576(35)185/1333(14) Erythromycin A117/576(20)131/1333(10) Telithromycin c 0/5761/1333 c MIC of  4.0 µg/mL Resistance in 1999

MM-27 Telithromycin: Main Respiratory Pathogens (North America) S. pneumoniae82467   S. pyogenes6519  H. influenzae M. catarrhalis L. pneumophila C. pneumoniae a M. pneumoniae Number of centers Number of strains 5090 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 Time (min) % Uptake Intracellular accumulation Time (min) % Efflux 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 MLS B resistance Low frequency of selection of resistant mutants Active against S. pneumoniae strains resistant to erythromycin A, penicillin G, tetracycline, cotrimoxazole, fluoroquinolones and cefotaxime

MM-31 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD MicrobiologyAndré Bryskier, MD Human PharmacologyVijay Bhargava, PhD Senior Director, Drug Metabolism and Pharmacokinetics, Aventis Clinical Efficacy and SafetyBruno Leroy, MD ECG AnalysisClaude Benedict, MD Conclusions Mindell Seidlin, MD

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) C 24h (µg/mL)0.03(72) AUC (0-24h) (µg.h/mL)8.3(43) 7.2(20)t ½, z (h) Data are mean (CV%) [Min-Max], N = 18 a Median (19) (31) (45) C max (µg/mL)1.92.3(42)(31) t max (h)1.0 a [0.5-4] [0.5-3]

MM-34 Tissue and Fluid Penetration of Telithromycin in Patients Tissue Mean (CV%) telithromycin concentration after 800 mg dose (µg/mL) 2-3h24h Alveolar macrophages a Tonsils (µg/g) b a Data from Honeybourne and Wise, N = 5-7 b Data from Gehanno, N = 6-8 Epithelial lining fluid a 12h (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/biliaryHepatic excretion Unchanged drug in feces Metabolized drug * Metabolism in liver and GI tractFirst pass effect Pathways of Telithromycin Disposition (13%) (37%) (7%) (33%) Non-P450 mediated CYP3A4- mediated ½½ *Telithromycin is not metabolized by CYP2D6

MM-37 First pass effect Telithromycin N=11 Telithromycin + ketoconazole N=11 AUC (0-24 h) (µg.h/mL)14.4(39)28.6(31) C max (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 bioavailability Hepatic excretion Metabolites Metabolism in liver and GI tract CYP3A4-mediated ½½ t ½, z (h) 11.2 (26)12.6 (27)

MM-38 Hepatic impairment N=12 Healthy N=12 Data are mean (CV%) Mild impairment: N = 2; Moderate impairment: N = 5; Severe impairment: N = 5 Effect of Hepatic Impairment C max (µg/mL)(52)(43) AUC (0-z) (µg.h/mL)(37)(30) CL R (L/h)(43)(16) Systemic bioavailability Renal excretion Hepatic excretion Metabolites Metabolism in liver and GI tract First pass effect t ½, z (h) 14.2 (14)10.3 (27)

MM-39 Hepatic impairment N=12 Healthy N=10 Day 1Day 7Day 1Day 7 t 1/2, z (h)12.5 (26)–10.6 (18) CL R (L/h) C max (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) Systemic bioavailability 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 Systemic bioavailability Renal excretion Unchanged drug in urine Renal function C max (µg/mL) (38)(26)(43) AUC (0-z) (µg.h/mL) (35)(41)(46) t ½, z (h) (25)(13)(27)

MM-41 AUC (0-24 h) (µg.h/mL)18.1 (63)25.9 (70) C max (µg/mL)2.8 (50)3.5 (63) Data are mean (CV%) <65 years N=142  65 years N=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 C max /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 MIC 90 of H. influenzae Plasma and extracellular (ELF) levels for telithromycin (C max 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 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD MicrobiologyAndré Bryskier, MD Human PharmacologyVijay Bhargava, PhD Clinical Efficacy and SafetyBruno Leroy, MD Senior Director, Clinical Development, Anti-Infectives, Aventis ECG AnalysisClaude Benedict, MD Conclusions Mindell Seidlin, MD

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 CAP800 mg qd7-10 days AECB800 mg qd5 days Acute sinusitis800 mg qd5 days 800 mg qd10 days Tonsillitis/ Pharyngitis800 mg qd5 days IndicationDosageDuration

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 of Therapy Visit 1 (Day 1) Visit 2 (Day 3 to 5) Visit 3 (Day 10 to 13) Visit 4 (Day 17 to 21) On TherapyOff Therapy

MM-50 Main Analysis Populations PopulationDefinition mITTAll subjects with disease who received at least one dose PPcAll mITT subjects excluding major protocol violators (clinically evaluable) PPbAll PPc subjects with a causative pathogen isolated at pretherapy/ entry (microbiologically evaluable)

MM-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

MM-52 CAP: Phase III Controlled Studies Study No.Treatment 3001TEL10 d800 mg qd AMX10 d1000 mg tid 3006TEL10 d800 mg qd CLA10 d500 mg bid TEL = Telithromycin; AMX = Amoxicillin; CLA = Clarithromycin; TVA = Trovafloxacin 3009TEL7-10 d800 mg qd TVA7-10 d200 mg qd 3 randomized, controlled, double-blind, comparative trials (Western countries) N (mITT)

MM-53 CAP: Other Studies Study No.Treatment 3000TEL7-10 d800 mg qd 3009 OL TEL7-10 d800 mg qd 3 Phase III open-label studies (Western countries) N (mITT) Phase II dose-comparison study (Japan) 3010TEL7 d800 mg qd TEL7 d600 mg qd TEL7 d800 mg qd 46 50

MM-54 CAP: Key Subject Background Characteristics, mITT (Western Studies)  65 years old 83(17)87(17)196(14) Pneumococcal22 (4)18(4)56(4) bacteremia Fine score:  III84(17)105(20)220(16) Consolidation187(37)190(36)791(58) Multiple lobes41(9)35 (7)161(12) Controlled studies TELComparatorTEL Subjects (%) withN=503N=521N=1373 All CAP studies

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 AMX3006 vs CLA3009 vs TVA TEL (7-10 d)Comparator (10 d) [–2.1; 11.1] a 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) /197(93) 3009 OL175/187(94) /357(93) TEL n/N (%) Study

MM-57 S. pneumoniae165/174(95)40/44(91) H. influenzae95/105(91)27/27(100) M. catarrhalis26/30(87)4/5(80) TELComparator 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 TOCLPTV 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 population356/391(91)356/394 (90) 1046/1132(92)  65 years old 53/60(88)56/66(85) 139/154(90) Pneumococcal15/15 (100)11/13(85) 43/47(91) bacteremia b Fine score  III56/61(92)65/78(83) 161/175(92) Controlled studies n/N(%)n/N(%)n/N(%) All CAP studies PPc population at TOC TELComparator a TEL a Study 3001: Amoxicillin; Study 3006: Clarithromycin; Study 3009: Trovafloxacin b PPb population

MM-60 CAP: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin Single and multiple pathogens Pen-R16/1913/163/3 Ery-R21/2513/168/9 Single pathogens Pen-R 11/12 8/9 3/3 Ery-R15/17 8/9 7/8 n/N Subjects PPb population at TOC AllWesternJapanese studiesstudiesstudy 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. pneumoniae38/4043/47 Pen-R4/54/6 Ery-R a 2/34/6 Pen-R and/or Ery-R5/67/9 PPb population at TOC SingleSingle and pathogensmultiple 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 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-64 AECB: Phase III Studies 3003 a TEL5 d800 mg qd AMC10 d500/125 mg tid 3007 TEL 5 d 800 mg qd CXM 10 d 500 mg bid AMC = Amoxicillin/clavulanic acid; CXM = Cefuroxime axetil Study No.TreatmentN (mITT) a Documented COPD

MM-65 AECB: Clinical Cure at TOC, PPc 86% 87% 83% 82% 0% 20% 40% 60% 80% 100% 3003 vs AMC3007 vs CXM TEL (5 d)Comparator (10 d) [–6.4; 14.3] a a 95% confidence intervals [–5.8; 12.4] a

MM-66 S. pneumoniae12/14(86)8/12(67) H. influenzae17/25(68)13/17(76) M. catarrhalis10/10(100)14/16(88) S. aureus2/2(100)3/3(100) TEL Comparator a 5 d 10 d n/N (%)n/N(%) AECB: Clinical Cure by Pathogen (Both Studies) PPb population at TOC a Study 3003: Amoxicillin/clavulanic acid, Study 3007: Cefuroxime axetil

MM-67 Chlamydia pneumoniae10/11(91) Mycoplasma pneumoniae1/1(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 Population220/255(86)210/254(83)  65 years old79/90 (88) 90/114(79) Morbidity risk factors a : At least 1128/148(87)116/142(82) At least 259/70(84)63/76(83) FEV 1 /FVC <60%56/68(82) 64/81(79) TELComparator 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 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-71 Acute Sinusitis: Phase III Studies 3002TEL5 d800 mg qd TEL10 d800 mg qd AMC10 d500/125 mg tid 3005TEL5 d800 mg qd TEL10 d800 mg qd AMC = Amoxicillin/clavulanic acid; CXM = Cefuroxime axetil Study No.TreatmentN (mITT) 3011TEL CXM116 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% [–7.7; 7.9] a 75% 73% 75% 3005 vs AMC [–12.7; 9.5] a [–9.9; 11.7] a a 95% confidence intervals 85% 82% 3011 vs CXM [–7.1; 13.4] a

MM-73 S. pneumoniae55/61(90)27/30(90) H. influenzae42/48(88)15/16(94) M. catarrhalis13/14(93)3/4(75) S. aureus18/19(95)4/4(100) TEL 5 dTEL10 d n/N (%)n/N(%) Acute Sinusitis: Clinical Cure by Pathogen (All Studies) PPb population at TOC

MM-74 Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin (All Studies) Single and multiple pathogens Pen-R8/103/311/13 Ery-R12/146/718/21 Single pathogens Pen-R 6/8 3/3 9/11 Ery-R8/10 5/6 13/16 n/N Subjects PPb population at TOC, according to treatment duration 5 and 5 days10 days10 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 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-77 Tonsillitis/Pharyngitis: Phase III Studies 3004TEL5 d800 mg qd PEN10 d500 mg tid 3008TEL5 d800 mg qd CLA10 d250 mg bid PEN = Penicillin VK; CLA = Clarithromycin Study No.TreatmentN (mITT)

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 PEN3008 vs CLA TEL (5 d)Comparator (10 d) [–14.3; 4.8] a a 95% confidence intervals [–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 GABHS tonsillitis/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 (FEV 1 /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 TotalControlledUncontrolled TELTELTEL N=3265N=2045N=1220 Subjects (%) in Phase III Safety Population Subjects who received  1 dose and safety assessment following randomization Men1631 (50.0)949(46.4)682(55.9) Women1634 (50.0)1096(53.6)538(44.1) years95 (2.9)68(3.3)27(2.2)  65 years372 (11.4)257(12.6)115(9.4)

MM-84 Subjects (%) with Treatment-Related Adverse Events (  2%) (Controlled Phase III Studies) TELComparator N=2045N=1672 All Treatment-rel. AEs 712(34.8)465(27.8) Diarrhea272(13.3)158(9.4) Nausea166(8.1)64(3.8) Dizziness73(3.6)26(1.6) Vomiting57(2.8)24(1.4) Headache45(2.2)51(3.1) Taste perversion34(1.7)35(2.1) Blurred vision10(0.5)0 (0)

MM-85 All adverse events98 (4.8)73 (4.4) Treatment-related AEs76 (3.7)51 (3.1) GI related events54 (2.6)33 (2.0) – Diarrhea19 (0.9)13 (0.8) – Nausea18 (0.9)9 (0.5) – Vomiting19 (0.9)6 (0.4) Other events25 (1.2)18 (1.1) Subjects (%) with Discontinuations Due to Adverse Events (Controlled Phase III Studies) TELComparator N=2045N=1672

MM-86 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. Cefuroxime axetil

MM-87 Treatment-Related Adverse Events by Age (Controlled Phase III Studies) 28% 36% 27% 19% 29% 26% yr  18  65 yr  65 yr TELComparator Age % Subjects

MM-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%)

MM-89 All serious adverse events40(2.0)41(2.5) All treatment-related serious AEs 8(0.4)4(0.2) Allergic reaction2(0.1)1(0.06) Asymptomatic transaminase elevation2(0.1)0(0) Pseudomem colitis a 1(0.05)1(0.06) Erythema multiforme1(0.05)0(0) Gastroenteritis1(0.05)1(0.06) Vomiting1(0.05)0(0) Dyspnea0(0)1(0.06) Serious Adverse Events (Controlled Phase III Studies) TELComparator N=2045N=1672 N (%) Subjects a Toxin C. difficile negative

MM-90 Subject 0502/ 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 events56 (2.7)48(2.9) Treatment-related hepatic AEs 40(2.0)33(2.0) Hepatic AEs leading to10 (0.5) 8 (0.5) discontinuation Hepatic Adverse Events (Controlled Phase III Studies) TELComparator N=2045N=1672 N (%) Subjects

MM-92 Frequency of Subjects with ALT  3x ULN During Treatment (Controlled Phase III Studies) n/N (%) Subjects ALT status at baselineTelithromycinComparator Normal8/1646(0.5)5/1324(0.4)  ULN24/283(8.5)25/226(11.1)

MM-93 Distribution of ALT Values During Treatment in Subjects with Normal ALT at Baseline (Controlled Phase III Studies) CAP StudiesNon-CAP Studies ULN % Subjects ULN = Upper limit of normal TEL (N=1251) Comparator (N=936) TEL (N=395) Comparator (N=388) 11 22 33 55  8 8  ULN 11 22 33 55  8

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 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD MicrobiologyAndré Bryskier, MD Human PharmacologyVijay Bhargava, PhD Clinical Efficacy and SafetyBruno Leroy, MD ECG AnalysisClaude Benedict, MD Senior VP, Preclinical and Early Clinical Development, Aventis Conclusions Mindell Seidlin, MD

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 (K ATP, K voltage-dependent, K Ca, Na, L-type Ca) Interaction with cloned channels (I kr (HERG), K v1.5, I KS ) Studies on isolated human atrial cells (I to, I kur, 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 IC 50 Ratio Drug (mg)µMµM IC 50 / [plasma] Investigations on HERG were all conducted at the same laboratory using the same methodology (CHO cells). Sparfloxacin Moxifloxacin Clarithromycin Telithromycin Erythromycin Levofloxacin

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 BaselineOn-Therapy Number of Subjects  QTc = 1.0 ± 21.1 ms  QTc (ms)

MM-101  QTcQT dispersion TreatmentN(ms)(ms)  QTc from Baseline and QT Dispersion Telithromycin (all studies)   9.8 Telithromycin (controlled studies)   9.2 All comparators   9.4 Beta-lactams   9.6 Clarithromycin   9.5 Trovafloxacin   8.5 Mean ± SD

MM-102  QTc vs Telithromycin Plasma Concentration Concentration (µg/mL)  QTc (ms) N=1512 patients Slope=0.88 ms/µg/mL r 2 =0.0025, p  0.05

MM-103  QTc vs Telithromycin Plasma Concentration Concentration (µg/mL)  QTc (ms) Concs  5µg/mL ConcQTc  QTc N=1512 patients Slope=0.88 ms/µg/mL r 2 =0.0025, p  0.05

MM-104 TelithromycinClarithromycin 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 ms30/393(7.6)29/414(7.0)  60 ms 0/393(0)0/414(0) QTc value:  450 ms, men1/175(0.6)1/190(0.5)  470 ms, women0/219(0)0/231(0)  500 ms, men or women0/394(0)0/421(0)

MM-105 TelithromycinNon-macrolides a 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 ms73/975(7.5)52/820(6.3)  60 ms 3/975(0.3)2/820(0.2) QTc value:  450 ms, men17/480(3.5)10/417(2.4)  470 ms, women4/508(0.8) 1/427(0.2)  500 ms, men or women2/988(0.2)1/844(0.1)

MM-106 GenderMen  22.9 Women  19.3 Age< 65 years  21.1  65 years  21.7 Hepatic Present  36.9 ImpairmentAbsent  20.8 Renal CL CR < 50 mL/min400.8  20.6 ImpairmentCL CR  50 mL/min  21.2 ConcomitantTaking  19.7 CYP3A4 inhibitorsNot taking  21.3 Clinical Risk Factors for QTc Prolongation (1)  QTc (ms) N Mean ± SD

MM-107 Drugs metabolizedTaking  23.4 by CYP2D6Not taking  20.8 QT-prolongingTaking  18.7 drugsNot taking  21.2 HypokalemiaPresent  20.4 or diureticsAbsent  21.2 CardiovascularPresent  21.1 DiseaseAbsent  21.2 Prolonged QTcPresent  24.2 at baselineAbsent  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) Mean  QTc (ms) –60 –40 –  310  350  390  430  470  – Error bars show ± std deviation N = –80 80

MM-109 TelithromycinComparators Adverse Event (N = 2045)(N = 1672) Incidence of Treatment-Related Adverse Events of Special Interest in QT Interval Assessment Number (%) Subjects Dizziness73(3.6)26(1.6) Vertigo4(0.2)2(0.1) Palpitation1(0.05)1(0.1) Hypotension1(0.05)0(0) Arrhythmia0(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) QTcQTfQTn QTc = QT / (RR ^ 0.5)QTf = QT / (RR ^ 0.33)QTn = QT / (RR ^ 0.284)

MM-112 Relationship Between  QTn and Concentration for Telithromycin Doses from 800 to 3200 mg (Phase I Data)

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) Telithromycin3 ± 11 Ketoconazole10 ± 9 Telithromycin + Ketoconazole9 ± 8 Placebo3 ± 10 N=16

MM-115 Drug Interaction Between Telithromycin and Cisapride Mean  QTn ± SD (ms) 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 PlaceboTelithromycin + Sotalol Sotalol C max (µg/mL) 1.49 ± ± 0.23 QTn (ms)469 ± ± 4  QTn (ms) 76 ± 558 ± 5 Slope (ms/µg/mL)4548 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 TELTELCLA 800 mg1600 mg500 mg C max (µg/mL)1.8 ± ± ± 1.2  QTn (ms)-0.8 ± ± ± 9.0  QTc (ms)3.0 ± ± ± 15 Holter: No arrhythmias recorded Mean ± SD Data corrected for placebo

MM-119 Subjects with CV Disease:  QTn vs Telithromycin Plasma Concentration Concentration (µg/mL)  QTn (ms) N = 24 subjects (800mg mg TEL) Slope = 1.53 ms/µg/mL

MM-120  QTc vs Telithromycin Plasma Concentration in RTI Patients with Cardiovascular Disease (Phase III)  QTc (ms) N = 284 subjects Slope = ms/µg/mL r 2 = , p = 0.65 Concentration (µg/mL)

MM-121 Summary of ECG Analysis (1) Telithromycin has a weak effect on I Kr 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 Telithromycin – Presentation Agenda IntroductionMindell Seidlin, MD MicrobiologyAndré Bryskier, MD Human PharmacologyVijay Bhargava, PhD Clinical Efficacy and SafetyBruno Leroy, MD ECG AnalysisClaude Benedict, MD Conclusions Mindell Seidlin, MD VP, 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