AFRT 8 nov 2002 A3-1 Why Another Antibiotic for Respiratory Tract Infections? C. Couturier

AFRT 8 nov 2002 A3-2 Community Acquired Pneumonia Bartlett et al. Clin Infect Dis 1998;26:811–38 Incidence2–3 millions Hospitalisations (env. 1/5) Mortalité (env. 1/50) No./an USA

AFRT 8 nov 2002 A3-3 Incidence increases with age –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 A3-4 LaForce. 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

AFRT 8 nov 2002 A3-5 Why Another Antibiotic for RTI S. pneumoniae Resistance Rates Penicillin G Erythromycin A Azithromycin Clarithromycin Clindamycin Cotrimoxazole Tetracycline Levofloxacin Antimicrobial US Worldwide agent(N=10,103)(N=16,672) % Resistance Source: PROTEKT US

AFRT 8 nov 2002 A3-6 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) % isolates Penicillin-sensitive (MIC  0.06 mg/L) Penicillin-intermediate (MIC 0.12–1 mg/L) Penicillin-resistant (MIC  2 mg/L)

AFRT 8 nov 2002 A3-7 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

AFRT 8 nov 2002 A3-8 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 Subunit 16S rRNA + 20 proteins 50S Subunit 23S and 5S rRNA + 32 proteins mRNA AA-tRNAPeptidyl tRNA J. Zhu, et al., J Struct Biol :

AFRT 8 nov 2002 A3-9 Telithromycin Mechanism of Action 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 23S rRNA

AFRT 8 nov 2002 A3-10 Consequence of Double Binding to 23S rRNA V II V Erythromycin ATelithromycin No link with domain V Resistance to erythromycin A Link with domain II Telithromycin retains activity against erythromycin A- resistant organisms 5S rRNA -cladinose O O O O O O (methylation) xx

AFRT 8 nov 2002 A3-11 Ribosomal Depletion 30S 50S 30S 50S 30S Depletion of ribosome in the bacterial 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 u Telithromycin activity is not altered by inducible methylases in S.pneumoniae erm(A)

AFRT 8 nov 2002 A3-14 Resistance Phenotype (N)MIC 50 MIC 90 Range Macrolide-susceptible (11,384) Macrolide-resistant (5,288) erm(B) (657) mef(A) (436) mef(A)+erm(B) (71) Penicillin-resistant (4,027) Levofloxacin-resistant (154) Multi-drug resistant (1,500) a 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) Number of Isolates   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 (log 10 CFU/mL) Time (hours) Control TEL 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 10 5 CFU/mL S. pneumoniae Pen S Ery S

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 LOG 10 cfu/mL LOG 10 cfu/mL Hours

AFRT 8 nov 2002 A3-18 In vitro Activity of Telithromycin Data from PROTEKT US; a PROTEKT Worldwide, Organism (N)MIC 50 MIC 90 Range S. pneumoniae (10,103)  H. influenzae (2,706) (  -lactamase positive; 769) M. catarrhalis (1,896) a S. pyogenes (3,918)  MIC (µg/mL)

AFRT 8 nov 2002 A3-19 Telithromycin Selection of Antibiotic Resistance Telithromycin does not induce MLS B 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 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) C 24h (mg/L)0.03(72) AUC (0-24h) (mg.h/L)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 (mg/L)1.92.3(42)(31) t max (h)1.0 a [0.5-4] [0.5-3]

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) 2-3h24h 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)

AFRT 8 nov 2002 A3-29 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

AFRT 8 nov 2002 A3-30 PK Modifications Under Various Conditions Comparisons with Healthy Control Subjects C max AUC Renal impairment CL CR <30 mL/min 1.5 x  2.0 x  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 CL CR <30 mL/min 3.4 x  4.5 x  x  2.7 x 

AFRT 8 nov 2002 A N= 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) , 61.6 (41)(31) C max,ss (mg/mL) , 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 CLA Dose of oral midazolam was 6 mg for TEL and KET and 4 mg for CLA TEL = Telithromycin; CLA = Clarithromycin; KET = Ketoconazole MidazolamParameterTELCLAKET IntravenousAUC 2.2 x  2.7 x  5 x  OralAUC 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 CAP800 mg qd7-10 days AECB800 mg qd5 days Acute sinusitis800 mg qd5 days 800 mg qd10 days IndicationDosageDuration

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 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

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 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 4 randomized, controlled, double-blind, comparative trials (Western countries) N (mITT) TEL5 d800 mg qd TEL7 d800 mg qd CLA10 d500 mg qd181

AFRT 8 nov 2002 A3-38 CAP: Other Studies Study No.Treatment 3000TEL7-10 d800 mg qd 3009 OL TEL7-10 d800 mg qd 4 Phase III open-label studies (Western countries) N (mITT) Phase II/III comparative studies (Japan) 3010TEL7 d800 mg qd TEL7 d600 mg qd TEL7 d800 mg qd TEL7 d800 mg qd TEL7 d600 mg qd LVX7 d100 mg tid 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 AMX3006 vs CLA3009 vs TVA [–2.1; 11.1] a a 95% confidence intervals [–7.9; 7.5] a [–13.6; 5.2] a 4003 vs CLA 89% 92% 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) /197(93) 3009 OL175/187(94) /357(93) /473(90) TEL n/N (%) Study

AFRT 8 nov 2002 A3-41 Key pathogens (PPb at TOC) S. pneumoniae300/318(94)63/70(90) H. influenzae206/229(90)42/44(95) M. catarrhalis44/50(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) TELComparators 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 pathogens PRSP24/27(89) ERSP44/50(88) PRSP and ERSP16/19(84) Single pathogens PRSP 15/16(94) ERSP29/32(91) PRSP and ERSP9/10(90) 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) 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 pathogens ERSP44/50(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 (FEV 1 /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 –> 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) TELComparator N=2702N=2139 Subjects with TEAEs 1348(49.9)1035(48.4) Diarrhea292(10.8)184(8.6) Nausea213(7.9)99(4.6) Dizziness (excl vertigo) 99(3.7)57(2.7) Vomiting79(2.9)48(2.2) Loose stools63(2.3)33(1.5) Headache148(5.5)125(5.5) Dysguesia43(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) TELComparator N=2702N=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 events58 (2.1)37 (1.7) – Diarrhea23 (0.9)13 (0.6) – Nausea19 (0.7)10 (0.5) – Vomiting21 (0.8)10 (0.5) TELComparator N=2702N=2139

AFRT 8 nov 2002 A3-53 Clinical Safety of Telithromycin Phase III clinical efficacy studies Large study in usual care setting (Study 3014) Post-marketing experience

AFRT 8 nov 2002 A3-54 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) TELComparator N=12,159N=11,978 Subjects with TEAEs 2807(23.1)2745(22.9) Diarrhea423(3.5)813(6.8) Nausea382(3.1)286(2.4) Headache230(1.9)144(1.2) Dizziness (excl vertigo) 192(1.6)59(0.5) Abdominal pain106(0.9)100(0.8) Vomiting102(0.8)115(1.0) Vaginosis fungal58(0.5)162(1.4)

AFRT 8 nov 2002 A3-59 Clinical Safety of Telithromycin Phase III efficacy studies Large study in usual care setting (Study 3014) Post-marketing experience

AFRT 8 nov 2002 A3-60 Safety in Post-Marketing Experience > 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 Summary of Telithromycin Safety (2) 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 Summary of Telithromycin Safety (3) 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