1. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-1 FDA Advisory Committee January 8, 2003 KETEK ™ (telithromycin) Aventis Pharmaceuticals

2. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-2 Introduction Steve Caffe, MD Vice President, US Regulatory Affairs, Aventis

3. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-3 Telithromycin – Background Ketolide antibiotic Claimed indications: –community-acquired pneumonia (CAP) –acute exacerbation of chronic bronchitis (AECB) –acute sinusitis (AS) April 2001, Advisory Committee recommended additional data be gathered, including: –resistant S. pneumoniae –larger safety database

4. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-4 Additional Safety and Efficacy Data June 2001, Approvable Letter for CAP, AECB, AS Clinical program designed in collaboration with the FDA, including: –PK studies in special populations –studies in CAP and AECB –large comparative study in a usual care setting (>24,000 subjects) Post-marketing data from  1.5 million exposures (including Germany, France, Italy and Spain)

5. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-5 Telithromycin – Presentation Agenda IntroductionSteve Caffe, MD Human PharmacologyVijay Bhargava, PhD MicrobiologyStephen Jenkins, PhD Clinical EfficacyBruno Leroy, MD ConclusionsPaul Iannini, MD Clinical SafetyPaul Lagarenne, MD Medical NeedPaul Iannini, MD

6. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-6 Experts in Attendance (1) H. Bodenheimer, MD, Beth Israel Medical Center, New York, NY W. Craig, MD, University of Wisconsin, Madison, WI J. Dohar, MD, University of Pittsburgh School of Medicine, Pittsburgh, PA D. Farrell, PhD, GR Micro Ltd, London, UK L. Fisher, PhD, University of Washington, Seattle, WA F. Fraunfelder, MD, Oregon Health Sciences University, Portland, OR G. Harding, MD, Aston University School of Medicine, Birmingham, UK P. Iannini, MD, Danbury Hospital, Danbury, CT S. Jenkins, PhD, Carolinas Medical Center, Charlotte, NC J. Jones, MD, The Degge Group Ltd, Arlington, VA

7. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-7 Experts in Attendance (2) J. Lewis, MD, Georgetown University Medical School, Georgetown, DC W. Maddrey, MD, Univ. of Texas Southwestern School of Medicine, Dallas, TX H. Paulus, MD, University of California at Los Angeles, Los Angeles, CA C. Pratt, MD, Baylor College of Medicine, Houston, TX E. Rubin, MD, Thomas Jefferson Univ. School of Medicine, Philadelphia, PA M. Sorrell, MD, University of Nebraska Medical School, Omaha, NE P. Watkins, MD, Univ. of North Carolina School of Medicine, Chapel Hill, NC G. Williams, MD, New York Medical College, Valhalla, NY

8. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-8 Medical Need Paul Iannini, MD Danbury Hospital, Danbury, Connecticut

9. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-9 A clinician’s needs: –targeted spectrum that satisfies criteria for empiric therapy –high potency against S. pneumoniae –concentration-dependent, rapid killing –reduced impact on other bacterial flora –safe and well tolerated Medical Need for a New Anti-infective for Community-Acquired RTIs (1)

10. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-10 Medical Need for a New Anti-infective for Community-Acquired RTIs (2) CAP: S. pneumoniae infections, including bacteremia and L. pneumophila, which have the highest risk of mortality AECB: patients with risk factors and documented obstruction AS: avoid complications by choosing the right drug the first time Once-daily dosage with short durations of therapy

11. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-11 Telithromycin Addresses an Unmet Medical Need Optimal RTI Spectrum of Activity Telithromycin Macrolides Amoxicillin-clavulanate Fluoroquinolones Atypicals ERSP PRSP Non-respiratory tract gram negative coverage S. pneumoniae H. influenzae M. catarrharis

12. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-12 Surveillance studies may overestimate resistance but trends are clear Rates of resistance to macrolides range from 22 to 32% and for penicillin G from 18 to 24% a Resistance to newer fluoroquinolones is low but increasing Multi-drug resistance rates (4 drugs) are ~10% Useful life of older agents may be diminishing S. pneumoniae Resistance in USA a Source: CDC, 2000; PROTEKT Studies 2000-2001; TRUST 2001-2002

13. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-13 Available agents do not meet current clinical needs: –sub-optimal drug concentrations for current levels of resistance (MICs  8.0 μg/mL for amoxicillin,  16.0 μg/mL for macrolides,  4.0 μg/mL for fluoroquinolones) –clinical failures of commonly used agents are emerging Implications of Increased Resistance

14. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-14 Increased mortality with S. pneumoniae with penicillin MICs  2.0 or 4.0 μg/mL and a statistically significant increase in suppurative complications a High likelihood of failure to prevent S. pneumoniae bacteremia with macrolide therapy for CAP caused by macrolide resistant strains b Fluoroquinolone failures in subjects with S. pneumoniae initial or acquired resistance mutations during therapy c Clinical Relevance of Resistance: A Debate a Metlay et al. CID 2000, Turret et al. CID; 1999, Fieken et al. Am J Pub Health. 2000. b Lonks et al. CID 2002, Kelly et al. CID. 2000. c Davidson et al. NEJM. 2002, Urban et al. JID. 2001, Empy et al. Ann Pharmacotherapy. 2001.

15. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-15 Optimal therapy for community-acquired RTIs requires antibiotics with a targeted spectrum that includes common and atypical pathogens Increased bacterial resistance to current antibiotics commonly used in the therapy of RTIs may shorten useful life There is a Medical Need for a New Anti-infective in Community-Acquired RTIs

16. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-16 Microbiology Stephen Jenkins, PhD Carolinas Medical Center Charlotte, North Carolina

17. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-17 Overview of the Microbiology Features of Telithromycin First ketolide antibiotic derived from macrolides Novel dual binding mechanism Focused spectrum of activity against all common outpatient RTI pathogens (minimal impact on usual bacterial host flora) Especially active against S. pneumoniae, including macrolide-, penicillin-, and/or multiple antibiotic-resistant strains

18. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-18 Telithromycin Mechanism of Action (1) Prevents bacterial protein synthesis by: –binding to two specific sites on the bacterial ribosome –interfering with elongation of nascent polypeptide chains Interacts strongly with both domain V and, unlike available macrolides, domain II of the 23S rRNA Result: Activity against most macrolide-resistant strains of S. pneumoniae (MIC 99 = 1 µg/mL) a a Source: PROTEKT Studies (data on file)

19. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-19 Telithromycin Mechanism of Action (2) 5S rRNA Domain V Domain II Pocket: peptidyl transferase site 5S rRNA 2058 752 V II V Erythromycin ATelithromycin 2058 752 30S 50S O O O O O O -cladinose 23S rRNA

20. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-20 Prevalence (%) of S. pneumoniae Antibiotic Resistance 26.4 31.8 11.8 PRSPERSPMDRSP North Central 21.7 26.5 7.9 Northeast PRSPERSPMDRSP 36.5 40.2 12.8 Southeast PRSPERSPMDRSP 32.7 38.6 7.7 South Central PRSPERSPMDRSP 27.1 29.3 11.3 Southwest PRSPERSPMDRSP 17.3 23.2 7.1 Northwest PRSPERSPMDRSP Source: PROTEKT Studies (data on file) PR = penicillin resistant; ER = erythromycin (macrolide) resistant; MDR = multi-drug resistant (penicillin, TMP/SXT, tetracycline, macrolides)

21. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-21 S. pneumoniae Antibiotic Resistance Rates (N=10,103) Penicillin G24.2 Erythromycin A31.7 Azithromycin31.5 Clarithromycin31.3 Clindamycin13.6 Cotrimoxazole31.1 Tetracycline22.1 Levofloxacin0.9 % Resistance Source: PROTEKT Studies (data on file)

22. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-22 In vitro Activity of Telithromycin Source: PROTEKT Studies (data on file) Organism (N)MIC 50 MIC 90 Range S. pneumoniae (16,672)0.0150.50.002 – 8 H. influenzae (8,064)1.02.00.002 – 32 (  -lactamase positive; 1,631)2.04.00.008 – 16 M. catarrhalis (1,156)0.060.120.004 – 0.5 (  -lactamase positive; 1,071)0.060.120.008 – 0.5 S. aureus (2,676)0.06  64  0.008 –  64 S. pyogenes (3,918)0.030.03  0.015 –  16 MIC (µg/mL)

23. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-23 Pathogen MIC 50 MIC 90 Range M. pneumoniae a 0.008 0.008 0.008 – 0.06 (N=47) C. pneumoniae b 0.0625 0.250.031 – 2 (N=19) L. pneumophila c,d 0.008 0.015  0.004 – 0.015 (N=26) Telithromycin Activity Against Atypical and Intracellular Pathogens MIC (µg/mL) a Kenny and Cartwright, Antimicrob Agents Chemother, 2001 b Hammerschlag et al., J Antimicrob Chemother, 2001 c PROTEKT Studies (data on file) d MCC 90 = 0.25 μg/mL

24. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-24 Resistance Phenotype (N)MIC 50 MIC 90 Range Macrolide-susceptible (11,384)0.0150.015  0.002 – 1 Macrolide-resistant (5,288) 0.121.00.008 – 8 erm(B) (657)0.060.50.008 – 8 mef(A) (436)0.120.50.008 – 1 mef(A) + erm(B) (71)0.50.50.06 – 1 Penicillin-resistant (4,027)0.121.00.004 – 8 Levofloxacin-resistant (154)0.030.50.004 – 1 Multi-drug-resistant (1,500) a 0.121.00.008 – 8 In vitro Activity of Telithromycin Against Antibiotic-Resistant S. pneumoniae Source: PROTEKT Studies (Data on file) (N=16,672) a resistant to penicillin, the macrolides, TMP/SXT, and tetracycline MIC (µg/mL)

25. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-25 Activities of Telithromycin and Macrolides Against Erythromycin-Resistant S. pneumoniae (N=3,131) 0 500 1000 1500 2000 2500 Number of Isolates  0.015 0.030.060.120.25 0.5 1248  16 MIC (µg/mL) Telithromycin Erythromycin Clarithromycin Azithromycin Source: PROTEKT Studies (Data on file)

26. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-26 Bactericidal Activity of Telithromycin Against Macrolide-Resistant S. pneumoniae S. pneumoniae Strain 5467 mef(A) MIC = 0.125 μg/mL S. pneumoniae Strain 5991 erm(B) MIC  0.015 μg/mL Hours 0 µg/mL 0.06 0.125 0.25 0.5 1 2 4 8 16 2 4 6 8 10 0246812 LOG 10 cfu/mL 0246812 2 4 6 8 10 LOG 10 cfu/mL Hours

27. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-27 Decreased Propensity of Telithromycin to Induce or Select for Antibiotic Resistance In vitro: –telithromycin does not induce MLS B resistance –in serial passage experiments, telithromycin less efficient in selecting resistant mutants of S. pneumoniae than azithromycin, clarithromycin, erythromycin, roxithromycin, or clindamycin In vivo: –in a clinical trial, telithromycin was shown to be less likely to select populations of mutants resistant to itself among the usual oropharyngeal viridans group streptococci than clarithromycin

28. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-28 Summary of Microbiology Features of Telithromycin First ketolide antibiotic Unlike macrolides: dual, strong binding mechanism Focused spectrum of activity against usual typical and atypical/intracellular RTI pathogens with minimal impact on GI or oropharyngeal flora Low propensity to select antibiotic-resistant mutants Especially active against S. pneumoniae, including macrolide-, penicillin-, and/or multiple antibiotic- resistant strains

29. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-29 Clinical Efficacy Bruno Leroy, MD Senior Director, Clinical Development Anti-infectives, Aventis

30. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-30 Dosing Regimen and Study Design Pretherapy/ Entry Comparators: 7-10 days TEL: 5 days Placebo: 5 days Posttherapy/ TOC Late Posttherapy Telithromycin: 7-10 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 Telithromycin: –CAP: 7-10 days –AECB: 5 days –Acute sinusitis: 5 and 10 days

31. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-31 CAP: Phase III Studies (Western) 4 randomized, controlled, double-blind, comparative studies: –total of 1583 subjects, 881 treated with telithromycin (TEL) 800 mg qd for 5-10 days –comparators: amoxicillin (AMX) 1000 mg tid for 10 days clarithromycin (CLA) 500 mg bid for 10 days (2 studies) trovafloxacin (TVA) 200 mg qd for 7-10 days 4 open, uncontrolled studies: –1408 subjects treated with TEL 7-10 days –3 studies “enriched” for S. pneumoniae

32. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-32 CAP: Phase II/III Studies (Japanese) 2 comparative studies: –TEL 600 mg qd for 7 days vs. TEL 800 mg qd for 7 days –TEL 600 mg qd for 7 days vs. levofloxacin 100 mg tid for 7 days 222 subjects treated with TEL 600 mg qd or 800 mg qd Only efficacy against S. pneumoniae resistant pathogens integrated with Western studies

33. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-33 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 143 162 138 156 141 149 137 152 72 80 81 86 a 95% confidence intervals [–7.9; 7.5] a [–13.6; 5.2] a 4003 vs CLA 89% 92% 142 159 143 161 134 146 TEL (7-10 d)Comparators (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

34. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-34 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) TelithromycinComparators a n/N (%)n/N(%) CAP: Clinical Cure by Pathogen (All Western Studies) a Study 3001: amoxicillin; Studies 3006 and 4003: clarithromycin; Study 3009: trovafloxacin

35. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-35 CAP: Bacteriological Eradication and Clinical Cure for S. pneumoniae Pathogens in TEL Subjects 0.0044/4(100) 4/4(100) 0.008123/125(98)121/125(97) 0.016 a 109/113(96) 106/113(94) 0.0321/23(91)21/23(91) 0.06 6/6(100) 6/6(100) 0.124/6(67) 4/6(67) 0.251/1 (100) 1/1(100) 0.53/3 (100) 3/3(100) 15/5(100)5/5(100) Total (all MICs)276/286(97)271/286(95) NA29/32(91) 29/32 (91) Total305/318(96)300/318(94) PPb population at TOC (All Western studies) NA = not available; a Data for MIC values of 0.015 and 0.016 µg/mL have been pooled Bact. EradicationClinical Cure n/N (%) Subjects MIC (μg/mL)

36. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-36 CAP: Bacteriological Eradication and Clinical Cure for H. influenzae Pathogens in TEL Subjects Bact. EradicationClinical Cure 0.0021/1(100) 1/1(100) 0.121/1(100) 1/1(100) 0.253/3(100)3/3(100) 0.5 3/5(60) 4/5(80) 141/47(87) 40/47(85) 286/96(90) 88/96(92) 435/40(88) 36/40(90) 811/11(100)11/11(100) Total (all MICs)181/204(89)184/204(90) NA23/25(92)22/25(88) Total204/229(89)206/229(90) n/N (%) Subjects PPb population at TOC (All Western studies) NA = not available MIC (μg/mL)

37. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-37 CAP: Clinical Cure for Resistant S. pneumoniae Isolates n/N (%) Subjects PPb population at TOC (All Western + Japanese studies) PRSP = penicillin G-resistant (MIC  2.0 µg/mL) ERSP = macrolide (erythromycin A)–resistant (MIC  1.0 µg/mL) PRSP24/27(89) ERSP44/50(88) erm(B)24/28(86) mef(A)16/18(89) erm(B) and mef(A)3/3(100) negative for erm(B) or mef(A)1/1(100)

38. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-38 CAP: Clinical Cure for Pneumococcal Bacteremia Blood culture positive All S. pneumoniae74/82(90) PRSP5/7(71) ERSP8/10(80) ERSP with urinary Ag positive only a 4/4(100) PPb population at TOC (All Western Studies) a Sputum positive, blood culture negative, S. pneumoniae urinary antigen positive (Binax test) n/N (%) Subjects

39. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-39 CAP: Clinical Cure by Risk Factors for Morbidity Total population641/711(90)490/540 (91) 1755/1925(91)  65 years old 93/111(84)83/96(87) 243/278(87) Pneumococcal32/33 (97)15/19(79) 74/82(90) bacteremia a Fine score  III107/123(87)93/110(85) 267/297(90) Controlled studies n/N(%)n/N(%)n/N(%) All CAP studies PPc population at TOC (Western Studies) TelithromycinComparatorsTelithromycin a PPb population

40. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-40 Summary of Efficacy in CAP Effective in outpatients at risk for complications (elderly, pneumococcal bacteremia, Legionella) Common pathogens –S. pneumoniae, including PRSP ERSP –H. influenzae –M. catarrhalis Atypical pathogens –M. pneumoniae –C. pneumoniae –L. pneumophila Telithromycin 800 mg once daily for 7 to 10 days is highly effective in CAP Targets key outpatient pathogens:

41. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-41 3 randomized, controlled, double-blind, comparative studies: –total of 1245 subjects, 612 treated with telithromycin (TEL) 800 mg qd for 5 days –comparators: amoxicillin-clavulanic acid (AMC) 500/125 mg tid for 10 days cefuroxime axetil (CXM) 500 mg bid for 10 days clarithromycin (CLA) 500 mg bid for 10 days AECB: Phase III Studies

42. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-42 AECB: Clinical Cure at TOC, PPc 86% 83% 82% 0% 20% 40% 60% 80% 100% 3003 vs AMC3013 vs CLA TEL (5 d)Comparators (10 d) 99 115 92 112 121 140 118 142 [–6.4; 14.3] a a 95% confidence intervals [–9.9; 3.1] a 86% 89% 193 225 206 231 [–5.8; 12.4] a 3007 vs CXM

43. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-43 AECB: Clinical Cure by Pathogen (All Studies) a Study 3003: amoxicillin-clavulanic acid, Study 3007: cefuroxime axetil; 3013: clarithromycin Key pathogens (PPb at TOC) S. pneumoniae 22/27(82)15/19(79) H. influenzae 44/60(73)45/53(85) M. catarrhalis 27/29(93)29/34(85) Atypical pathogens (PPc at TOC) C. pneumoniae 11/12(92) 8/11(73) Telithromycin (5 d) Comparators (10 d) a n/N (%)n/N(%)

44. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-44 AECB: Clinical Cure by Risk Factors for Morbidity Total Population413/480(86)416/485(86)  65 years old157/184 (85) 179/215(83) Morbidity risk factors at least 1290/338(86)284/332(86) at least 2142/171(83)152/181(84) FEV 1 /FVC <60%117/149(79) 129/157(82) TelithromycinComparators n/N (%)n/N(%) PPc population at TOC

45. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-45 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 –C. pneumoniae Effective in outpatients at risk for complications (elderly, significant obstruction)

46. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-46 Acute Sinusitis: Phase III Studies 3 randomized, double-blind studies comparing: –5 days and 10 days telithromycin (TEL) 800 mg qd* –5 days and 10 days TEL 800 mg qd to amoxicillin- clavulanic acid (AMC) 500/125 mg tid for 10 days –5 days TEL 800 mg qd to cefuroxime axetil (CXM) 250 mg bid for 10 days* Total of 1298 subjects, 608 treated 5 days and 372 treated 10 days with TEL * Bacterial documentation in all subjects

47. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-47 Acute Sinusitis: Clinical Cure at TOC, PPc 0% 20% 40% 60% 80% 100% TEL (5 d)TEL (10 d)Comparators (10 d) 91% 3002 112 123 121 133 [–7.7; 7.9] a 75% 73% 75% 3005 vs AMC 110 146 102 137 102 140 [–12.7; 9.5] a [–9.9; 11.7] a a 95% confidence intervals 85% 82% 3011 vs CXM 161 189 73 89 [–7.1; 13.4] a

48. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-48 S. pneumoniae55/61(90)27/30(90)14/16(88) H. influenzae42/48(88)15/16(94)13/15(87) M. catarrhalis13/14(93)3/4(75)7/7(100) S. aureus18/19(95)4/4(100)3/4(75) TEL (5 d)TEL (10 d)Comp (10 d) a n/N (%)n/N(%)n/N(%) Acute Sinusitis: Clinical Cure by Pathogen (All Studies) PPb population at TOC TEL = telithromycin, Comp = comparators a Study 3005: amoxicillin – clavulanic acid; Study 3011: cefuroxime axetil

49. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-49 Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates (All Studies) PRSP8/103/311/13 ERSP12/146/718/21 n/N Subjects (TEL) PPb population at TOC 5 d10 d5+10 d PRSP = penicillin G resistant (MIC  2.0 µg/mL) ERSP = macrolide (erythromycin A)–resistant (MIC  1.0 µg/mL)

50. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-50 Acute Sinusitis: Clinical Cure in Subgroups of Interest Total population271/335(81)175/226 (77) 383/458(84)  7 days of symptoms229/281(81)135/173(78) 266/325(82) Pathogens at entry a 90/107(84)44/57(77) 155/177(88) Severe illness45/55(82)35/45(78)82/95(86) at entry b Total opacity on X-ray 84/98(86)33/43(77) 153/173(88) Controlled studies n/N(%)n/N(%)n/N(%) All AS studies PPc population at TOC TEL (5 d)Comp (10 d)TEL (5 d) a PPb population; b According to investigator assessment at entry

51. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-51 Summary of Efficacy in Acute Sinusitis Telithromycin 800 mg once daily for 5 days equivalent to 10 days of treatment with amoxicillin-clavulanic acid or cefuroxime axetil 5-day treatment effective against: –S. pneumoniae, including PRSP ERSP –H. influenzae –M. catarrhalis –S. aureus

52. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-52 Telithromycin Efficacy in RTIs Effective in 3 targeted RTI indications: –demonstrated in 14 studies (800 mg qd) –AECB and acute sinusitis (5-day treatment) –CAP (7- to 10-day treatment) Effective in outpatients at risk for complications Effective against key outpatient respiratory pathogens, including common, atypical and resistant pathogens

53. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-53 Human Pharmacology Vijay Bhargava, PhD Senior Director, Drug Metabolism and Pharmacokinetics, Aventis

54. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-54 Human Pharmacology Program Telithromycin has been extensively studied: –plasma and tissue pharmacokinetics –effect of impairment of elimination pathways on exposure of telithromycin –effect of telithromycin on exposure of other drugs (CYP3A4 substrates)

55. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-55 Pharmacokinetics in Healthy Subjects Single dose Repeated dose (7d) 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] 0.07 12.5 9.8 Telithromycin 800 mg (oral)

56. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-56 Tissue and Fluid Penetration in Subjects with RTIs Tissue Mean (CV%) concentration after TEL 800 mg (µg/mL) 2h24h Alveolar macrophages69162 N = 6 TEL = telithromycin Epithelial lining fluid 12h 14.90.83.3 318 (76)(62)(51) (60)(59)(73)

57. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-57 Oral administration (  90% absorbed, <10% unabsorbed) Systemic bioavailability (57%) Renal excretion Unchanged drug in urine GI tract/biliaryHepatic excretion Unchanged drug in feces Total metabolized drug (~70%)* Metabolism in liver and GI tractFirst pass effect Multiple Pathways of Elimination (13%) (37%) (7%) (33%) Non-P450 mediated CYP3A4- mediated (~35%) *Telithromycin is not metabolized by CYP2D6 (~35%)

58. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-58 Studies to Investigate Effects of Elimination Pathway Impairments Pathway ImpairedStudy Population HepaticSubjects with mild, moderate, and severe hepatic impairment vs. healthy control subjects RenalSubjects with mild, moderate, and severe renal impairment vs. healthy control subjects CYP3A4Crossover study in healthy subjects receiving telithromycin with and without ketoconazole MultipleSubjects  60 years of age with renal impairment impairment, receiving ketoconazole to block CYP3A4

59. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-59 Hepatic impairment N=13 Healthy N=13 Day 1Day 7Day 1Day 7 t 1/2, z (h)11.9 (21)–11.0 (20) CL R (L/h) C max (µg/mL) 1.5 (33)1.8 (23)1.7 (32)1.9 (30) AUC 0-24h (µg.h/mL) 9.1 (36)12.4 (20)8.8 (32)13.3 (27) – 14.6 (48)14.8 (45)10.7 (20)11.7 (15) Data are mean (CV%) Child Pugh score: 5-6 = 4 subjects; 7-9 = 6 subjects; 10-11 = 3 subjects Effect of Hepatic Impairment Systemic bioavailability Renal excretion Hepatic excretion Metabolites Telithromycin 800 mg qd; 7-day repeated dose

60. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-60 CL CR (mL/min)>8050-8030-49<30 N=9N=8N=8N=8 C max,ss (µg/mL)2.1 (39)2.6 (13.4)2.2 (48)3.0 (40) AUC 0-24h,ss (µg.h/mL)12.4 (48)16.0 (22)14.8 (41)23.6 (29) CL R (L/h)12.7 (28)7.3 (31)4.1 (31)2.1 (41) Effect of Renal Impairment Systemic bioavailability Renal excretion Unchanged drug in urine Study also investigated TEL 400 and 600 mg qd Telithromycin 800 mg qd; 5-day repeated dose Mean (%CV)

61. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-61 Telithromycin N=11 Telithromycin + Ketoconazole N=11 C max (µg/mL)2.0(38)3.1(36) AUC (0-24 h) (µg.h/mL)14.4(39)28.6(31) t ½, z (h)11.2(26)12.6(27) Data are mean (CV%): telithromycin 800 mg qd (5 days), ketoconazole 400 mg qd (7 days) Itraconazole: less interaction, grapefruit juice: no interaction Effect of CYP3A4 Inhibition First pass effect Systemic bioavailability Hepatic excretion Metabolites Metabolism in liver and GI tract CYP3A4-mediated ~35%

62. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-62 Effect of Multiple Impairments (Renal + Ketoconazole) First pass effect Systemic bioavailability Hepatic excretion Metabolism in liver and GI tract CYP3A4- mediated metabolites ~35% Renal excretion Unchanged drug in urine non-CYP3A4- mediated metabolites ~35%

63. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-63 Creatinine clearance (mL/min)30-80 Mean age (years)74 N=10 2 subjects in the TEL + Keto had CL CR  30 mL/min (28, 24 mL/min): C max = 5.4, 8.8 μg/mL; AUC (0-24h) = 51.7, 61.6 μg.h/mL Effect of Multiple Impairments (Renal + Ketoconazole) C max,ss (µg/mL)3.6 (22) AUC (0-24h) (µg.h/mL)33.4 (31) CL R (L/h)6.1 (30) TEL + Keto Mean (CV%) exposure to TEL or CLA TEL = telithromycin CLA = clarithromycin Keto = ketoconazole First pass effect Systemic bioavailability Hepatic excretion Metabolism in liver and GI tract CYP3A4- mediated metabolites Renal excretion Unchanged drug in urine non-CYP3A4- mediated metabolites ~35%

64. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-64 Creatinine clearance (mL/min)30-8030-80 Mean age (years)7469 N=10N=6 2 subjects in the TEL + keto had CL CR  30 mL/min (28, 24 mL/min): C max = 5.4, 8.8 μg/mL; AUC (0-24h) = 51.7, 61.6 μg.h/mL Effect of Multiple Impairments (Renal + Ketoconazole) C max,ss (µg/mL)3.6 (22)6.2 (36) AUC (0-24h) (µg.h/mL)33.4 (31)112.2 (41) CL R (L/h)6.1 (30)6.4 (48) TEL + KetoCLA + Keto Mean (CV%) exposure to TEL or CLA First pass effect Systemic bioavailability Hepatic excretion Metabolism in liver and GI tract CYP3A4- mediated metabolites Renal excretion Unchanged drug in urine non-CYP3A4- mediated metabolites TEL = telithromycin CLA = clarithromycin Keto = ketoconazole ~35%

65. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-65 AUC 0-24h,ss (µg.h/mL) 0 50 100 150 N= 6 CLA + Keto Study 1063 10 TEL + Keto Study 1063 0 3 6 9 C max,ss (µg/mL) N= 6 CLA + Keto Study 1063 10 TEL + Keto Study 1063 Telithromycin and Clarithromycin Exposure in Subjects with Multiple Impairment TEL = telithromycin CLA = clarithromycin Keto = ketoconazole CLA impairedTEL impaired

66. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-66 AUC 0-24h,ss (µg.h/mL) 0 50 100 150 N= 126 CLA + Keto Study 1063 CLA van Haarst et al. * 1810 TEL Study 1008 TEL + Keto Study 1063 0 3 6 9 C max,ss (µg/mL) N= 126 CLA + Keto Study 1063 CLA van Haarst et al. * 1810 TEL Study 1008 TEL + Keto Study 1063 Telithromycin and Clarithromycin Exposure in Subjects with Multiple Impairment TEL = telithromycin CLA = clarithromycin Keto = ketoconazole CLA healthyCLA impairedTEL healthyTEL impaired x1.6 x2.2 x2.7 x3.3 * van Haarst et al. Clin Pharmacol Ther, 1998.

67. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-67 a Mean age 59 years; b Mean age 74 years Summary of Exposures: Ratios of Impaired to Healthy Subjects Telithromycin exposure ratios Hepatic impairment1.0(0.8–1.2)1.0(0.8–1.1) Renal impairment a CL CR 50-80 mL/min1.3(1.0–1.8)1.4(1.0–1.9) CL CR 30-49 mL/min1.0(0.8–1.4)1.2(0.9–1.7) CL CR  30 mL/min1.5(1.1–2.0)2.0(1.5–2.8) CYP3A4 inhibition Ketoconazole1.5(1.1–2.0)1.9(1.5–2.5) Itraconazole1.2(1.0–1.4)1.5(1.4–1.7) Renal impairment + keto b CL CR 30-80 mL/min1.62.7 CL CR  30 mL/min3.14.5 Subjects withC max (90% CI)AUC(90% CI)

68. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-68 Comparison of Effects on CYP3A4 Substrate: Simvastatin Dosing regimen: telithromycin 800 mg qd for 5 days, simvastatin 40 mg once on Day 5. a Study 1048 b Study 1067 c Lilja et al. Clin Pharmacol Ther, 1998. d Neuvonen et al. Clin Pharmacol Ther, 1998. Telithromycin a 5.38.914.911.9 Clarithromycin b 8.27.914.313.9 Grapefruit juice c 91677 Itraconazole d 10101719 Fold increase in Exposure SimvastatinSimvastatin acid C max AUC

69. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-69 Reduction of Simvastatin Interaction with Different Time of Administration TEL = telithromycin a After 40 mg single dose of simvastatin, before and after telithromycin 800 mg qd for 5 days. Data from Study 1065 Concomitant 12 hours apartN=14 SimvastatinC max 7.7 (6.3–9.5)3.4 (2.8–4.2) AUC8.4 (5.9–11.9)3.8 (2.8–5.1) SimvastatinC max 10.0 (8.3–12.1)3.2 (2.6–3.8) acidAUC9.4 (7.4–11.9)4.3 (3.3–5.4) Fold increase in exposure a (90% confidence interval)

70. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-70 Effect of Telithromycin on Other CYP3A4 Substrates a Midazolam data from Gorski et al. Clin Pharmacol Ther, 1998. b Cisapride data from van Haarst et al. Clin Pharmacol Ther, 1998. Telithromycin2.66.12.02.4 Clarithromycin a,b 372.73.2 Fold increase in midazolam / cisapride exposure MidazolamCisapride C max AUC

71. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-71 Summary of Telithromycin Human Pharmacology Pharmacokinetics reproducible and predictable under various conditions Targeted plasma and respiratory tissue concentrations rapidly achieved Multiple elimination pathways limit the potential for increased exposure in special populations Similar CYP3A4 inhibition to clarithromycin, but telithromycin is dosed once daily and for shorter treatment duration in RTIs

72. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-72 Clinical Safety Paul Lagarenne, MD VP, Clinical Safety Analysis, Aventis Global Pharmacovigilance

73. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-73 Clinical Safety of Telithromycin Phase III studies: –4,472 telithromycin subjects, including 2,702 in controlled studies Large comparative study in usual care setting (Study 3014): –12,159 telithromycin subjects Post-marketing experience: –  1.5 million exposures as of December 1 st, 2002* * based upon Aventis internal sales data to retail and outpatient pharmacies

74. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-74 Phase III Clinical Studies

75. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-75 Most Frequent Adverse Events in Controlled Phase III Studies TelithromycinComparators N=2702N=2139 Subjects (%) with AEs 1348(49.9)1035(48.4) Diarrhea292(10.8)184(8.6) Nausea213(7.9)99(4.6) Headache148(5.5)125(5.8) Dizziness99(3.7)57(2.7) Vomiting79(2.9)48(2.2) Loose stools63(2.3)33(1.5) Dysgeusia43(1.6)77(3.6)

76. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-76 Adverse Events Leading to Discontinuation and Serious Adverse Events in Controlled Phase III Studies Adverse events leading 119(4.4)92(4.3) to discontinuation All serious adverse events 59(2.2)61(2.9) All treatment-related serious AEs 9(0.3)6(0.3) Deaths a 7(0.3)9(0.4) TELComparators N=2702N=2139 N (%) Subjects a No treatment-related deaths TEL = telithromycin

77. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-77 Blurred Vision with Telithromycin in Controlled Phase III Studies Uncommon event: 0.6% subjects Generally mild Limited duration and fully reversible No sequelae No serious reports Single subject required discontinuation of drug

78. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-78 Investigation of Visual Effects Two Phase I studies with high doses (2400 mg): –mostly described as a delay in focusing from near to far vision –onset within a few hours (median: 3 h) –rapid recovery within 2 to 3 h –no decreases in visual acuity –severe etiologies ruled out (e.g., angle-closure glaucoma or retinopathy)

79. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-79 ECG Analysis in Phase III Studies ECGs performed at pretherapy and on- therapy (Day 3-5) in 12 Phase III studies (N = 2411 subjects) Minimal change in mean QTc* interval of approximately 1.5 ms No difference in QTc outliers vs. comparators * Bazett correction formula

80. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-80  QTc vs Telithromycin Plasma Concentration in Phase III Studies Concentration (µg/mL)  QTc (ms) 024681012 -160 -120 -80 -40 0 40 80 120 Concs  5µg/mL ConcQTc  QTc 5.2410-7.4 5.2364-24.5 5.241113.1 5.2409-3.3 5.3428-0.9 5.843117.0 6.24251.5 6.241010.1 6.4391-38.8 6.4381-5.1 6.4393-6.0 6.743518.0 7.240817.8 7.83960.1 9.94278.7 N=1512 patients Slope=0.88 ms/µg/mL r 2 =0.0025, p  0.05

81. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-81 Hepatic Events in Controlled Phase III Studies ALT >3x ULN in 1.6% TEL and 1.7% comparator subjects Hepatic adverse events in 3.4% TEL and 3.2% comparator subjects Single subject with clinical hepatitis: –first episode: pre-existing ALT elevation and eosinophilia liver biopsy: scattered lesions, predominant macrophages, background eosinophils –second episode: 9 months later without re-exposure to telithromycin second biopsy: autoimmune hepatitis and early cirrhosis –no recurrence since November 1998

82. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-82 Large Comparative Study in Usual Care Setting (Study 3014)

83. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-83 Study 3014: Key Design Features Designed in collaboration with the FDA: –randomized, open-label comparative study –24,140 subjects enrolled and treated –enrichment of at-risk populations: minimal exclusion criteria expanded treatment duration for AECB 46% subjects 50 years or older 40% with CAP or AECB TEL = telithromycin, AMC = amoxicillin-clavulanic acid

84. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-84 Study 3014: Collection of Safety Data Designed to capture adverse events of special interest (AESIs) Office visits at pretherapy (Day 1) and post-therapy (Day 17-22) Follow-up contact at late post-therapy (Day 30-35) Hepatic laboratory testing at pretherapy and post-therapy Investigators reviewed all AEs, with particular focus on AESIs

85. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-85 Study 3014: AESI Criteria Hepatic: Hepatitis, jaundice, any worsening of a pre-existing hepatic condition, alanine aminotransferase (ALT) values  3x ULN Cardiac: Torsades de pointes, ventricular arrhythmias, syncope, cardiac arrest, or unwitnessed or unexplained death Visual: Blurred vision Vasculitic: Purpura or other signs of vasculitis Broadly defined to capture all potential endpoint cases

86. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-86 Study 3014: Investigation of AESIs All AEs and lab values reviewed to ensure complete collection of AESIs AESIs investigated using standardized questionnaires ALT  3x ULN investigated using standardized lab kits: –bilirubin, ALT, AST, alkaline phosphatase, CBC with differential, prothrombin time, viral hepatitis serologies AESIs followed up to clinical resolution All AESIs reviewed by independent, blinded clinical events committees (CECs) and adjudicated to identify safety endpoints

87. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-87 Study 3014: Follow-up Status TELAMCTotal Treated12,16111,97924,140 Safety evaluable 12,159 (99.9)11,978 (99.9)24,137 (99.9) Follow-up at Day 28 or later: – AE status12,096 (99.5)11,883 (99.2)23,979 (99.3) – Vital status 12,138 (99.8)11,941 (99.7)24,079 (99.8) Number (%) of subjects TEL = telithromycin, AMC = amoxicillin-clavulanic acid

88. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-88 Study 3014: Most Frequent Adverse Events (AEs), AEs Leading to Discontinuation, and Serious AEs TELAMC N=12,159N=11,978 Total with AEs 2807(23.1)2745(22.9) Diarrhea423(3.5)813(6.8) Nausea382(3.1)286(2.4) Headache230(1.9)144(1.2) Dizziness192(1.6)59(0.5) AEs leading to discontinuation467(3.8)557(4.7) Serious AEs155(1.3)133(1.1) TEL = telithromycin, AMC = amoxicillin-clavulanic acid Number (%) of subjects

89. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-89 Study 3014: Adverse Events in Subgroups Subjects with AEs2807/12159(23)2745/11978(23)  65 years518/2273(23)526/2203(24) Hepatic impairment 31/97(32)41/119(35) Renal impairment19/78(24)16/76(21) Cardiovascular disease793/2965(27)737/2915(25) CYP3A4 substrates1499/5834(26)1542/5795(27) –HMG CoA reductase inhib.347/1420(24)305/1341(23) TEL AMC n/N (%) subjects with AEs TEL = telithromycin, AMC = amoxicillin-clavulanic acid

90. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-90 Study 3014: Hepatic AESIs Uncommon and balanced: –TEL: 111 (0.9%), AMC: 98 (0.8%) All AESIs followed up to clinical and/or lab resolution –except 1 AMC subject No chronic or immune-mediated hepatic injury No drug-related severe hepatotoxicity (hepatic failure, liver transplant, death)

91. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-91 Study 3014: Hepatic Endpoint Definition: possibly drug-related significant hepatic injury –clinical signs and symptoms –ALT values of at least 3x ULN –exclusion of other common causes –new onset of symptoms Day 5 or later Final endpoint in all cases determined by blinded CEC Positively-adjudicated endpoints in: –TEL: 3 / 12,096 subjects (95% CI: 0.5 - 7.2 / 10,000) –AMC: 2 / 11,883 subjects (95% CI: 0.2 - 6.1 / 10,000)

92. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-92 Study 3014: Hepatic Endpoint with Liver Biopsy Liver biopsy performed in 1 TEL endpoint subject: –72-year-old subject with concomitant cholelithiasis requiring cholecystectomy after 10-day treatment for CAP: Day 23: increased ALT, alkaline phosphatase, bilirubin (absolute eosinophils 270/mm 3 ) Day 30: abdominal ultrasound of gallbladder Day 36: laparoscopic cholecystectomy confirmed cholelithiasis and cholecystitis; – liver biopsy revealed cholestasis with fibrosis, minimal inflammation, no eosinophils complete recovery

93. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-93 Study 3014: Noteworthy Hepatic Laboratory Analytes at any Post-Therapy Visit n/N (%) of subjects TEL AMC ALT  3x ULN110/11570(1.0)96/11311(0.8) ALT  8x ULN19/11570(0.2)10/11311(0.1) ALT  3x ULN and total3/10864(0.028)6/10600(0.057) billirubin  1.5x ULN a ALT  3x ULN and total0/108641/10600 bilirubin  3 mg/dL and alk. phosphatase  2x ULN TEL = telithromycin, AMC = amoxicillin-clavulanic acid a Denominator includes subjects with simultaneous assessment of ALT and bilirubin after Day 3

94. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-94 Study 3014: Cardiac AESIs Cardiac AESIs: –TEL: 39 (0.3%), AMC: 34 (0.3%) Deaths within Day 35: –TEL: 10, AMC: 14 –no treatment-related deaths Presumed arrhythmic deaths assessed: – TEL: 7, all  7 days after treatment – AMC: 4, all  2 days after treatment

95. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-95 Study 3014: Cardiac AESIs in At-Risk Populations TELAMC n/N (%) of Subjects Elderly (  65 years)21/2273(0.9)21/2203(1.0) CV disease:27/2965(0.9)20/2915(0.7) Diuretics13/1776(0.7)12/1710(0.7) Drugs with potential11/1965(0.6)10/1899(0.5) to prolong QT CYP3A4 inhibitors15/2309(0.6)11/2201(0.5) TEL = telithromycin; AMC = amoxicillin-clavulanic acid

96. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-96 Study 3014: Cardiac Endpoint Definition: events likely to represent malignant ventricular arrhythmias Final endpoint in all cases determined by the CEC Positively-adjudicated endpoints in: –TEL: 0 / 12,096 subjects –AMC: 1 / 11,883 subjects

97. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-97 Study 3014: Visual AESIs and Visual Endpoints Definition: drug-related blurred vision Positively adjudicated visual endpoints: 75 (0.6%) TEL vs. 5 (0.04%) AMC subjects –median onset: 1 hour after dosing –median duration: 2 hours –majority mild or moderate Severe events in 0.04% TEL subjects Discontinuation for visual events in 0.2% TEL subjects Impacted activity in 0.3% TEL subjects –no accidental injuries All cases were reversible

98. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-98 Post-marketing Experience

99. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-99 Post-Marketing Experience  1.5 million post-marketing exposures to TEL since first marketed in Europe in October 2001: –includes Germany, France, Belgium, Italy, Spain, Brazil, Mexico ~1 million exposures in Germany and France 10% of prescriptions are re-exposure Intensive follow-up of all adverse events: –use of standard questionnaires as guidance for AESI follow-up No new or unexpected safety signals identified

100. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-100 Visual events generally similar to clinical trial experience: –most common events: blurred vision, abnormal accommodation, visual abnormality –78% reported in patients  50 years of age –generally of limited duration, with full recovery noted –no sequelae identified –no reports of accidental injuries Visual Findings in Post-Marketing Experience

101. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-101 No increased risk for ventricular arrhythmic events: –no reports of sudden, unexplained death –no confirmed torsades de pointes in  1.5 million exposures: 2 questionable reports: 1)terminal VF in CAD patient; no QT prolongation or torsades de pointes on ECG, as confirmed by expert review 2)no identifiable patient, no event confirmed; no record of admission or treatment for torsades de pointes or other ventricular arrhythmia Cardiac Findings in Post-Marketing Experience

102. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-102 Hepatic Findings in Post-Marketing Experience (1) Hepatic events were uncommon (64 events in 28 patients) No patients with hepatocellular jaundice: –4 patients with cholestatic jaundice: one with acute mononucleosis all recovered No chronic or immune-mediated hepatic injury

103. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-103 Hepatic Findings in Post-Marketing Experience (2) No reports of drug-related severe hepatotoxicity (hepatic failure, liver transplant, death) Fatal acute hepatitis A (IgM) with hepatic failure in an elderly man –case also confounded by: high-dose (  4g daily) acetaminophen use for 4-5 days prior to event pre-existing underlying hard nodular liver concurrent acute Q fever Overall experience comparable to marketed antibiotics

104. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-104 Safety Summary (1) Extensive experience: –  16,000 subjects in clinical studies and  1.5 million post-marketing exposures Overall safety profile similar to marketed antibiotics: –gastrointestinal events most common –low discontinuation rate

105. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-105 Safety Summary (2) Uncommon visual events: –generally mild and limited duration –mechanism consistent with delay in focusing –severe etiologies excluded –no permanent sequelae –no accidental injuries

106. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-106 Safety Summary (3) Extensive cardiac evaluation, with no confirmed cardiac safety signal: –no increase in cardiac events or deaths in Phase III studies or Study 3014 –no increase in ventricular arrhythmic events in post-marketing surveillance: no torsades de pointes

107. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-107 Safety Summary (4) Extensive hepatic evaluation, with no confirmed hepatic safety signal: –no difference in clinical hepatic events –no hepatocellular jaundice –no chronic or immune-mediated hepatic injury –no drug-related severe hepatotoxicity (hepatic failure, liver transplant, death)

108. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-108 Summary and Conclusions Paul Iannini, MD Danbury Hospital, Danbury, Connecticut

109. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-109 Optimal therapy for community-acquired RTIs requires antibiotics with a targeted spectrum that includes common and atypical pathogens Increased bacterial resistance to current antibiotics commonly used in the therapy of RTIs may shorten useful life There is a Medical Need for a New Anti-infective in Community-Acquired RTIs

110. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-110 β-lactams: –atypicals –penicillin-resistant S. pneumoniae –β-lactamase positive H. influenzae Macrolides: –macrolide-resistant S. pneumoniae Fluoroquinolones: –not targeted to RTI pathogens Limitations of Current Therapy in Community-Acquired RTIs

111. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-111 Efficacy of Telithromycin Highly effective in CAP, AECB, and AS Key added benefits: –novel mechanism of action –concentration-dependent, rapid killing –targeted RTI spectrum –active against emerging resistant strains of S. pneumoniae –short treatment duration

112. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-112 Safety of Telithromycin Extensive exposure (  1.5 million subjects) Safety comparable to widely prescribed antibiotics: –most common side effects were gastrointestinal –uncommon, mild, reversible visual events –no increased cardiac risk –no difference in clinical hepatic events –limited drug-drug interactions

113. Aventis KETEK_AC2 26-May-16 Main Presentation Version 6-5 MM-113 Telithromycin Fulfills a medical need Brings additional benefits Safety profile comparable to marketed antibiotics Valuable option for the treatment of CAP, AECB, and AS in outpatients