1. Ketek  (telithromycin) NDA Background Janice Soreth, M.D. Director Division of Anti-Infective Drug Products CDER/FDA

2. 2 Telithromycin - Background Regulatory History Overview of First Advisory Committee FDA Action Letter New Studies

3. 3 Telithromycin - Regulatory History NDA submitted to FDA February 28, 2000 First Advisory Cmte. met April 26, 2001 FDA issued approvable letter June 1, 2001 Amendment submitted July 24, 2002

4. 4 Telithromycin - April 2001 Advisory Committee Four indications proposed: –community-acquired pneumonia* –acute exacerbations of chronic bronchitis* –acute sinusitis* –tonsillopharyngitis * including penicillin- and erythromycin-resistant Streptococcus pneumoniae

5. 5 Telithromycin- April 2001 Advisory Phase III Clinical Database by Type of Study and Indication

6. April 2001 AC6 CAP: Clinical Response -TOC (N) 95% C.I. ComparatorsTelithromycin 1 Amoxicillin, 2 Clarithromycin (-9.9, 6.5) (212)81(204)79 3006 (-0.5, 15.3) (205)79(199)86 3001 mITT (-7.9, 7.5) (156)88(162)88 3006 2 (-2.1, 11.1) (152)90(149)95 3001 1 PPc (%)%

7. April 2001 AC7 AECB: Clinical Response -TOC (N) 95% C.I. Comparators 10 days Telithromycin 5 days 1 Augmentin, 2 Cefuroxime axetil (-3.5, 15.1) (191)72(182)78 3007 (-6.3, 12.6) (160)78(160)81 3003 mITT (-5.7, 12.4) (142)83(140)86 3007 2 (-6.4, 14.3) (112)82(115)86 3003 1 PPc (%)%

8. April 2001 AC8 Sinusitis: Clinical Response - TOC (N) (-2.2, 18.2)(116)72(240)80 3011 (-7.1, 13.4)(89)82(189)85 3011 2 1 Amoxicillin/clavulanate, 2 Cefuroxime axetil (-8.2, 10.9)(202)68(201)70 3005 mITT (-9.9, 11.7)(137)75(146)75 3005 1 PPc (%)%(N)% 95% C.I. Comparators 10 day Telithromycin 5 day

9. April 2001 AC9 Tonsillopharyngitis Primary efficacy based on microbiologic eradication Comparative study: success rates were 84% telithromycin v. 89% pen [-14,5] FDA guidance: 85% success for “first line” Further discussion tabled

10. April 2001 AC10 Drug Resistant Streptococcus pneumoniae

11. April 2001 AC11 Telithromycin - PRSP CAP *

12. April 2001 AC12 Telithromycin - ERSP CAP*

13. April 2001 AC13 April 2001 - Efficacy Summary FDA’s efficacy analyses consistent with those of the company for pneumonia, bronchitis, and sinusitis Substantial evidence for approval entails both efficacy and safety

14. April 2001 AC14 Telithromycin- Phase 3 Safety Data

15. April 2001 AC15 Deaths No deaths in phase I trials 11 deaths in phase III (10 CAP, 1 pharyngitis) –7 deaths in telithromycin pts, 4 in comparator pts –None directly attributed to drug –6 deaths (4 Ketek, 2 comp) scored as tx failures –6/7 telithromycin-treated patients who died had CV cause –0/4 comparator patients who died had CV cause Most CAP deaths occurred in high-risk patients (Fine category III or higher)

16. April 2001 AC16 Serious AEs - Phase 3 4 drug-related SAEs in uncontrolled trials: gastroenteritis, vasculitis, hepatitis, leukopenia

17. April 2001 AC17 AEs - Phase 3

18. 18 Telithromycin - April 2001 Advisory Focus on Safety Cardiac Hepatic Visual

19. April 2001 AC19 QT c effects: in vitro and preclinical data Inhibits IK r channel (major repolarization current) –K i 42.5 µM (moxifloxacin 129 µM) –Mean serum C max 2.4 µM (Phase 1); observed maximum Conc. 12 µM (Phase 3) –Rat myocardial:serum conc. ratio = 6 Prolongs action potentials in isolated fibers –>75% increase in APD 90 at K i –Potentiates sotalol-induced APD prolongation Prolongs QT c and increases HR in dogs –30 ms  1 min after single IV dose (17 ms for clari) –27-30 ms after multiple oral doses (100 mg/kg/d)

20. April 2001 AC20  QTc with telithromycin: Phase 1 * p<0.05 vs. placebo

21. April 2001 AC21 CYP3A4 inhibitor interactions Telithromycin C max increased by 52% with ketoconazole Telithromycin AUC increased by 95% with ketoconazole *comparison with placebo

22. April 2001 AC22 Telithromycin - Concentration Variation Phase 1 –Nonlinear pharmacokinetics –Single dose (800 mg) mean C max : 1.99 mg/L maximum C max : 5.13 mg/L (renally impaired subject) –Multiple dose (800 mg) mean C max : 2.07 mg/L maximum C max : 6.66 mg/L (elderly subject) Phase 3 –Maximum observed concentration: 7.6 - 9.9 mg/L

23. April 2001 AC23 Telithromycin pharmacokinetics in special populations Elderly subjects: C max and AUC  by 100% Hepatic impairment –AUC and C max similar to healthy subjects, but renal clearance increases to compensate –Potential accumulation if  CrCl with hepatic impairment Renal impairment (single dose) –Moderate impairment (CrCl 40-80 mL/min): C max  by 33%; AUC  by 42% –Severe impairment (CrCl <40 mL/min): C max  by 44%; AUC  by 59%

24. April 2001 AC24 QT c : Phase 3 Telithromycin increased QTc in phase 3 –Small but consistent increase in controlled trials –Possible interactions with CYP3A4 and CYP2D6 substrates in exploratory analyses Mean with CYP3A4 + CYP2D6: 11.5 msec (clarithromycin 5.4 msec)

25. April 2001 AC25 Telithromycin - Hepatic Data Pre-Clinical –Hepatotoxicity in Dogs, Rats, Monkeys (Increased AST & ALT; liver necrosis in 4-week rat study; hepatocellular hypertrophy, multinucleated hepatocytes) Phase I –Clustering of hepatic AEs in elderly at 2000 mg x1 –No clear dose-response for hepatic AEs Phase III –Similar AE rates telithromycin and comparators –No apparent drug-induced hepatic deaths

26. April 2001 AC26 Telithromycin - Hepatic Data Phase III (cont’d) –2 Hepatic SAEs plausibly assoc. with telithromycin –Liver biopsy in 1 pt: centrilobular necrosis and eosinophilic infiltration (ALT & Eos  Day 1) –More AST and ALT elevations in telithromycin- treated CAP patients with normal baseline values Not seen in Non-CAP patients –Concomitant low-level AST / ALT & T.Bili. elevations only in telithromycin-treated patients

27. April 2001 AC27 Telithromycin - Visual Data Phase 1 –40/1003 (0.4%) subjects reported blurred vision with supratherapeutic doses Phase 3 –14/2045 (0.7%) Ketek v. 1/1672 (0.1%) comparator Majority of patients female and < 40 years Transient but variable time course (minutes to hours to days)

28. 28 April 2001 AC- Safety Summary Potential confluence of multiple risk factors –(1) QTc prolongation –(2) Concentration dependence of QTc effect –(3) Concentration variation in special populations –(4) Potential for hepatotoxicity –(5)  exposure in elderly pts, hepatic/renal disease –(6)  exposure with concomitant medications Limited data on at-risk subjects Potential for wide population exposure

29. 29 Outpatient Antimicrobial Therapy, U.S. (millions of courses in 1992) McCaig LF and Hughes JM. JAMA 1995; 273:214-9 Otitis media URI (non-specific) Bronchitis Pharyngitis Sinusitis All other diagnoses 23.6 17.9 16.3 13.1 12.9 26.5

30. 30 Telithromycin - April 2001 AC Vote Do the efficacy and safety data presented support the use of Ketek in –community-acquired pneumonia 7 yes 3 no –exacerbation of chronic bronchitis0 yes 10 no –acute sinusitis2 yes 8 no Are the data sufficient for a claim of pneumonia due to pen-resistant S. pneumoniae?3 yes 7 no If approved, should Ketek have a specific indication for erythro-resistant S. pneumoniae?3 yes 7 no

31. 31 April 2001 AC Recommendations Recommendations for additional studies: Safety –Larger number of patients need to be enrolled in studies to determine safety. –Special populations should be targeted (elderly, patients with hepatic impairment, renal impairment); more PK –Drug interactions need to be evaluated. Efficacy –More data requested in patients with drug-resistant S. pneumoniae (including bacteremia)

32. June, 200132 Telithromycin - June 2001 Action Letter NDA approvable for pneumonia, bronchitis, and sinusitis Additional safety and efficacy data requested to assess risks/benefits –large safety trial in respiratory tract infections –PK studies in special populations –additional experience with drug-resistant S. pneumoniae, H. influenzae

33. 33 Telithromycin NDA Amendment - New Studies Safety/Phase 3 Study 3014: Randomized, open-label multi-center trial comparing telithromycin to amoxicillin/clavulanate in outpatients with CAP, AECB, or AS in a usual care setting 24,000 patients enrolled Designed as a large safety study to examine adverse events of special interest (cardiac, hepatic, visual)

34. 34 Telithromycin NDA Amendment - New Studies Efficacy/Phase 3 To address request for additional data in CAP on drug- resistant S. pneumoniae study 4003: randomized, double-blind, comparative trial of telithromycin (800 mg qd, 5 v. 7d) versus clarithromycin (500 mg bid, 10d)) study 3012: non-comparative CAP trial, 800 mg x 7d study 3107 (Japan) To address request for more data in AECB study 3013: r, db, telithromycin versus clari

35. 35 Telithromycin NDA Amendment- New Studies Safety/Phase I Studies Cardiac –1062: multiple dose telithromycin; assessed PK and QT interval changes in subjects with renal impairment –1063: multiple dose telithromycin + ketoconazole; assessed effect by ketoconazole on PK of telithromycin in elderly subjects with renal impairment. Included assessment of QT.

36. 36 Telithromycin NDA Amendment- New Studies Safety/Phase I Studies Visual –1059: single dose,randomized,placebo-controlled,double- blind,cross-over study in young subjects with normal vision and subjects (50-65 yo) with presbyopia. Telithromycin given as single 800 and 2400 mg dose. Ophthalmologic evaluations performed; telithromycin concentration measured in plasma and tears. –1064: single dose (2400 mg),randomized,placebo- controlled,double-blind,cross-over study in healthy subjects 18-65 yo. Assessments similar to study 1059 above.

37. 37 Telithromycin NDA Amendment- New Studies Safety/Phase I Studies Hepatic –1060 : Multiple-dose study (800 mg daily for 7 days) of telithromycin in patients with hepatic impairment and healthy subjects

38. 38 Telithromycin NDA Amendment - Additional Data Post-marketing experience from 1-1.5 million exposures (as of October 2002) in Europe and Latin America

39. 39 In the Best Interest of the Public Review of a new class of drugs presents opportunities and challenges Potential benefit to increase our armamentarium of agents to treat infections, including resistant pathogens Potential risks of toxicities Balance of risk/benefit in setting of wide usage