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

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

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

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

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) (-6.3, 12.6) (160)78(160) mITT (-5.7, 12.4) (142)83(140) (-6.4, 14.3) (112)82(115) PPc (%)%

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

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

April 2001 AC10 Drug Resistant Streptococcus pneumoniae

April 2001 AC11 Telithromycin - PRSP CAP *

April 2001 AC12 Telithromycin - ERSP CAP*

April 2001 AC13 April 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

April 2001 AC14 Telithromycin- Phase 3 Safety Data

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)

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

April 2001 AC17 AEs - Phase 3

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

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)

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

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

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: mg/L

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 mL/min): C max  by 33%; AUC  by 42% –Severe impairment (CrCl <40 mL/min): C max  by 44%; AUC  by 59%

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)

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

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

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 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 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

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 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)

June, 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 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 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 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 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 yo. Assessments similar to study 1059 above.

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

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