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Ketek  (telithromycin) NDA Background

Ketek  (telithromycin) NDA Background. Janice Soreth, M.D. Director Division of Anti-Infective Drug Products CDER/FDA. Telithromycin - Background. Regulatory History Overview of First Advisory Committee FDA Action Letter New Studies. Telithromycin - Regulatory History.

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Ketek  (telithromycin) NDA Background

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  1. 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

  6. Telithromycin Comparators 95% C.I. % (N) % (N) (%) PPc 30011 95 (149) 90 (152) (-2.1, 11.1) 30062 88 (162) 88 (156) (-7.9, 7.5) mITT 3001 86 (199) 79 (205) (-0.5, 15.3) 3006 79 (204) 81 (212) (-9.9, 6.5) 1 Amoxicillin, 2 Clarithromycin CAP: Clinical Response -TOC April 2001 AC

  7. Telithromycin 5 days Comparators 10 days 95% C.I. % (N) % (N) (%) PPc 30031 86 (115) 82 (112) (-6.4, 14.3) 30072 86 (140) 83 (142) (-5.7, 12.4) mITT 3003 81 (160) 78 (160) (-6.3, 12.6) 3007 78 (182) 72 (191) (-3.5, 15.1) 1 Augmentin, 2 Cefuroxime axetil AECB: Clinical Response -TOC April 2001 AC

  8. Telithromycin 5 day Comparators 10 day 95% C.I. % (N) % (N) (%) PPc 30051 75 (146) 75 (137) (-9.9, 11.7) 30112 85 (189) 82 (89) (-7.1, 13.4) mITT 3005 70 (201) 68 (202) (-8.2, 10.9) 3011 80 (240) 72 (116) (-2.2, 18.2) 1Amoxicillin/clavulanate , 2 Cefuroxime axetil Sinusitis: Clinical Response - TOC April 2001 AC

  9. 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 AC

  10. Drug Resistant Streptococcus pneumoniae April 2001 AC

  11. Telithromycin - PRSP CAP * April 2001 AC

  12. Telithromycin - ERSP CAP* April 2001 AC

  13. 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 April 2001 AC

  14. Telithromycin- Phase 3 Safety Data April 2001 AC

  15. 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 AC

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

  17. AEs - Phase 3 April 2001 AC

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

  19. QTc effects: in vitro and preclinical data • Inhibits IKr channel (major repolarization current) • Ki 42.5 µM (moxifloxacin 129 µM) • Mean serum Cmax 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 APD90 at Ki • Potentiates sotalol-induced APD prolongation • Prolongs QTc 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 AC

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

  21. CYP3A4 inhibitor interactions *comparison with placebo • Telithromycin Cmax increased by 52% with ketoconazole • Telithromycin AUC increased by 95% with ketoconazole April 2001 AC

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

  23. Telithromycin pharmacokinetics in special populations • Elderly subjects: Cmax and AUC  by 100% • Hepatic impairment • AUC and Cmax 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): • Cmax by 33%; AUC  by 42% • Severe impairment (CrCl <40 mL/min): • Cmax by 44%; AUC  by 59% April 2001 AC

  24. QTc: 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 AC

  25. 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 AC

  26. 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 AC

  27. 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) April 2001 AC

  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) URI (non-specific) 17.9 Otitis media 23.6 Bronchitis 16.3 Pharyngitis 13.1 All other diagnoses 26.5 Sinusitis 12.9 McCaig LF and Hughes JM. JAMA 1995; 273:214-9

  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 bronchitis 0 yes 10 no • acute sinusitis 2 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)

  32. 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 June, 2001

  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 18-65 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 1-1.5 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

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