1 Hepatic Effects of Ketek (Telithromycin) Edward Cox, MD, MPH Medical Officer FDA

2 Ketek - Hepatic Effects Overview Pre-Clinical Studies Phase I Studies in Humans Phase III Data –Adverse Events (AEs) –Analysis of Laboratory Data –Serious Adverse Events (SAEs) Summary of the Findings

3 Pre-Clinical Hepatotoxicity in Rats, Dogs, and Monkeys –Increased AST & ALT –Hepatic necrosis in 4-week rat study –Hepatocellular hypertrophy & multinucleated hepatocytes Hepatic Effects of Ketek more than clarithromycin

4 Phase I

5 Study Elderly Subjects Single doses 1200, 1600, 2000 mg Ketek and placebo 3 with ALT/AST U/L (ALT>AST) –72yo F 7-days post 2000 mg –69yo M 17-days post 2000 mg –62yo M 7-days post placebo (14-days post 2000 mg) Possible Drug-Effect w/ 7-17 day latency period

6 Phase III Hepatic Adverse Events (AEs) Rates –Similar for Ketek and Comparators Treatment Discontinuation Rates for Hepatic AEs –Similar for Ketek and Comparators Serious Hepatic AEs –Comp Studies - Ketek 2 vs. Comparators 1 –Non-Comp Studies - 1 Ketek serious AE Hepatic Deaths –No Deaths Attributed to Drug-Induced Hepatic Injury

7 Laboratory Abnormalities Comparative Studies in Patients Normal at Baseline –AST and ALT changes CAP Studies - more AST & ALT elevations at On-Therapy and Post-Therapy in Ketek Arm Non-CAP Studies - Ketek & comparator similar

8 AST Changes at On-Therapy (Day 2 to 5) in Patients Normal at Baseline – CAP Studies

9 AST Changes at Post-Therapy (Day 17 to 21) in Patients Normal at Baseline – CAP Studies

10 ALT Changes at On-Therapy (Day 2 to 5) in Patients Normal at Baseline – CAP Studies

11 ALT Changes at Post-Therapy (Day 17 to 21) in Patients Normal at Baseline – CAP Studies

12 Combined ALT/AST & T. Bili. Abnormalities > ULN & < 2xULN

13 Combined ALT/AST & T. Bili. Abnormalities Drug-induced hepatocellular injury w/ overt jaundice - mortality of at least 10% - “Hy’s Law” –AST or ALT > 3xULN & T. Bili >1.5xULN Ketek ALT 19x ULN & T. Bili. 1.55x ULN* AST 3.1x ULN & T. Bili. 1.48x ULN AST 2.8x ULN & T. Bili. 1.48x ULN Comparator None * Local Lab Data, ALT 81 at baseline (NR<49 U/L)

14 Serious Adverse Events Phase III Studies

15 Serious Adverse Events Comparator SAE #1 61 yo male w/ CAP & h/o CHF & EtOHism on Digoxin Treated w/Clarithromycin 500mg po BID Day 1-10 Jaundiced on Day 17 - CT Scan and U/S exams disseminated neoplasm - hepatic vs. renal origin –T.Bili. 103 umol/L (NR 3-21) –Alk. Phos. 658 U/L (NR <121) –AST & ALT normal

16 Serious Adverse Events Ketek #1 76 yo Female w/ CAP & h/o hyperchol. & hyperuricemia on pravastatin 20 mg po QD and allopurinol 20 mg po QD chronically. Treated w/ Ketek 800 mg po QD on Day 1 thru 6

17 Serious Adverse Events Ketek #2 19 yo male w/TonsPhar +GABHS & no Sig. PMHx Treated w/ Ketek 800 mg po QD Day Evening of Day 12 - EtOH

18 Serious Adverse Events Ketek # 3 53 yo male w/ CAP & h/o Asthma & DM on inhaled salbutamol, fluticasone, Atrovent,Nasonex, and po Ca ++. Acetaminophen Day 13 - ? Treated w/ Ketek 800 mg po QD on Day 1 thru 10. Day 14 fever/vomiting/diarrhea - fever persists

19 Serious Adverse Events Ketek # 3 (cont’d) Serologies for Hepatitis A, B, and C - negative Liver Biopsy on Day 29 ALT nearly normalized by 3 months 2 nd Event - 8 months after the 1 st - ALT 1331 –Anti-smooth muscle antibodies + at 1:1000 –Elevated IgG and IgA –No Eosinophilia –2 nd Liver Biopsy at 9 months

20 Review of the Pathology Zachary D. Goodman, MD, PhD Chief, Division of Hepatic Pathology Armed Forces Institute of Pathology Department of Defense

21 Summary of Ketek - Hepatic Effects Pre-Clinical –Hepatotoxicity in Dogs, Rats, Monkeys Phase I –Clustering of hepatic AEs in elderly at 2000 mg x1 –No clear dose-response for hepatic AEs Phase III –Similar AE rates Ketek and Comparators –No apparent drug-induced hepatic deaths

22 Summary of Ketek - Hepatic Effects Phase III (cont’d) –2 Hepatic SAEs plausibly assoc. with Ketek –1 of these events w/centrilobular necrosis and eosinophilic infiltration (ALT & Eos  Day 1) –More AST and ALT elevations in Ketek-treated CAP patients with normal baseline values Not seen in Non-CAP patients –Concomitant Low-Level AST / ALT & T.Bili. elevations only in Ketek treated patients