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Hepatic Effects of Ketek (Telithromycin)

Edward Cox, MD, MPH

Medical Officer

FDA

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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

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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

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Phase IKetekDose

Single-DoseStudies

Multiple-DoseStudies

(mg) Hepatic AEs Hepatic AEsn/N (%) n/N (%)

50-200 0/19 0 0/16 0400-600 0/64 0 0/53 0

800 5/401 1 1/170 <1900 - - 0/8 0

1200 0/8 0 0/10 01600 0/74 0 0/24 02000 3/16 19 - -2400 0/47 0 - -3200 1/24 4 - -Total 9/653 1 1/281 <1

Placebo 1/98 1 0/42 0

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Phase I

Study 1030 • 8 Elderly Subjects• Single doses 1200, 1600, 2000 mg Ketek and placebo• 3 with ALT/AST 100-300 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

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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

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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

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

Ketek Comparators*Changes in AST N=320 N=314

(ULN) n % n %

<1x 284 89 293 93

>1x & < 2x 33 10 18 6>2x & < 3x 1 <1 1 <1

>3x & < 5x 2 <1 2 <1

>5x 0 0 0 0* Clarithromycin 500 mg po bid x 10d Amoxicillin 1000 mg po tid x 10d, Trovafloxacin 200 mg po qd x 7-10d

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

Ketek Comparators*Changes in AST N=296 N=293

(ULN) n % n %

<1x 275 93 287 98

>1x & < 2x 18 6 6 2>2x & < 3x 2 <1 0 0

>3x & < 5x 1 <1 0 0

>5x 0 0 0 0* Clarithromycin 500 mg po bid x 10d Amoxicillin 1000 mg po tid x 10d, Trovafloxacin 200 mg po qd x 7-10d

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

Ketek Comparators*Changes in ALT N=320 N=314

(ULN) n % n %

< 1x 279 87 283 90

>1x & < 2x 35 11 28 9>2x & < 3x 5 2 2 <1

>3x & < 5x 1 <1 0 0

>5x 0 0 1 <1* Clarithromycin 500 mg po bid x 10d Amoxicillin 1000 mg po tid x 10d, Trovafloxacin 200 mg po qd x 7-10d

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

Ketek Comparators*Changes in ALT N=296 N=293

(ULN) n % n %

< 1x 256 86 265 90

>1x & < 2x 36 12 27 9>2x & < 3x 4 1 0 0

>3x & < 5x 0 0 1 <1

>5x 0 0 0 0* Clarithromycin 500 mg po bid x 10d Amoxicillin 1000 mg po tid x 10d, Trovafloxacin 200 mg po qd x 7-10d

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

Lab AnalytesKetek Comparators

AST & ALT & T.Bili. 5/2358 0/1224

ALT & T. Bili. 5/2358 0/1224

AST & T. Bili. 1/2358 0/1224

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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)

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Serious Adverse Events

Phase III Studies

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Serious Adverse EventsComparator 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

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Serious Adverse Events

Analyte Normal Range Day 1 Day 5 Day 7 Day 12AST (9-34 U/L) 37 295 66 24ALT (6-32 U/L) 24 418 200 64T. Bili. (3-21 umol/L) 17 22 10 -Alk. Phos. (35-115 U/L) 79 146 131 -

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

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Serious Adverse Events

Analyte Normal RangeDay

1Day

4Day13

Day21

Day31

AST (11-36 U/L) 23 ND 273 29 19ALT (6-43 U/L) 27 ND 124 44 28T. Bili. (3-21 umol/L) 21 ND 14 22 15Alk. Phos. (<250 U/L) 93 ND 79 79 79GGT (10-61 U/L) 31 ND 37 39 35

Ketek #2•19 yo male w/TonsPhar +GABHS & no Sig. PMHx•Treated w/ Ketek 800 mg po QD Day 1 - 5•Evening of Day 12 - EtOH

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Serious Adverse Events

Analyte Normal Range Day 1 Day 21 Day 24 Day 35AST (<49 U/L) 38 - - -ALT (<49 U/L) 81 354 1529 518T. Bili. (2-20 umol/L) 9 nl 29 15Alk. Phos. (60-275 U/L) nl nl 169 261Eosinophils (<500 cells/uL) 774 960 1062 2856

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

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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

• 2nd Event - 8 months after the 1st - ALT 1331

– Anti-smooth muscle antibodies + at 1:1000– Elevated IgG and IgA – No Eosinophilia– 2nd Liver Biopsy at 9 months

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Review of the Pathology

Zachary D. Goodman, MD, PhD

Chief, Division of Hepatic Pathology

Armed Forces Institute of Pathology

Department of Defense

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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

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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