Telithromycin Integrated Summary of Safety

1. Telithromycin Integrated Summary of Safety Anti-Infective Drugs Advisory Committee January 8, 2003 Charles Cooper, M.D. Medical Officer Division of Anti-Infective Drug Products Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. Outline • Description of safety database • Overview of safety-related events • Cardiac risk profile • Hepatic risk profile • Visual risk profile • Summary

3. Phase 3 safety database* • Treatment groups balanced for age, sex, race, weight • 15.8% telithromycin pts were  65 yo, vs. 19.4% of comparator pts • 59 telithromycin pts were <18 yo for NDA *Does not include data from study 3014

4. Deaths in Phase 3 trials

5. Nonfatal serious AEs in controlled Phase 3 trials

6. AEs in controlled Phase 3 trials

7. AEs resulting in discontinuation in controlled Phase 3 trials

8. Cardiac Risk Profile

9. Cardiac toxicity: Pre-clinical/Phase 1 • Blocks IKr (major repolarization current) • Prolongs action potentials in isolated fibers • Prolongs QT and increases HR in dogs • Concentration-dependent  in QTc in Phase 1 studies (2 msec/mg/L) • Increased exposure w/ CrCl <30 mL/min and/or concomitant CYP 3A4 inhibitor/ substrate

10. Cardiac AEs in controlled Phase 3 trials

11. Telithromycin patients: 3 / 2702 (0.1%) in controlled studies 5 / 1770 (0.3%) in uncontrolled studies Comparator patients: 8 /2139 (0.4%) No serious cardiac AEs related to study drug Serious cardiac AEs in telithromycin patients: Cardiac arrest Cardiac failure NOS LV failure (drug discont.) Acute MI (drug discont.) Angina pectoris Cardiac failure aggrav. Cardiomyopathy NOS LV failure Serious cardiac AEs in all Phase 3 trials

12. ECG data in Phase 3 trials • ECG data from 3013 added to previous NDA* • Mean on-therapy QTC (Bazett’s formula): • 1.5  22.3 msec in telithromycin-treated patients for all Phase 3 trials combined • 3.8  19.3 msec for telithromycin vs. 3.3  19.6 msec for clarithromycin in controlled studies (3006, 3008, 3013) * ECG data not consistently collected for new studies 4003 and 3012

13. Hepatic Risk Profile

14. Hepatic toxicity: pre-clinical • Hepatotoxicity in rats, dogs, monkeys • Increased AST and ALT • Hepatic necrosis in 4-week rat study • Hepatocellular hypertrophy and multinucleated hepatocytes • Hepatic effects of telithromycin greater than those of clarithromycin in animals

15. Hepatic toxicity: Phase 1 • Study 1030 • 8 elderly subjects • Single doses of 1200, 1600, 2000 mg telithromycin or placebo • 3 subjects with  ALT/AST to 100-300 U/L (ALT>AST) • 72 yo F - 7 days post 2000 mg • 69 yo M - 17 days post 2000 mg • 62 yo M - 7 days post placebo (14 days post 2000 mg) • Patients asymptomatic • Possible drug effect with 7-17 day latency period

16. Hepatic AEs in controlled Phase 3 trials

17. Serious hepatic AEs in all Phase 3 clinical trials • Four patients with serious hepatic AEs (3 telithromycin, 1 comparator) • Drug effect unlikely in comparator patient and 1 telithromycin patient • Drug effect plausible in 2 telithromycin-treated patients • 76 yo F on allopurinol/pravastatin; asympto-matic  in ALT/AST on telithromycin • 53 yo M with eosinophilic hepatitis

18. Patient 502/1069 PMH: 53 yo M w/ asthma, DM Meds: Inhaled salbutamol, fluticasone, Atrovent, Nasonex, po Ca++, ? DM medication Course: D1-10 Telithromycin 800 mg po qd for CAP D13 -? Acetaminophen (500 mg x 6 over 1 wk) D14 fever/vomiting/diarrhea - fever persists

19. Patient 502/1069 (cont.) D23 Hospitalized for hepatitis Hepatitis A, B, C serologies negative D29 Liver bx: centrilobular necrosis and eosinophilic infiltration D94 LFTs virtually normal At follow up, 9 mos after event, on routine testing: ALT 1331, tot. bili. 25 uM (nl < 20). Hep A, B, C neg. Anti-smooth muscle Ab + (1:1000). No eosinophilia. Patient asymptomatic. Second liver bx: Zone 3 and portal fibrosis, piecemeal necrosis, plasma cell infiltrate; consistent with autoimmune hepatitis

20. Incidence of ALT increases in controlled CAP trials* * Patients with normal ALT at baseline

21. Visual Risk Profile

22. Blurred vision in Phase 3 trials • 15/20 telithromycin-treated patients with mild blurring; 4 with moderate blurring; 1 with severe blurring • Median duration 2d (range1-10d); median onset 2nd d (range1-6 ) • 4 discontinuations due to visual adverse events * Patients not randomized by 3A4 inhibitor intake

23. Blurred vision in Phase 1 studies • Two studies (1059 and 1064) of telithromycin-associated visual blurring • 13-50% incidence of blurring in subjects receiving 2400 mg telithromycin • Higher incidence in younger subjects • Median onset 3 h (range 1-5 h) • Median duration 2.8 h (range 0.9-20.3 h) • Likely due to interference with accommodation

24. Serious visual adverse events • One telithromycin-treated subject with SAE of “unable to accommodate.” • AE determined to be “significantly disabling” • Began 2 hours after study drug administered • Patient seen by ophthalmologist who gave diagnosis of “unable to accommodate.” • AE was initially assessed as related to study drug • Telithromycin was discontinued and AE resolved • 5 months later, causality of AE changed to “not related to study medication”

25. Summary of ISS • Overall • Most common AEs are GI • Cardiac • Concentration-dependent QT • No drug-related serious cardiac adverse events • Hepatic • Hepatotoxicity in pre-clinical studies • Cluster of pts with  transaminases in Phase 3 •  incidence of low-level ALT elevations in Phase 3 • One patient with eosinophillic hepatitis in Phase 3 • Visual • Incidence of blurred vision 0.6% in controlled studies • Possibly due to interference with accommodation