FDA Advisory Committee January 8, 2003

1
FDA Advisory CommitteeJanuary 8, 2003

• KETEK (telithromycin)
• Aventis Pharmaceuticals

2
Introduction

• Steve Caffe, MD

Vice President, US Regulatory Affairs, Aventis
3
Telithromycin Background

• Ketolide antibiotic
• Claimed indications
• community-acquired pneumonia (CAP)
• acute exacerbation of chronic bronchitis (AECB)
• acute sinusitis (AS)
• April 2001, Advisory Committee recommended
  additional data be gathered, including
• resistant S. pneumoniae
• larger safety database

4
Additional Safety and Efficacy Data

• June 2001, Approvable Letter for CAP, AECB, AS
• Clinical program designed in collaboration with
  the FDA, including
• PK studies in special populations
• studies in CAP and AECB
• large comparative study in a usual care setting
  (24,000 subjects)
• Post-marketing data from ?1.5 million exposures
  (including Germany, France, Italy and Spain)

5
Telithromycin Presentation Agenda
Introduction
Steve Caffe, MD
Medical Need
Paul Iannini, MD
Microbiology
Stephen Jenkins, PhD
Clinical Efficacy
Bruno Leroy, MD
Human Pharmacology
Vijay Bhargava, PhD
Clinical Safety
Paul Lagarenne, MD
Conclusions
Paul Iannini, MD
6
Experts in Attendance (1)

• H. Bodenheimer, MD, Beth Israel Medical Center,
  New York, NY
• W. Craig, MD, University of Wisconsin, Madison,
  WI
• J. Dohar, MD, University of Pittsburgh School of
  Medicine, Pittsburgh, PA
• D. Farrell, PhD, GR Micro Ltd, London, UK
• L. Fisher, PhD, University of Washington,
  Seattle, WA
• F. Fraunfelder, MD, Oregon Health Sciences
  University, Portland, OR
• G. Harding, MD, Aston University School of
  Medicine, Birmingham, UK
• P. Iannini, MD, Danbury Hospital, Danbury, CT
• S. Jenkins, PhD, Carolinas Medical Center,
  Charlotte, NC
• J. Jones, MD, The Degge Group Ltd, Arlington, VA

7
Experts in Attendance (2)

• J. Lewis, MD, Georgetown University Medical
  School, Georgetown, DC
• W. Maddrey, MD, Univ. of Texas Southwestern
  School of Medicine, Dallas, TX
• H. Paulus, MD, University of California at Los
  Angeles, Los Angeles, CA
• C. Pratt, MD, Baylor College of Medicine,
  Houston, TX
• E. Rubin, MD, Thomas Jefferson Univ. School of
  Medicine, Philadelphia, PA
• M. Sorrell, MD, University of Nebraska Medical
  School, Omaha, NE
• P. Watkins, MD, Univ. of North Carolina School of
  Medicine, Chapel Hill, NC
• G. Williams, MD, New York Medical College,
  Valhalla, NY

8
Medical Need

• Paul Iannini, MD

Danbury Hospital, Danbury, Connecticut
9
Medical Need for a New Anti-infective for
Community-Acquired RTIs (1)

• A clinicians needs
• targeted spectrum that satisfies criteria for
  empiric therapy
• high potency against S. pneumoniae
• concentration-dependent, rapid killing
• reduced impact on other bacterial flora
• safe and well tolerated

10
Medical Need for a New Anti-infective for
Community-Acquired RTIs (2)

• CAP S. pneumoniae infections, including
  bacteremia and L. pneumophila, which have the
  highest risk of mortality
• AECB patients with risk factors and documented
  obstruction
• AS avoid complications by choosing the right
  drug the first time
• Once-daily dosage with short durations of therapy

11
Telithromycin Addresses an Unmet Medical Need
Optimal RTI Spectrum of Activity
Telithromycin
Macrolides
Amoxicillin-clavulanate
Fluoroquinolones
ERSP PRSP
Non-respiratory tract gram negative coverage
S. pneumoniaeH. influenzaeM. catarrharis
Atypicals
12
S. pneumoniae Resistance in USA

• Surveillance studies may overestimate resistance
  but trends are clear
• Rates of resistance to macrolides range from 22
  to 32 and for penicillin G from 18 to 24 a
• Resistance to newer fluoroquinolones is low but
  increasing
• Multi-drug resistance rates (4 drugs) are 10
• Useful life of older agents may be diminishing

a Source CDC, 2000 PROTEKT Studies 2000-2001
TRUST 2001-2002
13
Implications of Increased Resistance

• Available agents do not meet current clinical
  needs
• sub-optimal drug concentrations for current
  levels of resistance (MICs ?8.0 µg/mL for
  amoxicillin, ?16.0 µg/mL for macrolides, ?4.0
  µg/mL for fluoroquinolones)
• clinical failures of commonly used agents are
  emerging

14
Clinical Relevance of Resistance A Debate

• Increased mortality with S. pneumoniae with
  penicillin MICs ?2.0 or 4.0 µg/mL and a
  statistically significant increase in suppurative
  complications a
• High likelihood of failure to prevent S.
  pneumoniae bacteremia with macrolide therapy for
  CAP caused by macrolide resistant strains b
• Fluoroquinolone failures in subjects with S.
  pneumoniae initial or acquired resistance
  mutations during therapy c

a Metlay et al. CID 2000, Turret et al. CID
1999, Fieken et al. Am J Pub Health. 2000. b
Lonks et al. CID 2002, Kelly et al. CID. 2000.
c Davidson et al. NEJM. 2002, Urban et al. JID.
2001, Empy et al. Ann Pharmacotherapy. 2001.
15
There is a Medical Need for a New Anti-infective
in Community-Acquired RTIs

• Optimal therapy for community-acquired RTIs
  requires antibiotics with a targeted spectrum
  that includes common and atypical pathogens
• Increased bacterial resistance to current
  antibiotics commonly used in the therapy of RTIs
  may shorten useful life

16
Microbiology

• Stephen Jenkins, PhD

Carolinas Medical Center Charlotte, North
Carolina
17
Overview of the Microbiology Features of
Telithromycin

• First ketolide antibiotic derived from macrolides
• Novel dual binding mechanism
• Focused spectrum of activity against all common
  outpatient RTI pathogens (minimal impact on usual
  bacterial host flora)
• Especially active against S. pneumoniae,
  including macrolide-, penicillin-, and/or
  multiple antibiotic-resistant strains

18
Telithromycin Mechanism of Action (1)

• Prevents bacterial protein synthesis by
• binding to two specific sites on the bacterial
  ribosome
• interfering with elongation of nascent
  polypeptide chains
• Interacts strongly with both domain V and, unlike
  available macrolides, domain II of the 23S rRNA
• Result Activity against most macrolide-resistant
  strains of S. pneumoniae (MIC99 1 µg/mL) a

a Source PROTEKT Studies (data on file)
19
Telithromycin Mechanism of Action (2)
23S rRNA
Domain V
5S rRNA
30S
Domain II
Pocket peptidyl transferase site
50S
Erythromycin A
Telithromycin
V
V
2058
2058
5S rRNA
O
O
5S rRNA
-cladinose
O
O
O
O
II
II
752
752
20
Prevalence () of S. pneumoniae Antibiotic
Resistance
North Central
Northwest
31.8
26.4
23.2
17.3
11.8
7.1
PRSP
ERSP
MDRSP
PRSP
ERSP
MDRSP
Northeast
Southwest
26.5
21.7
29.3
27.1
7.9
11.3
PRSP
ERSP
MDRSP
PRSP
ERSP
MDRSP
Southeast
South Central
40.2
36.5
38.6
32.7
12.8
7.7
PRSP
ERSP
MDRSP
Source PROTEKT Studies (data on file) PR
penicillin resistant ER erythromycin
(macrolide) resistant MDR multi-drug
resistant (penicillin, TMP/SXT, tetracycline,
macrolides)
PRSP
ERSP
MDRSP
21
S. pneumoniae Antibiotic Resistance Rates
(N10,103)
Resistance
Penicillin G 24.2 Erythromycin A 31.7 Azithromycin
31.5 Clarithromycin 31.3 Clindamycin 13.6 Cotrimo
xazole 31.1 Tetracycline 22.1 Levofloxacin 0.9
Source PROTEKT Studies (data on file)
22
In vitro Activity of Telithromycin
MIC (µg/mL)

• Organism (N) MIC50 MIC90 Range
• S. pneumoniae (16,672) 0.015 0.5 0.002 8
• H. influenzae (8,064) 1.0 2.0 0.002 32
• (?-lactamase positive 1,631) 2.0 4.0 0.008 16
• M. catarrhalis (1,156) 0.06 0.12 0.004 0.5
• (?-lactamase positive 1,071) 0.06 0.12 0.008
  0.5
• S. aureus (2,676) 0.06 ?64 ?0.008 ?64
• S. pyogenes (3,918) 0.03 0.03 ?0.015 ?16

Source PROTEKT Studies (data on file)
23
Telithromycin Activity Against Atypical and
Intracellular Pathogens
MIC (µg/mL)
Pathogen MIC50 MIC90 Range M. pneumoniae a
0.008 0.008 0.008 0.06 (N47) C. pneumoniae
b 0.0625 0.25 0.031 2 (N19) L. pneumophila
c,d 0.008 0.015 ?0.004 0.015 (N26)
a Kenny and Cartwright, Antimicrob Agents
Chemother, 2001b Hammerschlag et al., J
Antimicrob Chemother, 2001c PROTEKT Studies
(data on file)d MCC90 0.25 µg/mL
24
In vitro Activity of Telithromycin
AgainstAntibiotic-Resistant S. pneumoniae
MIC (µg/mL)

• Resistance Phenotype (N) MIC50 MIC90 Range
• Macrolide-susceptible (11,384) 0.015 0.015
  ?0.002 1
• Macrolide-resistant (5,288)
  0.12 1.0 0.008 8
• erm(B) (657) 0.06 0.5 0.008 8
• mef(A) (436) 0.12 0.5 0.008 1
• mef(A) erm(B) (71) 0.5 0.5 0.06 1
• Penicillin-resistant (4,027) 0.12 1.0 0.004 8
• Levofloxacin-resistant (154) 0.03 0.5 0.004 1
• Multi-drug-resistant (1,500) a 0.12 1.0 0.008 8

Source PROTEKT Studies (Data on file) (N16,672)
a resistant to penicillin, the macrolides,
TMP/SXT, and tetracycline
25
Activities of Telithromycin and Macrolides
Against Erythromycin-Resistant S. pneumoniae
(N3,131)
2500
2000
1500
Number of Isolates
1000
Azithromycin
500
Clarithromycin
Erythromycin
0
Telithromycin
1
2
4
8
0.5
0.03
0.06
0.12
0.25
?16
?0.015
MIC (µg/mL)
Source PROTEKT Studies (Data on file)
26
Bactericidal Activity of Telithromycin Against
Macrolide-Resistant S. pneumoniae
S. pneumoniae Strain 5467 mef(A) MIC 0.125 µg/mL
S. pneumoniae Strain 5991 erm(B) MIC ? 0.015
µg/mL
10
10
8
8
LOG10 cfu/mL
LOG10 cfu/mL
6
6
0 µg/mL
4
4
0.06
0.125
0.25
2
2
0.5
1
0
2
4
6
8
12
0
2
4
6
8
12
2
Hours
Hours
4
8
16
27
Decreased Propensity of Telithromycin to Induce
or Select for Antibiotic Resistance

• In vitro
• telithromycin does not induce MLSB resistance
• in serial passage experiments, telithromycin
  less efficient in selecting resistant mutants of
  S. pneumoniae than azithromycin, clarithromycin,
  erythromycin, roxithromycin, or clindamycin
• In vivo
• in a clinical trial, telithromycin was shown to
  be less likely to select populations of mutants
  resistant to itself among the usual oropharyngeal
  viridans group streptococci than clarithromycin

28
Summary of Microbiology Features of Telithromycin

• First ketolide antibiotic
• Unlike macrolides dual, strong binding mechanism
  
• Focused spectrum of activity against usual
  typical and atypical/intracellular RTI pathogens
  with minimal impact on GI or oropharyngeal flora
• Low propensity to select antibiotic-resistant
  mutants
• Especially active against S. pneumoniae,
  including macrolide-, penicillin-, and/or
  multiple antibiotic-resistant strains

29
Clinical Efficacy

• Bruno Leroy, MD

Senior Director, Clinical Development
Anti-infectives, Aventis
30
Dosing Regimen and Study Design

• Telithromycin
• CAP 7-10 days
• AECB 5 days
• Acute sinusitis 5 and 10 days

31
CAP Phase III Studies (Western)

• 4 randomized, controlled, double-blind,
  comparative studies
• total of 1583 subjects, 881 treated with
  telithromycin (TEL) 800 mg qd for 5-10 days
• comparators
• amoxicillin (AMX) 1000 mg tid for 10 days
• clarithromycin (CLA) 500 mg bid for 10 days (2
  studies)
• trovafloxacin (TVA) 200 mg qd for 7-10 days
• 4 open, uncontrolled studies
• 1408 subjects treated with TEL 7-10 days
• 3 studies enriched for S. pneumoniae

32
CAP Phase II/III Studies (Japanese)

• 2 comparative studies
• TEL 600 mg qd for 7 days vs. TEL 800 mg qd for 7
  days
• TEL 600 mg qd for 7 days vs. levofloxacin 100 mg
  tid for 7 days
• 222 subjects treated with TEL 600 mg qd or 800
  mg qd
• Only efficacy against S. pneumoniae resistant
  pathogens integrated with Western studies

33
CAP Clinical Cure at TOC, PPc (Controlled
Western Studies)
9.7 4.7 a,b
2.1 11.1 a
7.9 7.5 a
13.6 5.2 a
10.2 4.3 a,c
100
95
94
92
90
90
89
88
89
89
80
60
40
20
143162
138156
141149
137152
7280
8186
142159
143161
134146
0
4003 vs CLA
3001 vs AMX
3006 vs CLA
3009 vs TVA
a 95 confidence intervals
b TEL (5 d) vs CLA
c TEL (7 d) vs CLA
34
CAP Clinical Cure by Pathogen(All Western
Studies)
Telithromycin Comparators a
n/N () n/N ()
Key pathogens (PPb at TOC) S. pneumoniae 300/318
(94) 63/70 (90) H. influenzae 206/229 (90) 42/44
(95) M. catarrhalis 44/50 (88) 7/9 (78) Atypical
pathogens (PPc at TOC) M. pneumoniae 36/37 (97)
20/22 (91) C. pneumoniae 34/36 (94)
18/19 (95) L. pneumophila 13/13 (100) 2/3 (67)
a Study 3001 amoxicillin Studies 3006 and
4003 clarithromycin Study 3009 trovafloxacin
35
CAP Bacteriological Eradication and Clinical
Cure for S. pneumoniae Pathogens in TEL Subjects
PPb population at TOC (All Western studies)
n/N () Subjects
MIC (µg/mL)
Bact. Eradication Clinical Cure
0.004 4/4 (100) 4/4 (100) 0.008 123/125 (98) 12
1/125 (97) 0.016 a 109/113 (96)
106/113 (94) 0.03 21/23 (91) 21/23 (91) 0.06
6/6 (100) 6/6 (100) 0.12 4/6 (67)
4/6 (67) 0.25 1/1 (100) 1/1 (100) 0.5 3/3
(100) 3/3 (100) 1 5/5 (100) 5/5 (100) Total
(all MICs) 276/286 (97) 271/286 (95) NA 29/32 (91
) 29/32 (91) Total 305/318 (96) 300/318 (94)
NA not available a Data for MIC values of
0.015 and 0.016 µg/mL have been pooled
36
CAP Bacteriological Eradication and Clinical
Cure for H. influenzae Pathogens in TEL Subjects
PPb population at TOC (All Western studies)
n/N () Subjects
MIC (µg/mL)
Bact. Eradication Clinical Cure
0.002 1/1 (100) 1/1 (100) 0.12 1/1 (100)
1/1 (100) 0.25 3/3 (100) 3/3 (100) 0.5
3/5 (60) 4/5 (80) 1 41/47 (87) 40/47 (85)
2 86/96 (90) 88/96 (92) 4 35/40 (88)
36/40 (90) 8 11/11 (100) 11/11 (100) Total (all
MICs) 181/204 (89) 184/204 (90) NA 23/25 (92) 22/
25 (88) Total 204/229 (89) 206/229 (90)
NA not available
37
CAP Clinical Cure for Resistant S. pneumoniae
Isolates
PPb population at TOC (All Western Japanese
studies)
n/N () Subjects
PRSP 24/27 (89) ERSP 44/50 (88) erm(B) 24/28 (86)
mef(A) 16/18 (89) erm(B) and
mef(A) 3/3 (100) negative for erm(B) or
mef(A) 1/1 (100)
PRSP penicillin G-resistant (MIC ?2.0 µg/mL)
ERSP macrolide (erythromycin A)resistant (MIC
?1.0 µg/mL)
38
CAP Clinical Cure for Pneumococcal Bacteremia
PPb population at TOC (All Western Studies)
n/N ()Subjects
Blood culture positive All S. pneumoniae 74/82 (9
0) PRSP 5/7 (71) ERSP 8/10 (80) ERSP with
urinary Ag positive only a 4/4 (100)
a Sputum positive, blood culture negative, S.
pneumoniae urinary antigen positive (Binax test)
39
CAP Clinical Cure by Risk Factors for Morbidity
PPc population at TOC (Western Studies)
All CAP studies
Controlled studies
Telithromycin Comparators Telithromycin
n/N () n/N () n/N ()
Total population 641/711 (90) 490/540 (91)
1755/1925 (91) ?65 years old
93/111 (84) 83/96 (87) 243/278 (87)
Pneumococcal 32/33 (97) 15/19 (79) 74/82 (90)
bacteremia a Fine score ?III 107/123 (87) 93
/110 (85) 267/297 (90)
a PPb population
40
Summary of Efficacy in CAP

• Telithromycin 800 mg once daily for 7 to 10 days
  is highly effective in CAP
• Targets key outpatient pathogens

• Atypical pathogens
• M. pneumoniae
• C. pneumoniae
• L. pneumophila

• Common pathogens
• S. pneumoniae, including
• PRSP
• ERSP
• H. influenzae
• M. catarrhalis

• Effective in outpatients at risk for
  complications (elderly, pneumococcal bacteremia,
  Legionella)

41
AECB Phase III Studies

• 3 randomized, controlled, double-blind,
  comparative studies
• total of 1245 subjects, 612 treated with
  telithromycin (TEL) 800 mg qd for 5 days
• comparators
• amoxicillin-clavulanic acid (AMC) 500/125 mg tid
  for 10 days
• cefuroxime axetil (CXM) 500 mg bid for 10 days
• clarithromycin (CLA) 500 mg bid for 10 days

42
AECB Clinical Cure at TOC, PPc
6.4 14.3 a
9.9 3.1 a
5.8 12.4 a
100
89
86
86
86
83
82
80
60
40
193225
206231
20
99115
92112
121140
118142
0
3003 vs AMC
3013 vs CLA
3007 vs CXM
a 95 confidence intervals
43
AECB Clinical Cure by Pathogen (All Studies)
Telithromycin (5 d) Comparators (10 d) a
n/N () n/N ()
Key pathogens (PPb at TOC) S. pneumoniae
22/27 (82) 15/19 (79) H. influenzae
44/60 (73) 45/53 (85) M. catarrhalis
27/29 (93) 29/34 (85) Atypical pathogens (PPc
at TOC) C. pneumoniae 11/12 (92) 8/11 (73)
a Study 3003 amoxicillin-clavulanic acid, Study
3007 cefuroxime axetil 3013 clarithromycin
44
AECB Clinical Cure by Risk Factors for Morbidity
PPc population at TOC
Telithromycin Comparators
n/N () n/N ()
Total Population 413/480 (86) 416/485 (86) ? 65
years old 157/184 (85) 179/215 (83) Morbidity
risk factors at least 1 290/338 (86) 284/332 (86)
at least 2 142/171 (83) 152/181 (84) FEV1/FVC
45
Summary of Efficacy in AECB

• Treatment with telithromycin 800 mg once daily
  for 5 days is effective in AECB due to
• S. pneumoniae
• H. influenzae
• M. catarrhalis
• C. pneumoniae
• Effective in outpatients at risk for
  complications (elderly, significant obstruction)

46
Acute Sinusitis Phase III Studies

• 3 randomized, double-blind studies comparing
• 5 days and 10 days telithromycin (TEL) 800 mg
  qd
• 5 days and 10 days TEL 800 mg qd to
  amoxicillin-clavulanic acid (AMC) 500/125 mg tid
  for 10 days
• 5 days TEL 800 mg qd to cefuroxime axetil (CXM)
  250 mg bid for 10 days
• Total of 1298 subjects, 608 treated 5 days and
  372 treated 10 days with TEL

Bacterial documentation in all subjects
47
Acute Sinusitis Clinical Cure at TOC, PPc
7.7 7.9 a
12.7 9.5 a
7.1 13.4 a
100
91
91
9.9 11.7 a
85
82
80
75
75
73
60
40
121133
102137
7389
112123
110146
102140
161189
20
0
3002
3005 vs AMC
3011 vs CXM
a 95 confidence intervals
48
Acute Sinusitis Clinical Cureby Pathogen (All
Studies)
PPb population at TOC
TEL (5 d) TEL (10 d) Comp (10 d)a
n/N () n/N () n/N ()
S. pneumoniae 55/61 (90) 27/30 (90) 14/16 (88) H.
influenzae 42/48 (88) 15/16 (94) 13/15 (87) M.
catarrhalis 13/14 (93) 3/4 (75) 7/7 (100) S.
aureus 18/19 (95) 4/4 (100) 3/4 (75)
TEL telithromycin, Comp comparators a Study
3005 amoxicillin clavulanic acid Study 3011
cefuroxime axetil
49
Acute Sinusitis Clinical Cure for S.
pneumoniae-Resistant Isolates (All Studies)
PPb population at TOC
n/N Subjects (TEL)
5 d 10 d 510 d
PRSP 8/10 3/3 11/13 ERSP 12/14 6/7 18/21
PRSP penicillin G resistant (MIC ?2.0 µg/mL)
ERSP macrolide (erythromycin A)resistant (MIC
?1.0 µg/mL)
50
Acute Sinusitis Clinical Cure in Subgroups of
Interest
PPc population at TOC
All AS studies
Controlled studies
TEL (5 d) Comp (10 d) TEL (5 d)
n/N () n/N () n/N ()
Total population 271/335 (81) 175/226 (77)
383/458 (84) ?7 days of symptoms 229/281 (81) 135/
173 (78) 266/325 (82) Pathogens at entry a
90/107 (84) 44/57 (77) 155/177 (88) Severe
illness 45/55 (82) 35/45 (78) 82/95 (86) at entry
b Total opacity on X-ray 84/98 (86) 33/43 (77)
153/173 (88)
a PPb population b According to investigator
assessment at entry
51
Summary of Efficacy in Acute Sinusitis

• Telithromycin 800 mg once daily for 5 days
  equivalent to 10 days of treatment with
  amoxicillin-clavulanic acid or cefuroxime axetil
• 5-day treatment effective against
• S. pneumoniae, including
• PRSP
• ERSP
• H. influenzae
• M. catarrhalis
• S. aureus

52
Telithromycin Efficacy in RTIs

• Effective in 3 targeted RTI indications
• demonstrated in 14 studies (800 mg qd)
• AECB and acute sinusitis (5-day treatment)
• CAP (7- to 10-day treatment)
• Effective in outpatients at risk for
  complications
• Effective against key outpatient respiratory
  pathogens, including common, atypical and
  resistant pathogens

53
Human Pharmacology

• Vijay Bhargava, PhD

Senior Director, Drug Metabolism and
Pharmacokinetics, Aventis
54
Human Pharmacology Program

• Telithromycin has been extensively studied
• plasma and tissue pharmacokinetics
• effect of impairment of elimination pathways on
  exposure of telithromycin
• effect of telithromycin on exposure of other
  drugs (CYP3A4 substrates)

55
Pharmacokinetics in Healthy Subjects
Telithromycin 800 mg (oral)
Repeated dose (7d)
Single dose
tmax (h)
1.0 a
1.0 a
0.5-4
0.5-3
Cmax (µg/mL)
1.9
2.3
(42)
(31)
C24h (µg/mL)
0.03
(72)
(45)
0.07
AUC0-24h (µg.h/mL)
8.3
(43)
(31)
12.5
7.2
(20)
t½,?z (h)
(19)
9.8
Data are mean (CV) Min-Max, N 18 a Median
56
Tissue and Fluid Penetration in Subjects with
RTIs
Mean (CV) concentration after TEL 800 mg (µg/mL)
Tissue
2h
24h
12h
Epithelial lining fluid
14.9
0.8
3.3
(76)
(62)
(51)
Alveolar macrophages
69
162
318
(60)
(59)
(73)
N 6 TEL telithromycin
57
Multiple Pathways of Elimination
Oral administration (? 90 absorbed, unabsorbed)
Metabolism in liver and GI tract
First pass effect
(33)
Systemic bioavailability (57)
Renal excretion
GI tract/biliary
Hepatic excretion
(13)
(37)
(7)
Unchanged drug in feces
Unchanged drug in urine
Total metabolized drug (70)
(35)
(35)
Non-P450 mediated
CYP3A4-mediated
Telithromycin is not metabolized by CYP2D6
58
Studies to Investigate Effects of Elimination
Pathway Impairments

• Pathway Impaired Study Population
• Hepatic Subjects with mild, moderate, and severe
• hepatic impairment vs. healthy control subjects
• Renal Subjects with mild, moderate, and severe
• renal impairment vs. healthy control subjects
• CYP3A4 Crossover study in healthy subjects
  receiving
• telithromycin with and without ketoconazole
• Multiple Subjects ?60 years of age with renal
• impairment impairment, receiving ketoconazole
  to block CYP3A4

59
Effect of Hepatic Impairment
Systemic bioavailability
Hepatic excretion
Renal excretion
Metabolites
Telithromycin 800 mg qd 7-day repeated dose
Hepatic impairment N13
Healthy N13
Day 1
Day 7
Day 1
Day 7
t1/2, ?z (h)
11.9 (21)

11.0 (20)

CLR (L/h)
14.6 (48)
14.8 (45)
10.7 (20)
11.7 (15)
Data are mean (CV) Child Pugh score 5-6 4
subjects 7-9 6 subjects 10-11 3 subjects
60
Effect of Renal Impairment
Systemic bioavailability
Renal excretion
Unchanged drug in urine
Telithromycin 800 mg qd 5-day repeated dose
Mean (CV)
CLCR (mL/min) 80 50-80 30-49 Cmax,ss (µg/mL) 2.1 (39) 2.6 (13.4) 2.2 (48) 3.0
(40) AUC0-24h,ss (µg.h/mL) 12.4 (48) 16.0
(22) 14.8 (41) 23.6 (29) CLR (L/h) 12.7 (28) 7.3
(31) 4.1 (31) 2.1 (41)
Study also investigated TEL 400 and 600 mg qd
61
Effect of CYP3A4 Inhibition
First pass effect
Metabolism in liver and GI tract
Systemic bioavailability
Hepatic excretion
Metabolites
35
35
CYP3A4-mediated
Telithromycin Ketoconazole N11
Telithromycin N11
Cmax (µg/mL) 2.0 (38) 3.1 (36) AUC(0-24 h)
(µg.h/mL) 14.4 (39) 28.6 (31) t½,?z
(h) 11.2 (26) 12.6 (27)
Data are mean (CV) telithromycin 800 mg qd (5
days), ketoconazole 400 mg qd (7 days)

• Itraconazole less interaction, grapefruit juice
  no interaction

62
Effect of Multiple Impairments (Renal
Ketoconazole)
First pass effect
Metabolism in liver and GI tract
Systemic bioavailability
Hepatic excretion
35
35
Renal excretion
CYP3A4-mediatedmetabolites
non-CYP3A4-mediatedmetabolites
Unchanged drug in urine
63
Effect of Multiple Impairments (Renal
Ketoconazole)
First pass effect
Metabolism in liver and GI tract
Systemic bioavailability
Hepatic excretion
Renal excretion
35
35
CYP3A4-mediated metabolites
Unchanged drug in urine
non-CYP3A4-mediated metabolites
TEL telithromycin CLA clarithromycin Keto
ketoconazole
Mean (CV) exposure to TEL or CLA
TEL Keto
Creatinine clearance (mL/min) 30-80 Mean age
(years) 74 N10
Cmax,ss (µg/mL) 3.6 (22) AUC(0-24h)
(µg.h/mL) 33.4 (31) CLR (L/h) 6.1 (30)
2 subjects in the TEL Keto had CLCR ? 30 mL/min
(28, 24 mL/min)Cmax 5.4, 8.8 µg/mL
AUC(0-24h) 51.7, 61.6 µg.h/mL
64
Effect of Multiple Impairments (Renal
Ketoconazole)
First pass effect
Metabolism in liver and GI tract
Systemic bioavailability
Hepatic excretion
Renal excretion
35
35
CYP3A4-mediated metabolites
Unchanged drug in urine
non-CYP3A4-mediated metabolites
TEL telithromycin CLA clarithromycin Keto
ketoconazole
Mean (CV) exposure to TEL or CLA
TEL Keto CLA Keto
Creatinine clearance (mL/min) 30-80 30-80 Mean
age (years) 74 69 N10 N6
Cmax,ss (µg/mL) 3.6 (22) 6.2 (36) AUC(0-24h)
(µg.h/mL) 33.4 (31) 112.2 (41) CLR (L/h) 6.1
(30) 6.4 (48)
2 subjects in the TEL keto had CLCR ? 30 mL/min
(28, 24 mL/min)Cmax 5.4, 8.8 µg/mL
AUC(0-24h) 51.7, 61.6 µg.h/mL
65
Telithromycin and Clarithromycin Exposure in
Subjects with Multiple Impairment
TEL telithromycin CLA clarithromycin Keto
ketoconazole
CLA impaired
TEL impaired
150
9
100
6
Cmax,ss (µg/mL)
AUC0-24h,ss (µg.h/mL)
50
3
N
6
10
N
6
10
0
0
CLA Keto Study 1063
TEL Keto Study 1063
CLA Keto Study 1063
TEL Keto Study 1063
66
Telithromycin and Clarithromycin Exposure in
Subjects with Multiple Impairment
TEL telithromycin CLA clarithromycin Keto
ketoconazole
CLA healthy
CLA impaired
TEL healthy
TEL impaired
150
9
100
6
x2.2
x3.3
Cmax,ss (µg/mL)
AUC0-24h,ss (µg.h/mL)
50
x1.6
3
x2.7
N
12
6
18
10
N
12
6
18
10
0
0
CLA Keto Study 1063
CLA van Haarst et al.
TEL Study 1008
TEL Keto Study 1063
CLA Keto Study 1063
CLA van Haarst et al.
TEL Study 1008
TEL Keto Study 1063
van Haarst et al. Clin Pharmacol Ther, 1998.
67
Summary of Exposures Ratios of Impaired to
Healthy Subjects
Telithromycin exposure ratios
Subjects with Cmax (90 CI) AUC (90 CI)
Hepatic impairment 1.0 (0.81.2) 1.0 (0.81.1) Ren
al impairment a CLCR 50-80 mL/min 1.3 (1.01.8)
1.4 (1.01.9) CLCR 30-49 mL/min 1.0 (0.81.4) 1.
2 (0.91.7) CLCR ? 30 mL/min 1.5 (1.12.0) 2.0 (1
.52.8) CYP3A4 inhibition Ketoconazole 1.5 (1.12
.0) 1.9 (1.52.5) Itraconazole 1.2 (1.01.4) 1.5
(1.41.7) Renal impairment keto b CLCR 30-80
mL/min 1.6 2.7 CLCR ?30 mL/min 3.1 4.5
a Mean age 59 years b Mean age 74 years
68
Comparison of Effects on CYP3A4 Substrate
Simvastatin
Fold increase in Exposure
Simvastatin Simvastatin acid
Cmax AUC Cmax AUC
Telithromycin a 5.3 8.9 14.9 11.9 Clarithromycin
b 8.2 7.9 14.3 13.9 Grapefruit juice
c 9 16 7 7 Itraconazole d 10 10 17 19
Dosing regimen telithromycin 800 mg qd for 5
days, simvastatin 40 mg once on Day 5. a Study
1048 b Study 1067 c Lilja et al. Clin
Pharmacol Ther, 1998. d Neuvonen et al. Clin
Pharmacol Ther, 1998.
69
Reduction of Simvastatin Interactionwith
Different Time of Administration
Fold increase in exposure a (90 confidence
interval)
Concomitant 12 hours apart N14 N14 Simvast
atin Cmax 7.7 (6.39.5) 3.4 (2.84.2) AUC 8.4
(5.911.9) 3.8 (2.85.1) Simvastatin Cmax 10.0
(8.312.1) 3.2 (2.63.8) acid AUC 9.4
(7.411.9) 4.3 (3.35.4)
TEL telithromycin a After 40 mg single dose of
simvastatin, before and after telithromycin 800
mg qd for 5 days. Data from Study 1065
70
Effect of Telithromycin on Other CYP3A4
Substrates
Fold increase in midazolam / cisapride exposure
Midazolam Cisapride
Cmax AUC Cmax AUC
Telithromycin 2.6 6.1 2.0 2.4 Clarithromycin
a,b 3 7 2.7 3.2
a Midazolam data from Gorski et al. Clin
Pharmacol Ther, 1998. b Cisapride data from van
Haarst et al. Clin Pharmacol Ther, 1998.
71
Summary of Telithromycin Human Pharmacology

• Pharmacokinetics reproducible and predictable
  under various conditions
• Targeted plasma and respiratory tissue
  concentrations rapidly achieved
• Multiple elimination pathways limit the potential
  for increased exposure in special populations
• Similar CYP3A4 inhibition to clarithromycin, but
  telithromycin is dosed once daily and for shorter
  treatment duration in RTIs

72
Clinical Safety

• Paul Lagarenne, MD

VP, Clinical Safety Analysis, Aventis Global
Pharmacovigilance
73
Clinical Safety of Telithromycin

• Phase III studies
• 4,472 telithromycin subjects, including 2,702 in
  controlled studies
• Large comparative study in usual care setting
  (Study 3014)
• 12,159 telithromycin subjects
• Post-marketing experience
• ?1.5 million exposures as of December 1st, 2002

based upon Aventis internal sales data to
retail and outpatient pharmacies
74
Phase III Clinical Studies
75
Most Frequent Adverse Events in Controlled Phase
III Studies
Telithromycin Comparators N2702 N2139
Subjects () with AEs 1348 (49.9) 1035 (48.4) Di
arrhea 292 (10.8) 184 (8.6) Nausea 213 (7.9) 99 (
4.6) Headache 148 (5.5) 125 (5.8) Dizziness 99 (
3.7) 57 (2.7) Vomiting 79 (2.9) 48 (2.2) Loose
stools 63 (2.3) 33 (1.5) Dysgeusia 43 (1.6) 77 (3
.6)
76
Adverse Events Leading to Discontinuation and
Serious Adverse Events in Controlled Phase III
Studies
N () Subjects
TEL Comparators N2702 N2139
Adverse events leading 119 (4.4) 92 (4.3)to
discontinuation All serious adverse events
59 (2.2) 61 (2.9) All treatment-related serious
AEs 9 (0.3) 6 (0.3) Deaths a 7 (0.3) 9 (0.4)
a No treatment-related deaths
TEL telithromycin
77
Blurred Vision with Telithromycin in Controlled
Phase III Studies

• Uncommon event 0.6 subjects
• Generally mild
• Limited duration and fully reversible
• No sequelae
• No serious reports
• Single subject required discontinuation of drug

78
Investigation of Visual Effects

• Two Phase I studies with high doses (2400 mg)
• mostly described as a delay in focusing from
  near to far vision
• onset within a few hours (median 3 h)
• rapid recovery within 2 to 3 h
• no decreases in visual acuity
• severe etiologies ruled out (e.g., angle-closure
  glaucoma or retinopathy)

79
ECG Analysis in Phase III Studies

• ECGs performed at pretherapy and on-therapy (Day
  3-5) in 12 Phase III studies (N 2411 subjects)
• Minimal change in mean QTc interval of
  approximately 1.5 ms
• No difference in QTc outliers vs. comparators

Bazett correction formula
80
?QTc vs Telithromycin Plasma Concentration in
Phase III Studies
Concs ? 5µg/mL
Conc QTc ?QTc 5.2 410 -7.4 5.2 364 -24.5 5.2 4
11 13.1 5.2 409 -3.3 5.3 428 -0.9 5.8 431 17.0
6.2 425 1.5 6.2 410 10.1 6.4 391 -38.8 6.4 381
-5.1 6.4 393 -6.0 6.7 435 18.0 7.2 408 17.8 7
.8 396 0.1 9.9 427 8.7
120
80
40
0
?QTc (ms)
-40
-80
N1512 patients Slope0.88 ms/µg/mL r20.0025,
p?0.05
-120
-160
0
2
4
6
8
10
12
Concentration (µg/mL)
81
Hepatic Events in Controlled Phase III Studies

• ALT 3x ULN in 1.6 TEL and 1.7 comparator
  subjects
• Hepatic adverse events in 3.4 TEL and 3.2
  comparator subjects
• Single subject with clinical hepatitis
• first episode
• pre-existing ALT elevation and eosinophilia
• liver biopsy scattered lesions, predominant
  macrophages, background eosinophils
• second episode
• 9 months later without re-exposure to
  telithromycin
• second biopsy autoimmune hepatitis and early
  cirrhosis
• no recurrence since November 1998

82
Large Comparative Study in Usual Care Setting
(Study 3014)
83
Study 3014 Key Design Features

• Designed in collaboration with the FDA
• randomized, open-label comparative study
• 24,140 subjects enrolled and treated
• enrichment of at-risk populations
• minimal exclusion criteria
• expanded treatment duration for AECB
• 46 subjects 50 years or older
• 40 with CAP or AECB

TEL telithromycin, AMC amoxicillin-clavulanic
acid
84
Study 3014 Collection of Safety Data

• Designed to capture adverse events of special
  interest (AESIs)
• Office visits at pretherapy (Day 1) and
  post-therapy (Day 17-22)
• Follow-up contact at late post-therapy (Day
  30-35)
• Hepatic laboratory testing at pretherapy and
  post-therapy
• Investigators reviewed all AEs, with particular
  focus on AESIs

85
Study 3014 AESI Criteria

• Hepatic Hepatitis, jaundice, any worsening of a
  pre-existing hepatic condition, alanine
  aminotransferase (ALT) values ?3x ULN
• Cardiac Torsades de pointes, ventricular
  arrhythmias, syncope, cardiac arrest, or
  unwitnessed or unexplained death
• Visual Blurred vision
• Vasculitic Purpura or other signs of
  vasculitis
• Broadly defined to capture all potential
  endpoint cases

86
Study 3014 Investigation of AESIs

• All AEs and lab values reviewed to ensure
  complete collection of AESIs
• AESIs investigated using standardized
  questionnaires
• ALT ?3x ULN investigated using standardized lab
  kits
• bilirubin, ALT, AST, alkaline phosphatase, CBC
  with differential, prothrombin time, viral
  hepatitis serologies
• AESIs followed up to clinical resolution
• All AESIs reviewed by independent, blinded
  clinical events committees (CECs) and adjudicated
  to identify safety endpoints

87
Study 3014 Follow-up Status
Number () of subjects
TEL AMC Total Treated 12,161 11,979 24,140 Safe
ty evaluable 12,159 (99.9) 11,978 (99.9) 24,137
(99.9) Follow-up at Day 28 or later AE
status 12,096 (99.5) 11,883 (99.2) 23,979
(99.3) Vital status 12,138 (99.8) 11,941
(99.7) 24,079 (99.8)
TEL telithromycin, AMC amoxicillin-clavulanic
acid
88
Study 3014 Most Frequent Adverse Events (AEs),
AEs Leading to Discontinuation, and Serious AEs
Number () of subjects
TEL AMC N12,159 N11,978
Total with AEs 2807 (23.1) 2745 (22.9) Diarrhea
423 (3.5) 813 (6.8) Nausea 382 (3.1) 286 (2.4) H
eadache 230 (1.9) 144 (1.2) Dizziness 192 (1.6) 5
9 (0.5) AEs leading to discontinuation 467 (3.8) 5
57 (4.7) Serious AEs 155 (1.3) 133 (1.1)
TEL telithromycin, AMC amoxicillin-clavulanic
acid
89
Study 3014 Adverse Events in Subgroups
n/N () subjects with AEs
TEL AMC

• Subjects with AEs 2807/12159 (23) 2745/11978 (23)
• ? 65 years 518/2273 (23) 526/2203 (24)
• Hepatic impairment 31/97 (32) 41/119 (35)
• Renal impairment 19/78 (24) 16/76 (21)
• Cardiovascular disease 793/2965 (27) 737/2915 (25)
  
• CYP3A4 substrates 1499/5834 (26) 1542/5795 (27)
• HMG CoA reductase inhib. 347/1420 (24) 305/1341 (2
  3)

TEL telithromycin, AMC amoxicillin-clavulanic
acid
90
Study 3014 Hepatic AESIs

• Uncommon and balanced
• TEL 111 (0.9), AMC 98 (0.8)
• All AESIs followed up to clinical and/or lab
  resolution
• except 1 AMC subject
• No chronic or immune-mediated hepatic injury
• No drug-related severe hepatotoxicity (hepatic
  failure, liver transplant, death)

91
Study 3014 Hepatic Endpoint

• Definition possibly drug-related significant
  hepatic injury
• clinical signs and symptoms
• ALT values of at least 3x ULN
• exclusion of other common causes
• new onset of symptoms Day 5 or later
• Final endpoint in all cases determined by
  blinded CEC
• Positively-adjudicated endpoints in
• TEL 3 / 12,096 subjects (95 CI 0.5 - 7.2 /
  10,000)
• AMC 2 / 11,883 subjects (95 CI 0.2 - 6.1 /
  10,000)

92
Study 3014 Hepatic Endpoint with Liver Biopsy

• Liver biopsy performed in 1 TEL endpoint subject
• 72-year-old subject with concomitant
  cholelithiasis requiring cholecystectomy after
  10-day treatment for CAP
• Day 23 increased ALT, alkaline phosphatase,
  bilirubin (absolute eosinophils 270/mm3)
• Day 30 abdominal ultrasound of gallbladder
• Day 36 laparoscopic cholecystectomy confirmed
  cholelithiasis and cholecystitis
• liver biopsy revealed cholestasis with fibrosis,
  minimal inflammation, no eosinophils
• complete recovery

93
Study 3014 Noteworthy Hepatic Laboratory
Analytes at any Post-Therapy Visit
n/N () of subjects
TEL AMC
ALT ?3x ULN 110/11570 (1.0) 96/11311 (0.8) ALT
?8x ULN 19/11570 (0.2) 10/11311 (0.1) ALT ?3x ULN
and total 3/10864 (0.028) 6/10600 (0.057)billirub
in ?1.5x ULN a ALT ?3x ULN and total 0/10864 1/10
600bilirubin ?3 mg/dL and alk. phosphatase ?2x
ULN
TEL telithromycin, AMC amoxicillin-clavulanic
acid a Denominator includes subjects with
simultaneous assessment of ALT and bilirubin
after Day 3
94
Study 3014 Cardiac AESIs

• Cardiac AESIs
• TEL 39 (0.3), AMC 34 (0.3)
• Deaths within Day 35
• TEL 10, AMC 14
• no treatment-related deaths
• Presumed arrhythmic deaths assessed
• TEL 7, all ?7 days after treatment
• AMC 4, all ?2 days after treatment

95
Study 3014 Cardiac AESIs in At-Risk Populations
n/N () of Subjects
TEL AMC
Elderly (?65 years) 21/2273 (0.9) 21/2203 (1.0) CV
disease 27/2965 (0.9) 20/2915 (0.7) Diuretics 13
/1776 (0.7) 12/1710 (0.7) Drugs with
potential 11/1965 (0.6) 10/1899 (0.5)to prolong
QT CYP3A4 inhibitors 15/2309 (0.6) 11/2201 (0.5)
TEL telithromycin AMC amoxicillin-clavulanic
acid
96
Study 3014 Cardiac Endpoint

• Definition events likely to represent malignant
  ventricular arrhythmias
• Final endpoint in all cases determined by the
  CEC
• Positively-adjudicated endpoints in
• TEL 0 / 12,096 subjects
• AMC 1 / 11,883 subjects

97
Study 3014 Visual AESIs and Visual Endpoints

• Definition drug-related blurred vision
• Positively adjudicated visual endpoints 75
  (0.6) TEL vs. 5 (0.04) AMC subjects
• median onset 1 hour after dosing
• median duration 2 hours
• majority mild or moderate
• Severe events in 0.04 TEL subjects
• Discontinuation for visual events in 0.2 TEL
  subjects
• Impacted activity in 0.3 TEL subjects
• no accidental injuries
• All cases were reversible

98
Post-marketing Experience
99
Post-Marketing Experience

• ?1.5 million post-marketing exposures to TEL
  since first marketed in Europe in October 2001
• includes Germany, France, Belgium, Italy, Spain,
  Brazil, Mexico
• 1 million exposures in Germany and France
• 10 of prescriptions are re-exposure
• Intensive follow-up of all adverse events
• use of standard questionnaires as guidance for
  AESI follow-up
• No new or unexpected safety signals identified

100
Visual Findings in Post-Marketing Experience

• Visual events generally similar to clinical trial
  experience
• most common events blurred vision, abnormal
  accommodation, visual abnormality
• 78 reported in patients ?50 years of age
• generally of limited duration, with full recovery
  noted
• no sequelae identified
• no reports of accidental injuries

101
Cardiac Findings in Post-Marketing Experience

• No increased risk for ventricular arrhythmic
  events
• no reports of sudden, unexplained death
• no confirmed torsades de pointes in ?1.5 million
  exposures
• 2 questionable reports
• terminal VF in CAD patient no QT prolongation or
  torsades de pointes on ECG, as confirmed by
  expert review
• no identifiable patient, no event confirmed no
  record of admission or treatment for torsades de
  pointes or other ventricular arrhythmia

102
Hepatic Findings in Post-Marketing Experience
(1)

• Hepatic events were uncommon (64 events in 28
  patients)
• No patients with hepatocellular jaundice
• 4 patients with cholestatic jaundice
• one with acute mononucleosis
• all recovered
• No chronic or immune-mediated hepatic injury

103
Hepatic Findings in Post-Marketing Experience
(2)

• No reports of drug-related severe hepatotoxicity
  (hepatic failure, liver transplant, death)
• Fatal acute hepatitis A (IgM) with hepatic
  failure in an elderly man
• case also confounded by
• high-dose (?4g daily) acetaminophen use for 4-5
  days prior to event
• pre-existing underlying hard nodular liver
• concurrent acute Q fever
• Overall experience comparable to marketed
  antibiotics

104
Safety Summary (1)

• Extensive experience
• ?16,000 subjects in clinical studies and ?1.5
  million post-marketing exposures
• Overall safety profile similar to marketed
  antibiotics
• gastrointestinal events most common
• low discontinuation rate

105
Safety Summary (2)

• Uncommon visual events
• generally mild and limited duration
• mechanism consistent with delay in focusing
• severe etiologies excluded
• no permanent sequelae
• no accidental injuries

106
Safety Summary (3)

• Extensive cardiac evaluation, with no confirmed
  cardiac safety signal
• no increase in cardiac events or deaths in Phase
  III studies or Study 3014
• no increase in ventricular arrhythmic events in
  post-marketing surveillance
• no torsades de pointes

107
Safety Summary (4)

• Extensive hepatic evaluation, with no confirmed
  hepatic safety signal
• no difference in clinical hepatic events
• no hepatocellular jaundice
• no chronic or immune-mediated hepatic injury
• no drug-related severe hepatotoxicity (hepatic
  failure, liver transplant, death)

108
Summary and Conclusions

• Paul Iannini, MD

Danbury Hospital, Danbury, Connecticut
109
There is a Medical Need for a New Anti-infective
in Community-Acquired RTIs

• Optimal therapy for community-acquired RTIs
  requires antibiotics with a targeted spectrum
  that includes common and atypical pathogens
• Increased bacterial resistance to current
  antibiotics commonly used in the therapy of RTIs
  may shorten useful life

110
Limitations of Current Therapy in
Community-Acquired RTIs

• ß-lactams
• atypicals
• penicillin-resistant S. pneumoniae
• ß-lactamase positive H. influenzae
• Macrolides
• macrolide-resistant S. pneumoniae
• Fluoroquinolones
• not targeted to RTI pathogens

111
Efficacy of Telithromycin

• Highly effective in CAP, AECB, and AS
• Key added benefits
• novel mechanism of action
• concentration-dependent, rapid killing
• targeted RTI spectrum
• active against emerging resistant strains of S.
  pneumoniae
• short treatment duration

112
Safety of Telithromycin

• Extensive exposure (?1.5 million subjects)
• Safety comparable to widely prescribed
  antibiotics
• most common side effects were gastrointestinal
• uncommon, mild, reversible visual events
• no increased cardiac risk
• no difference in clinical hepatic events
• limited drug-drug interactions

113
Telithromycin

• Fulfills a medical need
• Brings additional benefits
• Safety profile comparable to marketed antibiotics
• Valuable option for the treatment of CAP, AECB,
  and AS in outpatients