Why Another Antibiotic for
Respiratory Tract Infections?
C. Couturier
AFRT 8 nov 2002 A3-1
Community Acquired Pneumonia
No./an USA
Incidence 2–3 millions
Hospitalisations 500 000 (env. 1/5)
Mortalité 45 000 (env. 1/50)
Bartlett et al. Clin Infect Dis 1998;26:811–38
AFRT 8 nov 2002 A3-2
Incidence increases with age
Age (years)
16–19
20–29
30–39
40–49
50–59
60–69
70–79
0 20 40 60 80 100 120 140
Cases per 1000 population/year
MacFarlane et al. Lancet 1993;341:511–14
AFRT 8 nov 2002 A3-3
Community Acquired Pneumopathy
Etiology
Other bacteria (12.5%) Viral (12.6%)
H. influenzae
Mycoplasma (6.7%) (14.3%)
Legionella (5.2%)
Chlamydia (3.7%)
S. pneumoniae
(44.9%)
Analysis of 16 studies of >3300 hospitalized patients (1960–1987)
LaForce. Clin Infect Dis 1992;14 (Suppl. 2):S233–7
AFRT 8 nov 2002 A3-4
Why Another Antibiotic for RTI
S. pneumoniae Resistance Rates
% Resistance
Antimicrobial US Worldwide
agent (N=10,103) (N=16,672)
Penicillin G 24.2 22.3
Erythromycin A 31.7 30.7
Azithromycin 31.5 30.9
Clarithromycin 31.3 30.6
Clindamycin 13.6 8.6
Cotrimoxazole 31.1 33.9
Tetracycline 22.1 15.9
Levofloxacin 0.9 0.8
Source: PROTEKT US
AFRT 8 nov 2002 A3-5
Penicillin-resistant S. pneumoniae
tend to be resistant to other -lactams
MIC distribution for ceftriaxone against
% isolates
S. pneumoniae
80
70
Penicillin-sensitive
60 (MIC 0.06 mg/L)
Penicillin-resistant
50
(MIC 2 mg/L)
40 Penicillin-intermediate
30 (MIC 0.12–1 mg/L)
20
10
0
0.004 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8
MIC (mg/L)
Goldstein et al. J Antimicrob Chemother 1996;38(Suppl. A):71–84
AFRT 8 nov 2002 A3-6
Telithromycin – R&D Target
Ketolides are developed in response to
Bacterial Resistance
•Tailored activity against pathogens from community RTIs:
common & atypicals
•Excellent antipneumococcal activity
SPN is the leading organism in frequency and morbidity
•includes activity against ERSP and PRSP
AFRT 8 nov 2002 A3-7
Macrolides Target the 50S Subunit
of the Bacterial Ribosome
AA-tRNA Peptidyl
tRNA
50S Subunit
23S and 5S rRNA +
mRNA
32 proteins
Exit site for the
30S Subunit
growing peptide
16S rRNA +
20 proteins
J. Zhu, et al., J Struct Biol. 1997
118:197-219
• Macrolide binding inhibits protein synthesis by
interfering with elongation of peptide synthesis
and preventing 50S subunit assembly
AFRT 8 nov 2002 A3-8
Telithromycin Mechanism of Action
23S rRNA
Domain V
5S rRNA
30S Domain II
Pocket: peptidyl transferase site
50S
Erythromycin A Telithromycin
2058 V V 2058
O O
5S rRNA 5S rRNA
O-cladinose
O O O
752 II II 752
AFRT 8 nov 2002 A3-9
Consequence of
Double Binding to 23S rRNA
Erythromycin A Telithromycin
2058 V V 2058
x (methylation) x (methylation)
O O
5S rRNA 5S rRNA
O O -cladinose O O
752 II II 752
No link with Link with
domain V domain II
Resistance to Telithromycin retains activity
erythromycin A against erythromycin A-
resistant organisms
AFRT 8 nov 2002 A3-10
Ribosomal Depletion
• Inhibition of ribosomal subunit formation
30S
30S 50S 50S
Erythromycin A
30S
Depletion of
ribosome in the
Telithromycin
bacterial cells
AFRT 8 nov 2002 A3-11
Macrolide Resistance
• Inactivating Enzymes
– Staphylococci
– Gram Negative Rods
• Efflux
– Wildly distributed
– Multi drug activity
• Target modification
– 23S Methylases
– 23 S Mutations
– r-Proteins Mutations
AFRT 8 nov 2002 A3-12
erm(A) S. pneumoniae are Inducibly
Resistant to ML Antibiotics
Strain no. erm ERYa CLR AZM JOS TYL SPI TEL LIN CLI STB PEN
357 (A) 1.56 0.78 6.25 0.39 3.12 0.39 0.006 3.12 0.10 1.56 0.012
357 + ERY 6.25 3.12 50 12.5 100 25 0.012 >100 >100 3.12 0.012
1255 (B) 3.12 1.56 50 0.78 25 3.12 0.006 >100 0.39 0.78 0.01
1255 + ERY >100 >100 >100 >100 >100 >100 0.012 >100 >100 >100 0.01
ATCC 49619 (N one) 0.02 0.02 0.10 0.20 0.78 0.39 0.006 0.78 0.10 3.12 0.39
a
14-m em bered m acrolid es: ERY = erythrom ycin, CLR = clarithrom ycin; 15-m em bered m acrolid e: AZM =
azithrom ycin; 16-m em bered m acrolid es: JOS = josam ycin, TYL = tylosin, SPI = spiram ycin; Ketolid e: TEL =
telithrom ycin; lincosam id es: LIN = lincom ycin, CLI= clind am ycin; STB = streptogram in B; PEN = Penicillin G.
erm(A) Telithromycin activity is not
altered by inducible methylases
in S.pneumoniae
AFRT 8 nov 2002 A3-13
In vitro Activity of Telithromycin
Against S. pneumoniae
MIC (µg/mL)
Resistance Phenotype (N) MIC50 MIC90 Range
Macrolide-susceptible (11,384) 0.015 0.015 0.004 - 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
aresistant to the macrolides, penicillin, cotrimoxazole, and tetracycline
Data from PROTEKT Worldwide, N = 16,672
AFRT 8 nov 2002 A3-14
Activities of Telithromycin and Macrolides
Erythromycin-Resistant S. pneumoniae (N=3,131)
2500
Number of Isolates
2000
1500
1000
Azithromycin
500
Clarithromycin
Erythromycin
0
Telithromycin
MIC (µg/mL)
Data from PROTEKT US 2000/2001
AFRT 8 nov 2002 A3-15
Bactericidal activity of telithromycin in vitro
Counts (log10 CFU/mL)
10
9 PenS EryS S. pneumoniae
8
7
Control
6 TEL at 2x MIC (0–0.6 mg/L)
TEL at 4x MIC (0–12 mg/L)
5 TEL at 8x MIC (0–25 mg/L)
AZI at 2x MIC (0–25 mg/L)
4 AZI at 4x MIC (0–5 mg/L)
AZI at 8x MIC (1 mg/L)
3
2
1
0
-5 0 5 10 15 20 25 30 -5
Time (hours)
Starting inoculum 105 CFU/mL Felmingham et al. 38th ICAAC 1998
AFRT 8 nov 2002 A3-16
Bactericidal Activity of telithromycin
Against Macrolide-Resistant S. pneumoniae
S. pneumoniae Strain 5467 S. pneumoniae Strain 5991
mef(A) erm(B)
10 10
LOG10 cfu/mL
LOG10 cfu/mL
8 8
6 6
4 0 µg/mL 4
0.06
0.125
0.25
2 0.5
2
0 2 4 6 8 12 1 0 2 4 6 8 12
Hours 2 Hours
4
8
16
AFRT 8 nov 2002 A3-17
In vitro Activity of Telithromycin
MIC (µg/mL)
Organism (N) MIC50 MIC90 Range
S. pneumoniae (10,103) 0.015 0.5 0.015 - 8
H. influenzae (2,706) 2.0 4.0 0.12 - 32
(-lactamase positive; 769) 2.0 4.0 0.12 - 16
M. catarrhalis (1,896) a 0.06 0.12 0.004 - 0.5
S. pyogenes (3,918) 0.03 0.03 0.015 - 16
Data from PROTEKT US; a PROTEKT Worldwide, 2000-2001
AFRT 8 nov 2002 A3-18
Telithromycin
Selection of Antibiotic Resistance
• Telithromycin does not induce MLSB resistance in
pneumococci
• In serial passage experiments, telithromycin was less
efficient in selecting resistant mutants of
pneumococci than azithromycin, clarithromycin,
erythromycin, or clindamycin
• Selection of resistant strains of viridans group
streptococci and other usual oropharyngeal flora less
efficient with telithromycin than azithromycin
• Selection of resistant strains of viridans group
streptococci and intestinal enterococci less efficient
with telithromycin than clarithromycin
AFRT 8 nov 2002 A3-19
Telithromycin
• Ketolide antibiotic, derived from macrolides
• Novel mechanism of action
• Tailored activity against pathogens from
community RTIs: common & atypicals
• Excellent antipneumococcal activity:
– leading organism in frequency and morbidity
– includes activity against ERSP and PRSP
• Short, simple course of treatment
AFRT 8 nov 2002 A3-20
Telithromycin – Development Strategy
•Global development ( +Japan specificities)
•Sharing indications
•Only one Database
•Resulting in 2 dossiers FDA & EMEA
AFRT 8 nov 2002 A3-21
Telithromycin – Development Strategy
Dose Ranging
•In vitro studies Phase II study was
•PK not performed
•PK/PD animal
Short duration
treatment choosen
AFRT 8 nov 2002 A3-22
Indications
• Community-acquired pneumonia (CAP)
• Acute exacerbation of chronic bronchitis
(AECB)
• Acute sinusitis (AS)
AFRT 8 nov 2002 A3-23
Antibacterial studies difficulties
• Bacteriological End
Point difficult to monitor
• Strains are fastidious
• Efficacy results in
absence of sputum
AFRT 8 nov 2002 A3-24
Large number of Patients >> few Strains
CAP Studies
• mITT 2511
• PPc 1925
• S. pneumoniae 318
• ERSP 50
• PRSP 27
AFRT 8 nov 2002 A3-25
Human Pharmacology Program
• Clinical pharmacokinetics of telithromycin
have been studied extensively:
– studies on plasma PK, studies on tissue
penetration
– interaction studies
– special population studies (elderly;
renal, hepatic, and multiple impairment)
AFRT 8 nov 2002 A3-26
Pharmacokinetics of Oral Telithromycin
in Healthy Subjects
800 mg 800 mg
single dose multiple dose (7 d)
tmax (h) 1.0 a [0.5-4] 1.0 a [0.5-3]
Cmax (mg/L) 1.9 (42) 2.3 (31)
C24h (mg/L) 0.03 (45) 0.07 (72)
AUC(0-24h) (mg.h/L) 8.3 (31) 12.5 (43)
t½,z (h) 7.2 (19) 9.8 (20)
Data are mean (CV%) [Min-Max], N = 18
a Median
AFRT 8 nov 2002 A3-27
Tissue and Fluid Penetration
of Telithromycin in Patients
Mean (CV%) telithromycin
concentration after 800 mg dose (mg/L)
Tissue 2-3h 12h 24h
Epithelial lining fluid a 14.9 3.3 0.8
(76) (51) (62)
Alveolar macrophages a 69.3 318.1 161.6
(60) (73) (59)
Tonsils (µg/g) b 4.0 0.9 0.7
(13) (56) (40)
a Data from Honeybourne and Wise, N = 5-7
b Data from Gehanno, N = 6-8
AFRT 8 nov 2002 A3-28
Pathways of Telithromycin Disposition
Oral administration ( 90% absorbed, 24,000 patients in post-marketing survey
– >750 000 global post-marketing exposures*
* based upon Aventis internal sales data to retail and outpatient pharmacies as
of 09 July 2002 (PSUR n°2 submitted September 9, 2002)
AFRT 8 nov 2002 A3-48
Subjects (%) with Treatment-Emergent Adverse
Events (2%) (Controlled Efficacy Studies)
TEL Comparator
N=2702 N=2139
Subjects with TEAEs 1348 (49.9) 1035 (48.4)
Diarrhea 292 (10.8) 184 (8.6)
Nausea 213 (7.9) 99 (4.6)
Dizziness (excl vertigo) 99 (3.7) 57 (2.7)
Vomiting 79 (2.9) 48 (2.2)
Loose stools 63 (2.3) 33 (1.5)
Headache 148 (5.5) 125 (5.5)
Dysguesia 43 (1.6) 77 (3.6)
AFRT 8 nov 2002 A3-49
Deaths in Clinical Efficacy Studies
• Reports of deaths balanced between TEL and
comparators:
– TEL: 7 (0.3%), comparators: 9 (0.4%)
– (uncontrolled studies: 10; 0.6%)
• No treatment related deaths
AFRT 8 nov 2002 A3-50
Serious Adverse Events
(Controlled Efficacy Studies)
N (%) Subjects
TEL Comparator
N=2702 N=2139
All serious adverse events 59 (2.2) 61 (2.9)
All treatment-related serious AEs 9 (0.3) 6 (0.3)
Most SAEs were in the infections and respiratory
SOCs, and were related to the underlying infection
AFRT 8 nov 2002 A3-51
Subjects (%) with Discontinuations due to
Adverse Events (Controlled Efficacy Studies)
TEL Comparator
N=2702 N=2139
Subjects with D/C 119 (4.4) 92 (4.3)
GI related events 58 (2.1) 37 (1.7)
– Diarrhea 23 (0.9) 13 (0.6)
– Nausea 19 (0.7) 10 (0.5)
– Vomiting 21 (0.8) 10 (0.5)
AFRT 8 nov 2002 A3-52
Clinical Safety of Telithromycin
• Phase III clinical efficacy studies
• Large study in usual care setting
(Study 3014)
• Post-marketing experience
AFRT 8 nov 2002 A3-53
Study 3014:
Key Design features
• Designed in consultation with the FDA:
– randomized, open-label comparative safety study
– Telithromycin vs Augmentin
– 24,000 subjects
– treatment: 5 days for AS, 7-10 days for AECB and CAP
• Usual care setting:
– primary care physicians
– minimal exclusion criteria
• Targeted subjects with comorbidities:
– 35% subjects 50 years or older
– 40% with CAP or AECB
AFRT 8 nov 2002 A3-54
Study 3014:
Collection of Safety Data
• Clinic visits at Visit 1 (Day 1) and Visit 2
(Day 17-22); late follow-up contact at Visit 3
(up to Day 30-35)
• Hepatic laboratory analytes collected at Visits 1
and 2
• Investigators monitored for all AEs, with particular
focus on adverse events of special interest
(AESIs)
AFRT 8 nov 2002 A3-55
Study 3014: AESI definitions
• Hepatic: hepatitis, jaundice, any worsening of a
pre-existing hepatic condition, alanine
aminotransferase (ALT) values
3x ULN
• Cardiac: torsades de pointes, ventricular
arrhythmias, syncope as defined by
total loss of consciousness, cardiac
arrest, or unwitnessed or unexplained
death
• Visual: blurred vision
• Vasculitic: purpura or other signs of vasculitis
AFRT 8 nov 2002 A3-56
Study 3014: Investigation of AESIs
• AESIs followed up using standardized questionnaires
and clinical work-up
• All adverse events and laboratory values reviewed
regularly to ensure collection of all AESIs
• All predefined safety endpoints adjudicated by
clinical events committees (CECs)
• Final adjudication data used for primary endpoint
incidence rates
AFRT 8 nov 2002 A3-57
Subjects (%) with Treatment-Emergent
Adverse Events (1%) (Study 3014)
TEL Comparator
N=12,159 N=11,978
Subjects with TEAEs 2807 (23.1) 2745 (22.9)
Diarrhea 423 (3.5) 813 (6.8)
Nausea 382 (3.1) 286 (2.4)
Headache 230 (1.9) 144 (1.2)
Dizziness (excl vertigo) 192 (1.6) 59 (0.5)
Abdominal pain 106 (0.9) 100 (0.8)
Vomiting 102 (0.8) 115 (1.0)
Vaginosis fungal 58 (0.5) 162 (1.4)
AFRT 8 nov 2002 A3-58
Clinical Safety of Telithromycin
• Phase III efficacy studies
• Large study in usual care setting
(Study 3014)
• Post-marketing experience
AFRT 8 nov 2002 A3-59
Safety in
Post-Marketing Experience
• >750 000 global post-marketing exposures* to
TEL since first approval in Europe in July 2001
– Germany, Italy, Spain, Mexico, Brazil and France
• Overall safety profile in first year of post-
marketing experience confirms findings in
clinical development
– no new or unanticipated safety signals identified
*As of July 9, 2002
AFRT 8 nov 2002 A3-60
Summary of Telithromycin Safety (1)
• Extensive patient safety data available to date:
– including 16,000 subjects in controlled clinical trials
and >1 million post-marketing exposures
• Well-characterized and well-tolerated safety
profile:
– pattern of adverse events similar to variety of
marketed antibiotics
– no excess toxicity in at-risk populations
– low incidence of serious adverse events and
discontinuations, similar to comparators
AFRT 8 nov 2002 A3-61
Summary of Telithromycin Safety (2)
• Acceptable hepatic safety profile:
– tendency toward slightly more frequent and
predominantly minimal transaminase elevations, with
no increase in clinically significant events
– no severe hepatotoxicity in >1 million exposures
• Acceptable cardiac safety profile
– small mean change in QTc Bazett (~1.5 msec), of no
detectible clinical significance
– no excess in cardiac mortality or arrhythmia
AFRT 8 nov 2002 A3-62
Summary of Telithromycin Safety (3)
• Well-characterized and consistent visual effects:
– uncommon, generally mild, transient, and reversible
events most consistent with a slight delay in
accommodation
• No signal for severe vasculitis detected
AFRT 8 nov 2002 A3-63
Telithromycin Registration Status
• Around 20 European countries including all EU
countries
•17 south American countries
•14 other countries (i.e. NZ, Singapore, Hongkong,
Egypt, Vietnam)
•Approved in the USA
•Awaited in Canada, Australia and Japan
AFRT 8 nov 2002 A3-64
Telithromycin – Marketing Status
•Marketed in the following major countries
– France, Germany, Spain, Italy
– Brazil, Mexico
•More than 1 Million subjects were treated with
Ketek
•Expected to increase sharply during the coming
winter
AFRT 8 nov 2002 A3-65