# Presentation: 494882

## FDA Advisory CommitteeApril 26, 2001

***KETEK******TM***** (telithromycin)**

## Telithromycin – Presentation Agenda

**Introduction****	****Mindell Seidlin, MD**
**	****VP, Clinical Development, ****	****Anti-Infectives, Aventis**
- Microbiology	André Bryskier, MD
- Human Pharmacology	Vijay Bhargava, PhD
- Clinical Efficacy and Safety	Bruno Leroy, MD
- ECG Analysis	Claude Benedict, MD
- Conclusions 	Mindell Seidlin, MD

## Need for New Antibiotics in Respiratory Tract Infections

- Driven by the emergence of multi-resistant strains
- Availability of a new class reduces resistance pressure on any existing classes
- Maintain coverage of all key RTI pathogens
- Simple, short course of therapy
- Recent Policy statements recommend NEW drug development:
- WHO
- HHS

## Pathogens of Community RTIs in 2001

- Most significant
*S. pneumoniae*
- multidrug resistance
- Other ‘bacterial’
*H. influenzae*
* *beta-lactamase +ve
*M. catarrhalis*
* *beta-lactamase +ve
*S. pyogenes*

- Atypical / Intracellular
*C.* *pneumoniae*
*M. pneumoniae*
*L. pneumophila*

- Importance ofintracellular levels

- Importance of plasmaand ECF levels

## Recognition of Clinical Relevance of Penicillin Resistance

- Impact of penicillin G nonsusceptibility was readily demonstrated in meningitis
- Recent outcome studies show impact for ‘high-level’ resistance in pneumonia
- Turett et al., Feikin et al. showed associated mortality
- Metlay et al. showed association with increased suppurative complications
- PRSP relevant for pneumonia at MIC 2 μg/mL,Heffelfinger et al.
- >60% of PRSP are multidrug resistant

## Recognition of Clinical Relevance of Erythromycin-Resistant S. pneumoniae

- 6 cases reported through 1992 (Lonks and Medeiros, *Infect Med* 1994;11:415-424)
- Reports of failure are increasing
- 	 Fogarty et al (3 azithromycin failures)
- Kelley et al (1 clarithromycin and 3 azithromycin failures)
- Waterer (azithromycin failure)
- All recently reported failures had *S. pneumoniae* with MIC 8 μg/mL to erythromycin A

## Evolution of Resistance of S. pneumoniae to Erythromycin in the US

- Source: CDC Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, published and unpublished data.

**% Resistant Isolates**

**M Phenotype**

**MLS****B**** Phenotype**

**All resistant isolates**
**MIC ********1 μg/mL**

**N=2508**

**N=3147**

**N=3110**

**N=3303**

**N=3435**

**N=2508**

**% Resistant Isolates**

**N=3147**

**N=3435**

**Resistant isolates with**
**MIC ********8 μg/mL**

**N=3110**

**N=3303**

**Notes:**
Source: s10/043t

## Therapy of RTI

- Community-Acquired Pneumonia

- Bacterial Infection

- _Risk DRSP_
- Fluoroquinolone

- _Known DRSP_
- Fluoroquinolone

- _No risk DRSP_
- Macrolide
- Doxycycline
- Fluoroquinolone

## Telithromycin

**Telithromycin**

- Novel mechanism of action
- Excellent antipneumococcal activity
- Activity against Ery-R and Pen-R *S. pneumoniae*
- Activity against other common, intracellular, and atypical pathogens
- Short, simple course of treatment

## Telithromycin – Proposed Indications

- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis due to Group A beta-hemolytic streptococci (GABHS)

## Telithromycin – Presentation Agenda

- Introduction	Mindell Seidlin, MD
**Microbiology****	****André Bryskier, MD**
**	****Senior Director, ****	****Clinical Microbiology, Aventis**** **
- Human Pharmacology	Vijay Bhargava, PhD
- Clinical Efficacy and Safety	Bruno Leroy, MD
- ECG Analysis	Claude Benedict, MD
- Conclusions 	Mindell Seidlin, MD

## Telithromycin

- Telithromycin, the first ketolide, is designed to overcome erythromycin A resistance within gram-positive cocci

**O**

**O**

**O**

**O**

**OCH****3**

**O**

**9**

**6**

**N**

**R**

**3**

**O**

**O**

**D - desosamine**

**New chemical ****class (3–keto)**

**Innovation****(C****11****–C****12**** carbamate)**

**11**

**12**

## Benefits of the 3–Keto Function

- High stability in acidic environment
- Antibacterial activity against *erm-*containing gram-positive cocci
- Inability to induce MLSB resistance

**3**

**O – ****cladinose**

**3–keto function**

## Benefits of Carbamate Residue and Side Chain at Position C11 – C12 

- Reduced impact of efflux mechanism of resistance
- Enhanced antibacterial activity against gram-positive bacteria
- Governs intracellular accumulation and efflux in phagocytes

**N**

**N**

**N**

**N**

**O**

**O**

**12**

**11**

- Butyl imidazolyl-pyridinylside chain

## Telithromycin: Mode of Action

**Telithromycin: Mode of Action**

- Inhibition of protein synthesis
- Depletion of ribosomes in bacterial cell

## Inhibition of Protein Synthesis (1)

- Bacterial ribosome

- 30S

- 50S
- subunit

- Target of erythromycin A and telithromycin is the peptidyl transferase site located in 23S rRNA

## Inhibition of Protein Synthesis (2)

- Inhibition of peptidyl transferase activity

**5S rRNA**

**Domain V**

**Domain II**

**Pocket: peptidyl transferase site**

**5S rRNA**

**5S rRNA**

**2058**

**752**

- V

- II

- V

- II

**Erythromycin A**

**Telithromycin**

**2058**

**752**

- 30S

- 50S

**O**

**O**

**O**

**-cladinose**

## Ribosomal Depletion

- 30S

- 50S

- 30S

- 50S

- 30S

**Depletion of**
**ribosome in the**
**bacterial cells**

**Erythromycin A**

**Telithromycin**

- Inhibition of ribosomal subunit formation

## Consequence of Double Binding to 23S rRNA

**2058**

**752**

**V**

**II**

**V**

**II**

**Erythromycin A**

**Telithromycin**

**2058**

**752**

- No link with
- domain V

- Resistance to erythromycin A,azithromycin, clarithromycin

- Link with
- domain II

- Telithromycin retains activity
- against erythromycin A-
- resistant organisms

**5S rRNA**

**5S rRNA**

**-cladinose**

**O**

**O**

**O**

**O**

**O**

**O**

**(methylation)**

**(methylation)**

**x**

**x**

## Telithromycin Activity Against Erythromycin A-Resistant S. pneumoniae

- 	Erythromycin A	Telithromycin

- Methylation *(erm)*	–	+
- Efflux  *(mef, msr, mre)**	*–	+
- Mutation (ribosomal protein L4)	–	+

## Telithromycin: Antipneumococcal Activity  (1)

**Telithromycin: ****Antipneumococcal Activity  (1)**

- Cumulative susceptibility of 400 strains of *S. pneumoniae*

**0**

**20**

**40**

**60**

**80**

**100**

**0.008**

**0.03**

**0.12**

**0.5**

**2**

**8**

**32**

**MIC (μg/mL)**

**Cumulative****% susceptible **

- Source: G Doern, 1999

## Telithromycin: Antipneumococcal Activity  (2)

- Phenotype	N	50	90	50	90

- Ery-S	537	0.01	0.03	0.03	0.06
- Ery-R (efflux)	47	0.25	0.5	2.0	4.0
- Ery-R (MLSB)	24	0.03	0.25	32.0	32.0

- Source: A Barry et al., 1997

- 	MIC (μg/mL)

**Telithromycin: ****Antipneumococcal Activity  (2)**

- Potent antipneumococcal activity, including erythromycin A-resistant *S. pneumoniae *strains:
- in vitro activity *vs* clarithromycin

## Telithromycin: Antipneumococcal Activity Against Resistant Isolates

- N	50	90	Reference

- Cefotaxime	S	102	 0.008	0.25	1
- 	I	168	0.06	0.5	1
- 	R	148	0.06	1.0	1
- Penicillin G	S	1495	0.004 - 0.06	0.004 - 0.12	2
- 	I	365	0.01 - 0.03	0.03 - 0.25	2
- 	R	867	0.004 - 0.12	0.01 - 2.0	2
- Tetracycline	R	15	0.01	0.01	3
- Cotrimoxazole	R	20	0.003	0.007	4
- Ofloxacin	R	15	0.001 - 0.03	0.001 - 0.03	3, 4

- (1) A Barry et al, 2000; (2) Data from 14 laboratories; (3) K Klugman et al, 1997; (4) R Reinert et al, 1997

- MIC (μg/mL)

## Telithromycin: Bactericidal Activity

**Telithromycin: Bactericidal Activity**

- Telithromycin exhibits bactericidal activity against *S. pneumoniae* resistant to erythromycin A and penicillin G (*erm*B)

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**0**

**2**

**4**

**6**

**12**

**24**

**Time (hours)**

**Log****10**** cfu/mL**

- Source: P Appelbaum, 2000

## Telithromycin: In VivoAntipneumococcal Activity

- Efficacy confirmed in animal models:
- disseminated infections in mice
- lung infections in mice
- 	using:
- erythromycin A–susceptible strains
*erm*– and *mef*–containing strains

## Antipneumococcal Activity in North American Isolates of S. pneumoniae Resistant to Penicillin G and Erythromycin A

- a Barry et al., 1999;  b Hoban et al., 1999

- 	             USA a		               Canada b
- 	n/N	(%)	n/N	(%)

- Penicillin G	203/576	(35)	185/1333	(14)
- Erythromycin A	117/576	(20)	131/1333	(10)
- Telithromycin c	0/576		1/1333

- c MIC of 4.0 μg/mL

- Resistance in 1999

## Telithromycin: Main Respiratory Pathogens (North America)

*S. pneumoniae*	8	2467	0.008 - 0.12	 0.008 - 0.25
*S. pyogenes**	*6	519	 0.008 - 0.03	0.015 - 0.06
*H. influenzae*	5	1071	1.0 - 2.0	2.0 - 4.0
*M. catarrhalis*	4	728	0.06	0.12
*L. pneumophila*	2	76	0.015 - 0.06	0.03 - 0.12
*C. pneumoniae* a*	*1	15	0.03 - 2.0	0.03 - 2.0
*M. pneumoniae*	1	49	0.12	0.25

- Number of centers

- Number of strains

- 50

- 90

- MIC range  (μg/mL)

- a MIC / MCC

## Intracellular Concentration of Telithromycin in Neutrophils

- Intracellular bioactivity demonstrated with *C. pneumoniae, **L. pneumophila, S. pneumoniae, *and* *other intracellular pathogens

**500**

**0**

**100**

**200**

**300**

**0**

**180**

**30**

**60**

**Time (min)**

**% Uptake**

**400**

**120**

**Intracellular accumulation **

**100**

**0**

**25**

**50**

**75**

**0**

**5**

**30**

**60**

**Time (min)**

**% Efflux**

**Intracellular concentration****(neutrophils) - efflux**

**Roxithromycin**

**Roxithromycin**

## Microbiology of Telithromycin: Summary (1)

- Telithromycin, the first ketolide, has a novel antibacterial mechanism of action
- Telithromycin exhibits antibacterial activity against common, atypical, and intracellular pathogens involved in community-acquired respiratory tract infections
- Telithromycin overcomes erythromycin A resistance

## Microbiology of Telithromycin: Summary (2)

- Telithromycin has rapid bactericidal activity against *S.pneumoniae*
- Does not induce MLSB resistance
- Low frequency of selection of resistant mutants
- Active against *S. pneumoniae* strains resistantto erythromycin A, penicillin G, tetracycline, cotrimoxazole, fluoroquinolones and cefotaxime

## Telithromycin – Presentation Agenda

- Introduction	Mindell Seidlin, MD
- Microbiology	André Bryskier, MD
**Human Pharmacology****	****Vijay Bhargava, PhD**** ****	****Senior Director,****	****Drug Metabolism and ****	****	****	****Pharmacokinetics, Aventis**
- Clinical Efficacy and Safety	Bruno Leroy, MD
- ECG Analysis	Claude Benedict, MD
- Conclusions 	Mindell Seidlin, MD

## Clinical Pharmacology Program

- Clinical pharmacology, bioavailability, and drug metabolism of telithromycin:
- plasma and tissue pharmacokinetic characteristics
- multiple pathways of disposition and exposure in special populations
- pharmacokinetic/pharmacodynamic rationale for doses used in Phase III clinical efficacy program

## Pharmacokinetics of Oral Telithromycin in Healthy Subjects

- 800 mg single dose

- 800 mg
- multiple dose (7 d)

- C24h (μg/mL)

- 0.03

- (72)

- AUC(0-24h) (μg.h/mL)

- 8.3

- (43)

- 7.2

- (20)

- t1⁄2,****z (h)

- Data are mean (CV%) [Min-Max], N = 18
- a Median

- (19)

- (31)

- (45)

- Cmax  (μg/mL)

- 1.9

- 2.3

- (42)

- (31)

- tmax (h)

- 1.0 a

- 1.0 a

- [0.5-4]

- [0.5-3]

- 0.07

- 12.5

- 9.8

**Notes:**
Source data: CSR 1008

## Tissue and Fluid Penetration of Telithromycin in Patients

- Tissue

- Mean (CV%) telithromycin concentration after 800 mg dose (μg/mL)

- 2-3h

- 24h

- Alveolar macrophages a

- 69.3

- 161.6

- Tonsils (μg/g) b

- 4.0

- 0.7

- a Data from Honeybourne and Wise, N = 5-7
- b Data from Gehanno, N = 6-8

- Epithelial lining fluid a

- 12h

- 0.9

- 14.9

- 0.8

- 3.3

- 318.1

- (76)

- (62)

- (51)

- (60)

- (59)

- (73)

- (13)

- (40)

- (56)

## Other Key Pharmacokinetic Features

- Absolute bioavailability ~60%
- Serum protein binding ~70%
- Similar pharmacokinetics in men and women
- Similar pharmacokinetics with or without food

## Pathways of Telithromycin Disposition

**Oral administration *****(************ 90% absorbed, <10% unabsorbed)***

***Systemic bioavailability (57%)***

**Renal excretion**

***Unchanged drug ***
***in urine***

**GI tract/biliary**

**Hepatic excretion**

***Unchanged drug***
***in feces***

**	*****Metabolized drug****** **********

***Metabolism in liver and GI tract ***

**First pass effect**

**Pathways of Telithromycin Disposition**

***(13%)***

***(37%)***

***(7%)***

***(33%)***

***Non-P450 mediated***

***CYP3A4-mediated***

***1⁄2***

***1⁄2***

- *	Telithromycin is not metabolized by CYP2D6

## Effect of CYP3A4 Inhibition

**First ****pass effect**

- Telithromycin
- N=11

- Telithromycin + ketoconazole
- N=11

- AUC(0-24 h) (μg.h/mL)	14.4	(39)	28.6	(31)
- Cmax (μg/mL)	2.0	(38)	3.1	(36)

- Data are mean (CV%): 	telithromycin 800 mg qd (5 days), ketoconazole 400 mg qd (7 days)

- Itraconazole: less interaction, grapefruit juice: no interaction

**Effect of CYP3A4 Inhibition**

***Systemic ******bioavailability***

**Hepatic ****excretion**

***Metabolites***

***Metabolism in ******liver and GI tract ***

***CYP3A4-mediated***

***1⁄2***

***1⁄2***

- t1⁄2,****z (h)

- 11.2   (26)

- 12.6  (27)

**Notes:**
Source data: CSR 1045

## Effect of Hepatic Impairment 

- Hepatic
- impairment
- N=12

- Healthy
- N=12

- Data are mean (CV%)
- Mild impairment: N = 2; Moderate impairment: N = 5; Severe impairment: N = 5

**Effect of Hepatic Impairment **

***Systemic ******bioavailability***

**Renal excretion**

**Hepatic ****excretion**

***Metabolites***

***Metabolism in ******liver and GI tract ***

**First ****pass effect**

**Notes:**
Source data: CSR 1015

## Effect of Hepatic Impairment  (Multiple Dose)

- N=12

- Healthy
- N=10

- Day 1

- Day 7

- Day 1

- Day 7

- t1/2, z (h)

- 12.5  (26)

- –

- 10.6  (18)

- CLR (L/h)

- Cmax  (μg/mL)

- 1.6  (26)

- 1.8  (23)

- 1.7  (26)

- 2.0  (32)

- AUC(0-24h)
-    (μg.h/mL)

- 9.5  (32)

- 12.3  (21)

- 9.0  (35)

- 13.8  (28)

- –

- 14.5  (50)

- 14.9  (47)

- 10.3  (20)

- 11.3  (16)

- Data are mean (CV%)
- Mild impairment: N = 4; Moderate impairment: N = 6; Severe impairment: N = 2

**Effect of Hepatic Impairment **** (Multiple Dose)**

***Systemic ******bioavailability***

**Renal excretion**

**Hepatic ****excretion**

***Metabolites***

***Metabolism in ******liver and GI tract ***

**First ****pass effect**

**Notes:**
Source data: CSR 1060

## Effect of Renal Impairment 

- N=10

- 41 to 80
- N=10

- 11 to 40
- N=10

- Creatinine clearance
- (mL/min)

- Data are mean (CV%)

**Effect of Renal Impairment **

***Systemic ******bioavailability***

**Renal excretion**

***Unchanged drug ***
***in urine***

- Renal function

**Notes:**
Source data: CSR 1016

## Exposure in CAP Patients: Elderly and Non-Elderly (Phase III/Study 3000)

- AUC(0-24 h) (μg.h/mL)	18.1 (63)	25.9 (70)
- Cmax (μg/mL)	2.8  (50)	3.5 (63)

- Data are mean (CV%)

- <65 years
- N=142

- 65 years
- N=20

**Exposure in CAP Patients: Elderly and ****Non-Elderly (Phase III/Study 3000)**

**Notes:**
Source data: CSR xxx (Study 3000)

## Selection of Telithromycin Dose Regimen (Mouse Thigh Infection Model - Craig)

**Selection of Telithromycin ****Dose Regimen**** ****(****Mouse Thigh Infection Model - Craig)**

- Effective dose was similar, irrespective of dosing frequency (3, 6, 12, 24 hours)
- Efficacy of telithromycin is concentration-dependent rather than time-dependent:
- AUC/MIC and Cmax/MIC are better predictors of efficacy than time above MIC

## Dose in humans was chosen to give unbound AUC/MIC values similar to, or higher than, AUC/MIC values at effective dose in mice
800 mg once-daily dose regimen is supported by high tissue levels in humans

- 800 mg once-daily dose regimen is supported by high tissue levels in humans

**Selection of Telithromycin Dose Regimen Based on PK/PD Model**

## Dose Selection: H. influenzae

**Dose Selection: *****H. influenzae***

- No well-validated animal model of lower RTI
- ELF peak levels (up to 14.9 μg/mL) exceed MIC90 of *H. influenzae*
- Plasma and extracellular (ELF) levels for telithromycin (Cmax ELF/MIC = 3.6 to 7.2) are well above those reported for azithromycin

## Summary of Human Pharmacology

- Telithromycin rapidly achieved targeted plasma and respiratory tissue concentrations
- Telithromycin has a well-characterized and reproducible PK profile
- Multiple elimination pathways limit the potential for increased exposure in special populations
- The PK/PD profile of telithromycin supports an 800 mg once-daily regimen

## Telithromycin – Presentation Agenda

- Introduction	Mindell Seidlin, MD
- Microbiology	André Bryskier, MD
- Human Pharmacology	Vijay Bhargava, PhD
**Clinical Efficacy and Safety****	****Bruno Leroy, MD**
**	****Senior Director, ****	****Clinical Development,****	****Anti-Infectives, Aventis**
- ECG Analysis	Claude Benedict, MD
- Conclusions 	Mindell Seidlin, MD

## Clinical Efficacy of Telithromycin

- Study design across indications
- Clinical efficacy by indication:
- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis

## Telithromycin Dosage Regimens in Phase III Studies

- CAP	800 mg qd	7-10 days
- AECB	800 mg qd	5 days
- Acute sinusitis	800 mg qd	5 days
- 		800 mg qd	10 days
- Tonsillitis/Pharyngitis	800 mg qd	5 days

- Indication	Dosage	Duration

## Generalized Study Design

## Main Analysis Populations

- Population	Definition

- mITT	All subjects with disease who received at least one dose
- PPc	All mITT subjects excluding major protocol violators (clinically evaluable)
- PPb	All PPc subjects with a causative pathogen isolated at pretherapy/ entry (microbiologically evaluable)

## Clinical Efficacy of Telithromycin

- Study design across indications
- Clinical efficacy by indication:
- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis

## CAP: Phase III Controlled Studies

- Study No.

- Treatment

- 3001

- TEL

- 10 d

- 800 mg qd

- AMX

- 10 d

- 1000 mg tid

- 3006

- TEL

- 10 d

- 800 mg qd

- CLA

- 10 d

- 500 mg bid

-  TEL = Telithromycin;  AMX = Amoxicillin;  CLA = Clarithromycin;  TVA = Trovafloxacin

- 3009

- TEL

- 7-10 d

- 800 mg qd

- TVA

- 7-10 d

- 200 mg qd

- 3 randomized, controlled, double-blind, comparative trials (Western countries)

- N (mITT)

- 199

- 205

- 204

- 212

- 100

- 104

**Notes:**
Source data: x06/006x

## CAP: Other Studies

- Study No.

- Treatment

- 3000

- TEL

- 7-10 d

- 800 mg qd

- 3009 OL

- TEL

- 7-10 d

- 800 mg qd

- 3 Phase III open-label studies (Western countries)

- N (mITT)

- 240

- 212

- 1 Phase II dose-comparison study (Japan)

- 3010

- TEL

- 7 d

- 800 mg qd

- 418

- 2105

- TEL

- 7 d

- 600 mg qd

- TEL

- 7 d

- 800 mg qd

- 46

- 50

**Notes:**
Source data: x06/006x and CSR 2105

## CAP: Key Subject Background Characteristics, mITT (Western Studies)

- 65 years old 	83	(17)	87	(17)	196	(14)
- Pneumococcal	22	 (4)	18	(4)	56	(4)
-   bacteremia
- Fine score:
- 	III	84	(17)	105	(20)	220	(16)
- Consolidation	187	(37)	190	(36)	791	(58)
- Multiple lobes	41	(9)	35	 (7)	161	(12)

- Controlled studies

- 	TEL	Comparator	TEL
- Subjects (%) with	N=503	N=521	N=1373

- All CAP
- studies

**Notes:**
Source data: v07/4x

## CAP: Clinical Cure at TOC, PPc  (Controlled Studies, Western Countries)

**CAP: Clinical Cure at TOC, PPc **** ****(Controlled Studies, Western Countries)**

**95%**

**88%**

**94%**

**90%**

**89%**

**90%**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**3001 *****vs***** AMX**

**3006 *****vs***** CLA**

**3009  *****vs***** TVA**

**	**** ****[–2.1; 11.1] ****a**

_**143**_**162**

_**138**_**156**

_**141**_**149**

_**137**_**152**

_**72**_**80**

_**81**_**86**

- 	a 95% confidence intervals

**[–7.9; 7.5] ****a**

**[–13.6; 5.2] ****a**

**Notes:**
Source data: v08/13x

## CAP: Clinical Cure at TOC, PPc(Uncontrolled Studies, Western Countries)

- 3000	183/197	(93)
- 3009 OL	175/187	(94)
- 3010	332/357	(93)

- TEL

-  	n/N 	(%)

- Study

**Notes:**
Source data: v08/13x

## CAP: Clinical Cure by Pathogen(All Western Studies) 

*H. influenzae*	95/105	(91)	27/27	(100)
*M. catarrhalis*	26/30	(87)	4/5	(80)

- 	TEL	Comparator a

- All Cultures:	n/N 	(%)	n/N	(%)

**CAP: Clinical Cure by Pathogen****(All Western Studies)**** **

- a 	Study 3001: Amoxicillin;  Study 3006: Clarithromycin;  Study 3009: Trovafloxacin

**PPb population at TOC**

**Notes:**
Source data: v08/45t

## CAP: Clinical Cure for Atypical Pneumonia  in Telithromycin Subjects (All Western Studies) 

*Chlamydia**	** *32/34	(94) 	 27/29	(93)*pneumoniae *
*Legionella**	** *12/12	(100) 	 7/7	(100)*pneumophila*

- 	TOC	LPTV a

- 	n/N 	(%)	n/N	(%)

**CAP: Clinical Cure for Atypical ****Pneumonia  in Telithromycin Subjects ****(All Western Studies)**** **

- a Late posttherapy visit (Day 31-45)

**PPc population, subjects without other ****causative pathogens**

**Notes:**
Source data: v08/17x

## CAP: Clinical Cure by Risk Factors for Morbidity (Western Studies)

- Total population	356/391	(91)	356/394	 (90)	 1046/1132	(92)
-    65 years old 	53/60	(88)	56/66	(85)	 139/154	(90)
-    Pneumococcal	15/15	 (100)	11/13	(85)	 43/47	(91)
-      bacteremia b
-    Fine score III	56/61	(92)	65/78	(83)	 161/175	(92)

- Controlled studies

- 	n/N	(%)	n/N	(%)	n/N	(%)

- All CAP
- studies

**PPc population at TOC**

- 	TEL	Comparator a	TEL

- a Study 3001: Amoxicillin; Study 3006: Clarithromycin; Study 3009: Trovafloxacin b PPb population

**Notes:**
Source data: v08/56t and v01/f0108c

## CAP: Clinical Cure forS. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin

*Single and multiple pathogens*
-   Pen-R	16/19	13/16	3/3
-   Ery-R	21/25	13/16	8/9
*Single pathogens*
-   Pen-R 	 11/12	 8/9	 3/3
-   Ery-R	15/17	 8/9	 7/8

- n/N Subjects

**PPb population at TOC**

- 		All	Western	Japanese
- 		studies	studies	study

- Pen-R = Penicillin G-resistant (MIC 2.0 μg/mL); Ery-R = Erythromycin A-resistant (MIC 1.0 μg/mL)

**Notes:**
Source data: v08/b20421t and v08/b20423t

## CAP: Clinical Cure for Subjects with Pneumococcal Bacteremia (Treatment with Telithromycin, All Western Studies)

- All *S. pneumoniae*	38/40	43/47
- 	Pen-R	4/5	4/6
- 	Ery-R a	2/3	4/6
- 	Pen-R and/or Ery-R	5/6	7/9

**PPb population at TOC**

- 		Single	Single and
- 		pathogens	multiple pathogens

- Pen-R = Penicillin G-resistant (MIC 2.0 μg/mL); Ery-R = Erythromycin A-resistant (MIC 1.0 μg/mL)
- a MIC to erythromycin A ranged from 4.0 to 32.0 for strains eradicated

- n/N Subjects

**Notes:**
Source data: s08/b200429t and Listing c220050d of CSR 3010

## Summary of Efficacy in CAP

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

- 	Common pathogens
*S. pneumoniae*
- Pen-R strains
- Ery-R strains
*H. influenzae*
*M. catarrhalis*

- 	Atypical pathogens
*M. pneumoniae*
*C. pneumoniae*
*L. pneumophila*

- Treatment with telithromycin 800 mg once daily for 7 to 10 days is effective in CAP due to:

## Clinical Efficacy of Telithromycin

- Study design across indications
- Clinical efficacy by indication:
- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis

## AECB: Phase III Studies

- 3003 a

- TEL

- 5 d

- 800 mg qd

- AMC

- 10 d

- 500/125 mg tid

- 3007

- TEL

- 5 d

- 800 mg qd

- CXM

- 10 d

- 500 mg bid

- AMC = Amoxicillin/clavulanic acid;  CXM = Cefuroxime axetil

- Study No.

- Treatment

- N (mITT)

- 160

- 160

- 182

- 191

- a Documented COPD

**Notes:**
Source data: x06/11x

## AECB: Clinical Cure at TOC, PPc

**AECB: Clinical Cure at TOC, PPc**

**86%**

**87%**

**83%**

**82%**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**3003 *****vs***** AMC**

**3007 *****vs***** CXM**

_**99**_**115**

_**92**_**112**

_**121**_**140**

_**118**_**142**

**	**** ****[–6.4; 14.3] ****a**

**	**a 95% confidence intervals

**[–5.8; 12.4] ****a**

**Notes:**
Source data: x08/20x

## AECB: Clinical Cure by Pathogen (Both Studies) 

*H. influenzae**	*17/25	(68)	13/17	(76)
*M. catarrhalis*	10/10	(100)	14/16	(88)
*S. aureus**	*2/2	(100)	3/3	(100)

- 	TEL 	Comparator a	 	5 d 	 10 d

- 	n/N 	(%)	n/N	(%)

**AECB: Clinical Cure ****by Pathogen (Both Studies) **

**PPb population at TOC**

- a Study 3003: Amoxicillin/clavulanic acid, Study 3007: Cefuroxime axetil

**Notes:**
Source data: q08/47t

## AECB: Clinical Cure for Atypical Pathogens (Both Studies) 

*Mycoplasma pneumoniae*	1/1	(100)

- 	n/N	(%)

**AECB: Clinical Cure for Atypical Pathogens (Both Studies) **

- PPc population at TOC, subjects without other causative pathogens

**Notes:**
Source data: x08/24x

## AECB: Clinical Cure by Baseline Characteristics (Both Studies)

- Total Population	220/255	(86)	210/254	(83)
-  65 years old	79/90	 (88) 	 90/114	(79)
- Morbidity risk factors a: 	At least 1	128/148	(87)	116/142	(82)	At least 2	59/70	(84)	63/76	(83)
- FEV1/FVC <60%	56/68	(82)	 64/81	(79)

- 	TEL	Comparator

- 	n/N 	(%)	n/N	(%)

- a 	COPD, pulmonary insufficiency, coronary atherosclerosis, history of inhaled steroids, diabetes mellitus, etc.

**PPc population at TOC**

**Notes:**
Source data: x08/56t and q07/62x and aecb/x1f0108a

## 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*
*S. aureus*
*C. pneumoniae*
- Effective in outpatients at risk for complications (elderly, significant obstruction)

## Clinical Efficacy of Telithromycin

- Study design across indications
- Clinical efficacy by indication:
- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis

## Acute Sinusitis: Phase III Studies

- 3002

- TEL

- 5 d

- 800 mg qd

- TEL

- 10 d

- 800 mg qd

- AMC

- 10 d

- 500/125 mg tid

- 3005

- TEL

- 5 d

- 800 mg qd

- TEL

- 10 d

- 800 mg qd

- AMC = Amoxicillin/clavulanic acid; CXM = Cefuroxime axetil

- Study No.

- Treatment

- N (mITT)

- 3011

- TEL

- 202

- 240

- 167

- 168

- 201

- 204

- CXM

- 116

- 5 d

- 10 d

- 250 mg bid

- 800 mg qd

**Notes:**
Source data: v06/1x

## Acute Sinusitis: Clinical Cure at TOC, PPc

**Acute Sinusitis: Clinical Cure ****at TOC, PPc**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**91%**

**91%**

**3002**

_**112**_**123**

_**121**_**133**

**[–7.7; 7.9] ****a**

**75%**

**73%**

**75%**

**3005 *****vs***** AMC**

_**110**_**146**

_**102**_**137**

_**102**_**140**

**[–12.7; 9.5] ****a**

**[–9.9; 11.7] ****a**

**	**a 95% confidence intervals

**85%**

**82%**

**3011 *****vs***** CXM**

_**161**_**189**

_**73**_**89**

**[–7.1; 13.4] ****a**

**Notes:**
Source data: v08/27x

## Acute Sinusitis: Clinical Cureby Pathogen (All Studies)

*H. influenzae*	42/48	(88)	15/16	(94)
*M. catarrhalis*	13/14	(93)	3/4	(75)
*S. aureus**	*18/19	(95)	4/4	(100)

- 	TEL 5 d	TEL10 d

- 	n/N 	(%)	n/N	(%)

**Acute Sinusitis: Clinical Cure****by Pathogen (All Studies)**

**PPb population at TOC**

**Notes:**
Source data: v08/49t

## Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin (All Studies)

*Single and multiple pathogens*
-   Pen-R	8/10	3/3	11/13
-   Ery-R	12/14	6/7	18/21
*Single pathogens*
-   Pen-R 	 6/8	 3/3	 9/11
-   Ery-R	8/10	 5/6	 13/16

- n/N Subjects

**PPb population at TOC, according to treatment duration**

- 				5 and
- 		5 days	10 days	10 days

- Pen-R = Penicillin G-resistant (MIC 2.0 μg/mL); Ery-R = Erythromycin A-resistant (MIC 1.0 μg/mL)

**Notes:**
Source data: v08/b200421t and v08/b200423t

## Summary of Efficacy in Acute Sinusitis

- Treatment with telithromycin 800 mg once daily for 5 days is equivalent to 10 days of standard treatment given 2 to 3 times daily (amoxicillin/clavulanic acid, cefuroxime axetil)
- Telithromycin 800 mg once daily for 5 days is effective in acute sinusitis due to:
*S. pneumoniae*
- Pen-R strains
- Ery-R strains
*H. influenzae*
*M. catarrhalis*
*S. aureus*

## Clinical Efficacy of Telithromycin

- Study design across indications
- Clinical efficacy by indication:
- Community-acquired pneumonia (CAP)
- Acute exacerbation of chronic bronchitis (AECB)
- Acute sinusitis
- Tonsillitis/Pharyngitis

## Tonsillitis/Pharyngitis:  Phase III Studies

- 3004

- TEL

- 5 d

- 800 mg qd

- PEN

- 10 d

- 500 mg tid

- 3008

- TEL

- 5 d

- 800 mg qd

- CLA

- 10 d

- 250 mg bid

- PEN = Penicillin VK;  CLA = Clarithromycin

- Study No.

- Treatment

- N (mITT)

- 198

- 197

- 232

- 231

**Notes:**
Source data: v06/1x

## Tonsillitis/Pharyngitis: Bacterial Eradication by Subject at TOC, PPb (Both Studies)

**Tonsillitis/Pharyngitis: Bacterial Eradication ****by Subject at TOC, PPb (Both Studies)**

**84%**

**91%**

**88%**

**89%**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**3004 *****vs***** PEN**

**3008 *****vs***** CLA**

_**97**_**115**

_**106**_**119**

_**137**_**150**

_**119**_**135**

**	**** ****[–14.3; 4.8] ****a**

- 	a 95% confidence intervals

**[–4.6; 11.0] ****a**

**Notes:**
Source data: s08/35x

## Summary of Efficacy in Tonsillitis/Pharyngitis

- Treatment with telithromycin 800 mg once daily for 5 days is effective in GABHStonsillitis/pharyngitis
- Equivalence demonstrated between 5-day telithromycin treatment and 10-day standard treatment (penicillin VK 500 mg tid or clarithromycin 250 mg bid)

## Summary of Efficacy in RTIs (1)

- Efficacy results consistent across analysis populations in 13 studies in 4 indications
- 5-day treatment effective in AECB, acute sinusitis and tonsillitis/pharyngitis *vs* 10-day treatment with comparators
- 7 to 10-day treatment effective in CAP

## Summary of Efficacy in RTIs (2)

- Effective in subjects at risk for complications:
- CAP: elderly, pneumococcal bacteremia, *Legionella *infection
- AECB: elderly, significant obstruction (FEV1/FVC < 60%)
- Effective in infections (CAP, acute sinusitis) due to *S. pneumoniae* resistant to penicillin G and erythromycin A

## Safety Results

- Phase III:
- general adverse event profile
- serious adverse events
- laboratory abnormalities
- ECG analysis

## Subjects (%) in Phase III Safety Population

- 		TEL	TEL	TEL
-  		N=3265	N=2045	N=1220

**Subjects (%) in Phase III ****Safety Population**

- Subjects who received 1 dose and safety assessment following randomization

- Men	**1631 ****	****(50.0)**	949	(46.4)	682	(55.9)
- Women	**1634 ****	****(50.0)**	1096	(53.6)	538	(44.1)
- 13-18 years	**95 ****	****(2.9)**	68	(3.3)	27	(2.2)
- 65 years	**372 ****	****(11.4)**	257	(12.6)	115	(9.4)

**Notes:**
Source data: v09/16t

## Subjects (%) with Treatment-Related Adverse Events  ( 2%)  (Controlled Phase III Studies)

- 	TEL	Comparator
-  	N=2045	N=1672

- All Treatment-rel. AEs 	712	(34.8)	465	(27.8)
- 	Diarrhea	272	(13.3)	158	(9.4)
- 	Nausea	166	(8.1)	64	(3.8)
- 	Dizziness	73	(3.6)	26	(1.6)
- 	Vomiting	57	(2.8)	24	(1.4)
- 	Headache	45	(2.2)	51	(3.1)
- 	Taste perversion	34	(1.7)	35	(2.1)
- Blurred vision	10	(0.5)	0	  (0)

**Notes:**
Source data: v09/17t

## Subjects (%) with Discontinuations Due to Adverse Events  (Controlled Phase III Studies)

- Treatment-related AEs	76 (3.7)	51 (3.1)
- 	GI related events	54 (2.6)	33 (2.0)
- 		–  Diarrhea	19 (0.9)	13 (0.8)
- 		–  Nausea	18 (0.9)	9 (0.5)
- 		–  Vomiting	19 (0.9)	6 (0.4)
- 	Other events	25 (1.2)	18 (1.1)

**Subjects (%) with Discontinuations Due to Adverse Events  (Controlled Phase III Studies)**

- 	TEL		Comparator
-  	N=2045		N=1672

**Notes:**
Source data: v09/161t

## Prevalence of Diarrhea for Telithromycin vs Comparator Drugs (Controlled Phase III Studies)

**Clarithromycin**

**Amoxicillin/**
**clavulanic acid**

**Day**

**% ****Subjects**

**Prevalence of Diarrhea for Telithromycin *****vs***** Comparator Drugs (Controlled Phase III Studies)**

- Prevalence included for each day from onset through last day of occurrence.

**Cefuroxime**
**axetil**

**Notes:**
Source data: mm_87_verify.doc (John Sanocki, 21 Feb 2001)

## Treatment-Related Adverse Eventsby Age  (Controlled Phase III Studies)

**Treatment-Related Adverse Events****by Age  (Controlled Phase III Studies)**

**28%**

**36%**

**27%**

**19%**

**29%**

**26%**

**0**

**20**

**40**

**60**

**80**

**100**

**13-18 yr**

******18 ********65 yr**

******65 yr**

**TEL**

**Comparator**

_**19**_**68**

_**13**_**69**

_**623**_**1720**

_**385**_
**1343**

_**70**_
**257**

_**67**_**260**

**Age**

**% ****Subjects**

**Notes:**
Source data: v09/299t

## Summary of Mortality(All Phase III Studies)

- Controlled studies:	Telithromycin = 2	Comparator = 4
- Uncontrolled studies:	Telithromycin = 5
- No treatment-related deaths
- Deaths occurred in CAP subjects(telithromycin 7/1415; 0.5%)

**Notes:**
Source data: v09/142t

## Serious Adverse Events(Controlled Phase III Studies)

- All treatment-related serious AEs 	8	(0.4)	4	(0.2)
- 	Allergic reaction	2	(0.1)	1	(0.06)
- 	Asymptomatic transaminase     elevation	2	(0.1)	0	(0)
- 	Pseudomem colitis a	1	(0.05)	1	(0.06)
- 	Erythema multiforme	1	(0.05)	0	(0)
- 	Gastroenteritis	1	(0.05)	1	(0.06)
- 	Vomiting	1	(0.05)	0	(0)
- 	Dyspnea	0	(0)	1	(0.06)

**Serious Adverse Events****(Controlled Phase III Studies)**

- 	TEL	Comparator	N=2045	N=1672

- N (%) Subjects

- a Toxin *C. difficile* negative

**Notes:**
Source data: v09/93t

## Subject 0502/1069

- 53 year-old man with CAP and baseline elevated transaminases,
- eosinophilia, history of diabetes, asthma, 3 recent courses
- of macrolides
- Episode 1: four days after completing telithromycin, new onset of fever and diarrhea; peak ALT 1529 U/L 8 days later
- Biopsy (6 days after peak transaminase): centrilobular necrosis, granulomas, eosinophil/plasma cell infiltration
- Resolved with return to baseline levels 8 weeks after starting therapy
- Episode 2: asymptomatic transaminase increase (1331 U/L ALT) 9 months after telithromycin therapy, with normalization 10 weeks later
- Second biopsy (~7 weeks after peak transaminase): centrilobular hepatic cell depletion without frank necrosis, plasma cell infiltration, bridging fibrosis

**Notes:**
Source: v10/201t, Briefing Document Appendix 19
CSR hmr3647a/3000

## Hepatic Adverse Events(Controlled Phase III Studies)

- Treatment-related hepatic AEs 	40	(2.0)	33	(2.0)
- Hepatic AEs leading to	10	 (0.5) 	 8 	 (0.5) discontinuation

**Hepatic Adverse Events****(Controlled Phase III Studies)**

- 	TEL	Comparator	N=2045	N=1672

- N (%) Subjects

**Notes:**
Source data: v09/814t
	v09/1091t (discontinuations)

## Frequency of Subjects with ALT 3x ULN During Treatment (Controlled Phase III Studies)

- n/N (%) Subjects

- ALT status
- at baseline	Telithromycin	Comparator

- Normal	8/1646	(0.5)	5/1324	(0.4)
-  ULN	24/283	(8.5)	25/226	(11.1)

**Notes:**
Source data: v10/042t
	v10/51t

## Distribution of ALT Values During Treatment in Subjects with Normal ALT at Baseline (Controlled Phase III Studies)

**Distribution of ALT Values During Treatment ****in Subjects with Normal ALT at Baseline ****(Controlled Phase III Studies)**

**CAP Studies**

**Non-CAP Studies**

**ULN**

**ULN**

**% Subjects**

**% Subjects**

**ULN = Upper limit of normal**

******1**

******2**

******3**

******5**

****** ****8**

**2.5**

**1.0**

**0.8**

**0.5**

**0.3**

**0.3**

**0**

**0**

**0.4**

**0.6**

**0.2**

**0.2**

**0**

**0**

**0.1**

**0**

**18.2**

**16.5**

**78.2**

**81.7**

**9.4**

**9.8**

**90.0**

**89.3**

**Notes:**
Source data: v10/042t
	v10/51t

## Summary of Phase III Safety

- Well tolerated:
- pattern of adverse events similar to macrolides
- GI events in the range seen with other antibiotics
- adverse event profile similar in different age groups
- rates of transaminase elevation similar to comparators
- Low incidence of serious adverse events and discontinuations, similar to comparators

## Telithromycin – Presentation Agenda

- Introduction	Mindell Seidlin, MD
- Microbiology	André Bryskier, MD
- Human Pharmacology	Vijay Bhargava, PhD
- Clinical Efficacy and Safety	Bruno Leroy, MD
**ECG Analysis****	****Claude Benedict, MD****	****Senior VP,****	****Preclinical and Early ****	****Clinical Development, Aventis**
- Conclusions 	Mindell Seidlin, MD

## Background

- Macrolides have been associated with changes in cardiac repolarization
- Telithromycin is structurally derived from macrolides
- Extensive preclinical and prospective clinical investigation of potential effect of telithromycin on cardiac repolarization and comparison to macrolides and non-macrolides
- Program was designed in accordance with EU guidelines and FDA recommendations

## Telithromycin: Preclinical Studies

- Binding to membrane ionic channels   (KATP, Kvoltage-dependent, KCa, Na, L-type Ca)
- Interaction with cloned channels(Ikr (HERG), Kv1.5, IKS)
- Studies on isolated human atrial cells(Ito, Ikur, AP duration)
- Rabbit Purkinje fibers:
- bradycardia, hypokalemia
- interaction with sotalol and quinidine
- Studies in awake dogs

## Plasma Levels and HERG Affinity of Selected Antibiotics

- 			Peak free
- 		 Oral dose	[plasma]	 HERG IC50	 Ratio
- 	 Drug 	(mg)	μM	μM	 IC50/ [plasma]

- Investigations on HERG were all conducted at the same laboratory using the same methodology (CHO cells).

- Sparfloxacin	400	1.8	17.9	10
- Moxifloxacin	400	5.9	129	22
- Clarithromycin	500	1.9	54.5	29
- Telithromycin	800	0.84	42.5	51
- Erythromycin	1000	0.9	50.7	56
- Levofloxacin	500	12	915	76

## ECG Phase III Analysis

- ECGs performed pre- and on-therapy (Day 3 to 5) and read by a single central reader in 10 Phase III studies (N=1872 patients)
- 625 patients at risk for QT prolongation (33.4%) included in Phase III program
- 1512 patients with a PK sample drawn within one hour of ECG
- QT measured as mean of longest and shortest QT intervals, corrected for heart rate by Bazett Formula (QTc)

**Notes:**
Source data: x07/34t  (ECGs performed)

## QTc Values at Baseline and On-Therapy for Telithromycin-treated Subjects 

**Baseline**

**On-Therapy**

**Number of Subjects**

******QTc = 1.0 ± 21.1 ms**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**450**

******310**

**330**

**350**

**370**

**390**

**410**

**430**

**450**

**470**

**490**

**510**

**530**

**QTc (ms)**

**Notes:**
Source data: x07/34t

## QTc from Baseline and QT Dispersion

- Treatment	N	(ms)	(ms)

******QTc from Baseline and QT Dispersion**

- Telithromycin 	(all studies)	1872	1.0  21.1	 21.0  9.8
- Telithromycin 	(controlled studies) 	1368	2.3  20.2	 21.8  9.2
- All comparators	 1234	-0.8  20.6	 22.3  9.4
- 	Beta-lactams	 721	-3.2  22.0	 21.5  9.6
- 	Clarithromycin	414	2.3  18.1	 23.7  9.5
- 	Trovafloxacin	 99	1.4  23.0	 21.0  8.5

- Mean ± SD

**Notes:**
Source data: x07/34t

## QTc vs Telithromycin Plasma Concentration 

**Concentration (μg/mL)**

******QTc  (ms)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**-160**

**-120**

**-80**

**-40**

**0**

**40**

**80**

**120**

**N=1512 patients**
**Slope=0.88 ms/μg/mL**
**r****2****=0.0025, p********0.05**

**Notes:**
Phase III QT analytical report  (Shashank Rohatagi)

## QTc vs Telithromycin Plasma Concentration 

**Concentration (μg/mL)**

******QTc  (ms)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**-160**

**-120**

**-80**

**-40**

**0**

**40**

**80**

**120**

- Concs  5μg/mL

- 	Conc	QTc	QTc
- 	5.2	410	-7.4
- 	5.2	364	-24.5
- 	5.2	411	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

**N=1512 patients**
**Slope=0.88 ms/μg/mL**
**r****2****=0.0025, p********0.05**

**Notes:**
Phase III QT analytical report  (Shashank Rohatagi)

## Frequency of QTc Outliers (Telithromycin vs Clarithromycin) 

**Frequency of QTc Outliers ****(Telithromycin vs Clarithromycin)**** **

- n/N (%) Subjects

- No telithromycin subjects had both QTc increase 60 ms and QTc value 450 ms (men) / 470 ms (women)

- QTc increase:
- 	30 and <60 ms	30/393	(7.6)	29/414	(7.0)
- 	60 ms  	0/393	(0)	0/414	(0)
- QTc value:
- 	450 ms, men	1/175	(0.6)	1/190	(0.5)
- 	470 ms, women	0/219	(0)	0/231	(0)
- 	500 ms, men or women	0/394	(0)	0/421	(0)

**Notes:**
Source data: s07/40t

## Frequency of QTc Outliers  (Telithromycin vs Non-macrolides) 

**Frequency of ****QTc Outliers **** ****(Telithromycin *****vs***** Non-macrolides)**** **

- a Trovafloxacin, amoxicillin, cefuroxime axetil, amoxicillin/clavulanic acid, penicillin VK

- n/N (%) Subjects

- No telithromycin subjects had both QTc increase 60 ms and QTc value 450 ms (men) / 470 ms (women)

- QTc increase:
- 	30 and <60 ms	73/975	(7.5)	52/820	(6.3)
- 	60 ms  	3/975	(0.3)	2/820	(0.2)
- QTc value:
- 	450 ms, men	17/480	(3.5)	10/417	(2.4)
- 	470 ms, women	4/508	(0.8)	 1/427	(0.2)
- 	500 ms, men or women	2/988	(0.2)	1/844	(0.1)

**Notes:**
Source data: x07/41t

## Clinical Risk Factors for QTc Prolongation (1)

- Age	< 65 years	1653	1.1  21.1	 65 years	219	0.0  21.7
- Hepatic  	Present	29	-2.4  36.9Impairment	Absent	1843	1.1  20.8
- Renal  	CLCR< 50 mL/min	40	0.8  20.6Impairment	CLCR 50 mL/min 	1832	1.0  21.2
- Concomitant	Taking	154	3.2  19.7CYP3A4 inhibitors	Not taking	1718	0.8  21.3

**Clinical Risk Factors for ****QTc Prolongation (1)**

- 			QTc (ms) 		N	 Mean ± SD

**Notes:**
Source data: q07/705t (gender)
	x07/081t (age)
	x07/196t (hepatic)
	x07/184t	(renal)
	x07/382t (CYP3A4)

## Clinical Risk Factors for QTc Prolongation (2)

- QT-prolonging	Taking	57	 3.0  18.7
- drugs	Not taking	 1815	 0.9  21.2
- Hypokalemia	Present	 103	 -0.2  20.4
- or diuretics	Absent	 1769	 1.1  21.2
- Cardiovascular	Present	358	0.9  21.1Disease	Absent	1514	1.0  21.2
- Prolonged QTc	Present	127	-18.0  24.2at baseline	Absent	1745	2.4  20.2

- 			QTc (ms) 		N	 Mean ± SD

**Clinical Risk Factors for ****QTc Prolongation (2)**

**Notes:**
Source data: x07/145t (CYP2D6)
	v07/896t (QT prolonging drugs)
	v07/894t (hypokalemia)
	v07/904t	(CV disease)
	x07/263t (Prolonged QTc)

## Association Between Baseline QTc and QTc

- Baseline QTc Interval  (ms)

- Mean QTc (ms)

**–****60**

**–****40**

**–****20**

**0**

**20**

**40**

**60**

******310**

******350**

******390**

******430**

******470**

******510**

- Error bars show ± std deviation

**N =****	****2****	****18****	****86****	****292****	****634****	****606****	****179****	****39****	****11****	****3****	****2**

**–****80**

**80**

## Incidence of Treatment-Related Adverse Events of Special Interest in QT Interval Assessment

- Adverse Event 	(N = 2045)	(N = 1672)

**Incidence of Treatment-Related ****Adverse Events of Special Interest ****in QT Interval Assessment**

- Number (%) Subjects

- Dizziness	73	(3.6)	26	(1.6)
- Vertigo	4	(0.2)	2	(0.1)
- Palpitation	1	(0.05)	1	(0.1)
- Hypotension	1	(0.05)	0	(0)
- Arrhythmia	0	(0)	2	(0.1)
- Ventricular arrhythmia	 0	(0)	0	(0)
- Torsades de pointes	 0	(0)	0	(0)
- Syncope	 0	(0)	0	(0)

**Notes:**
Source data: v09/17t

## Further Characterization of Telithromycin Effect on Cardiac Repolarization

- Evaluation of concentration *vs* QT at up to 4 times the therapeutic dose
- Evaluation of heart rate correction formulas for QT

## Comparison between Correction Formulas for Heart Rate Effects Using Data Obtained at Baseline (Phase I Data)

**QTc**

**QTf**

**QTn**

**QTc = QT / (RR ^ 0.5)**

**QTf = QT / (RR ^ 0.33)**

**QTn = QT / (RR ^ 0.284)**

**Notes:**
Phase I analytical report (Jun Shi)

## Relationship Between QTn and Concentration for Telithromycin Doses from 800 to 3200 mg (Phase I Data)

**Notes:**
Phase I analytical report (Jun Shi)

## Drug Interactions of Special Interest

- Ketoconazole (potent CYP3A4 inhibitor)
- Cisapride (exclusively metabolized by CYP3A4)
- Sotalol (class III antiarrhythmic drug)

## Effect of Telithromycin and Ketoconazole on QTn

- QTn
- Mean ± SD (ms)

- Telithromycin

- 3 ± 11

- Ketoconazole

- 10 ± 9

- Telithromycin + Ketoconazole

- 9 ± 8

- Placebo

- 3 ± 10

- N=16

**Notes:**
Source Data:  CSR hmr3647a/1045

## Drug Interaction Between Telithromycin and Cisapride

**Mean ********QTn ± SD (ms)**

**-20**

**-10**

**0**

**10**

**20**

**30**

**40**

**50**

**1**

**1.5**

**2**

**2.5**

**3**

**6**

**12**

- Telithromycin 800 mg once daily for 6 days + cisapride 20 mg single dose, N=14

- Telithromycin 800 mg once daily for 5 days, N=14

- Cisapride 20 mg single dose  N=14

- Placebo  N=14

**Time  (hours)**

**Notes:**
Source Data:  CSR hmr3647a/1041

## Effect of Telithromycin on Sotalol-Induced Prolongation of QTn

- 	Placebo	Telithromycin
- 	+ Sotalol 	+ Sotalol

- Sotalol Cmax (μg/mL) 	1.49 ± 0.26	1.0 ± 0.23
- QTn (ms)	469 ± 4	 451 ± 4
- QTn (ms) 	76 ± 5	58 ± 5
- Slope (ms/μg/mL)	45	48

- Mean ± SD, N=24

- Holter monitoring: No rhythm disorders

**Notes:**
Source Data:  CSR hmr3647a/1057

## Study in Subjects with CV Disease: Design/Population

- Single-dose, double-blind, randomized, placebo-controlled, 4-way crossover study
- Telithromycin 800 and 1600 mg, clarithromycin 500 mg x2, placebo
- 24 high-risk subjects with underlying cardiovascular disease
- ECG and 24-hour Holter recording before and after dosing

**Notes:**
Source Data:  CSR hmr3647a/1049

## Subjects with CV Disease: Mean Changes in QTn and QTc

- 	TEL	TEL	CLA 	800 mg	1600 mg	500 mg

- Cmax (μg/mL)	1.8 ± 0.9	3.1 ± 1.0	2.5 ± 1.2
- QTn  (ms)	-0.8 ± 10	1.0 ± 9.0	2.0 ± 9.0
- QTc  (ms)	3.0 ± 13	6.5 ± 13.5	3.2 ± 15

- Holter: No arrhythmias recorded

- Mean ± SD

- Data corrected for placebo

**Notes:**
Source Data:  CSR hmr3647a/1049

## Subjects with CV Disease: QTn vs Telithromycin Plasma Concentration

**Subjects with CV Disease: ********QTn *****vs***** Telithromycin Plasma Concentration**

**Concentration (μg/mL)**

******QTn (ms)**

**0**

**2**

**4**

**6**

**-100**

**-50**

**0**

**50**

**100**

**N = 24 subjects  (800mg + 1600 mg TEL)**
**Slope = 1.53 ms/μg/mL**

**Notes:**
Source Data:  CSR hmr3647a/1049

## QTc vs Telithromycin Plasma Concentration in RTI Patients with Cardiovascular Disease (Phase III)

******QTc  (ms)**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**11**

**12**

**-160**

**-120**

**-80**

**-40**

**0**

**40**

**80**

**120**

**N = 284 subjects**
**Slope = -0.42 ms/μg/mL**
**r****2 ****= 0.00069, p = 0.65**

**Concentration (μg/mL) **

**Notes:**
Phase III analytical report (Shashank Rohatagi)

## Summary of ECG Analysis  (1)

**Summary of ECG Analysis  (1)**

- Telithromycin has a weak effect on IKr channels
- In patients with respiratory infections, the mean change in QTc observed was small (~1 ms)
- Shallow relationship between QTc and plasma telithromycin concentrations over a wide range of concentrations
- No difference in the frequency of QTc outliers between telithromycin and macrolide and non-macrolide antibiotics

## Summary of ECG Analysis  (2)

**Summary of ECG Analysis  (2)**

- Analysis of at-risk subpopulations did not reveal a propensity for enhanced effect on cardiac repolarization
- No increase in the incidence of cardiovascular adverse events, including no torsades de pointes, no ventricular tachycardias, and no syncope associated with QT prolongation
- Limited risk due to brief duration of treatment and multiple pathways of elimination that limit exposure

## Telithromycin – Presentation Agenda

- Introduction	Mindell Seidlin, MD
- Microbiology	André Bryskier, MD
- Human Pharmacology	Vijay Bhargava, PhD
- Clinical Efficacy and Safety	Bruno Leroy, MD
- ECG Analysis	Claude Benedict, MD
**Conclusions ****	****Mindell Seidlin, MD****	****VP, Clinical Development, ****	****Anti-Infectives, Aventis**

## Medical Need for New Antibiotics

- Resistance in respiratory tract pathogens is increasing
*S. pneumoniae*: High level penicillin or macrolide resistance in >15% strains
- threat of multi-drug resistance
- beta-lactamase + strains of *M. catarrhalis* and *H. influenzae*
- increasing importance of atypical pathogens
- Respiratory infections are associated with significant morbidity and mortality
- more patients with underlying illness are being treated in the community

## Microbiological and PK Features

- Telithromycin, the first ketolide, has:
- two sites of interaction with 50S ribosomalsubunit; also interferes with assembly of both ribosomal subunits
- potent in vitro antipneumococcal activity
- activity against erythromycin-resistant strains
- activity against common, intracellular, and atypical respiratory pathogens
- Well-characterized pharmacokinetic profile, with therapeutic plasma and sustained tissue levels

## Summary of Efficacy in Respiratory Tract Infections

**Summary of Efficacy in ****Respiratory Tract Infections**

- Consistently effective in all analyses in 13 Phase III trials
- CAP:
- elderly: cure rate 90%
- pneumococcal bacteremia: cure rate 91%
- atypical infections (including *Legionella*: cure rate 100%)
- AECB, Acute Sinusitis, Tonsillitis/Pharyngitis:
- 5-day once-daily telithromycin treatment was equivalent to 10-day, 2-3 doses per day comparator treatment
- Efficacy in resistant *S. pneumoniae* infections in CAP and Acute Sinusitis

## Summary of Safety

**Summary of Safety**

- Safety studied in a broad spectrum of patients:
- incidence of GI events comparable to other widely used antibiotics
- hepatic events and transaminase elevation similar to comparators
- discontinuations and serious events equivalent to comparators
- small effect on QTc (~1 ms mean increase) in patients with RTIs

## The Advantages that Telithromycin Brings

**The Advantages that ****Telithromycin Brings**

- Highly effective in pneumococcal infections
- No cross-resistance in pneumococci to macrolides, beta-lactams, quinolones
- Effective against common, atypical, and intracellular RTI pathogens
- 5-day once-daily regimen for common infections
- Expands the options for outpatient management of RTIs