# Presentation: 191210

## FDA Advisory CommitteeJanuary 8, 2003

***KETEK******TM***** (telithromycin)**
**Aventis Pharmaceuticals**

## Introduction

**Steve Caffe, MD**

**Vice President, US Regulatory Affairs, Aventis**

## 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

## 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)

## Telithromycin – Presentation Agenda

- Introduction

- Steve Caffe, MD

- Human Pharmacology

- Vijay Bhargava, PhD

- Microbiology

- Stephen Jenkins, PhD

- Clinical Efficacy

- Bruno Leroy, MD

- Conclusions

- Paul Iannini, MD

- Clinical Safety

- Paul Lagarenne, MD

- Medical Need

- Paul Iannini, MD

## 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

## 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

## Medical Need

**Paul Iannini, MD**

**Danbury Hospital, Danbury, Connecticut**

## A clinician’s 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

- 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

**Medical Need for a New Anti-infective ****for Community-Acquired RTIs (1)**

## 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

## Telithromycin Addresses an Unmet Medical Need

**Telithromycin Addresses an ****Unmet Medical Need**

**Optimal RTI Spectrum of Activity**

**Telithromycin **

**Macrolides**

**Amoxicillin-clavulanate**

**Fluoroquinolones**

**Atypicals**

**ERSP PRSP**

**Non-respiratory tract gram negative coverage**

***S. pneumoniae******H. influenzae******M. catarrharis***

## 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

- 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

***S. pneumoniae***** Resistance in USA**

**a**** Source: CDC, 2000; PROTEKT Studies 2000-2001; TRUST 2001-2002**

## 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

- 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

**Implications of Increased Resistance**

## 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

- 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

**Clinical Relevance of Resistance: A Debate**

*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.*

## 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

- Increased bacterial resistance to current antibiotics commonly used in the therapy of RTIs may shorten useful life

**There is a Medical Need for a New ****Anti-infective in Community-Acquired RTIs**

## Microbiology

**Stephen Jenkins, PhD**

**Carolinas Medical Center**
**Charlotte, North Carolina **

## Overview of the Microbiology Features of Telithromycin

**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

## Telithromycin Mechanism of Action (1)

**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)

## Telithromycin Mechanism of Action (2)

**Telithromycin Mechanism of Action (2)**

**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**

**O**

**O**

**O**

**-cladinose**

**23S rRNA**

## Prevalence (%) of S. pneumoniae Antibiotic Resistance

**26.4**

**31.8**

**11.8**

**PRSP**

**ERSP**

**MDRSP**

**North Central**

**21.7**

**26.5**

**7.9**

**Northeast**

**PRSP**

**ERSP**

**MDRSP**

**36.5**

**40.2**

**12.8**

**Southeast**

**PRSP**

**ERSP**

**MDRSP**

**32.7**

**38.6**

**7.7**

**South Central**

**PRSP**

**ERSP**

**MDRSP**

**27.1**

**29.3**

**11.3**

**Southwest**

**PRSP**

**ERSP**

**MDRSP**

**17.3**

**23.2**

**7.1**

**Northwest**

**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)**

## S. pneumoniae Antibiotic Resistance Rates  (N=10,103)

***S. pneumoniae***** Antibiotic Resistance Rates **** (N=10,103)**

- Penicillin G	24.2
- Erythromycin A	31.7
- Azithromycin	31.5
- Clarithromycin	31.3
- Clindamycin	13.6
- Cotrimoxazole	31.1
- Tetracycline	22.1
- Levofloxacin	0.9

- % Resistance

** ****Source: PROTEKT Studies (data on file)**

## In vitro Activity of Telithromycin

**In vitro Activity of Telithromycin**

- Source: PROTEKT Studies (data on file)

- 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

- MIC (μg/mL)

## Telithromycin Activity Against Atypical and Intracellular Pathogens

*M. pneumoniae** *a	 0.008	 0.008	 0.008 – 0.06
- (N=47)
*C. pneumoniae* b	 0.0625	 0.25	0.031 – 2
- (N=19)
*L. pneumophila** *c,d	 0.008	 0.015	0.004 – 0.015
- (N=26)

**Telithromycin Activity Against ****Atypical and Intracellular Pathogens**

- MIC (μg/mL)

- 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

## 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

- 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

**In vitro Activity of Telithromycin Against****Antibiotic-Resistant *****S. pneumoniae***

- Source: PROTEKT Studies (Data on file) (N=16,672) a resistant to penicillin, the macrolides, TMP/SXT, and tetracycline

- MIC (μg/mL)

## Activities of Telithromycin and Macrolides Against Erythromycin-Resistant S. pneumoniae (N=3,131)

**Activities of Telithromycin and Macrolides ****Against Erythromycin-Resistant *****S. pneumoniae *****(N=3,131)**

**0**

**500**

**1000**

**1500**

**2000**

**2500**

**Number of Isolates**

******0.015**

**0.03**

**0.06**

**0.12**

**0.25**

**0.5**

**1**

**2**

**4**

**8**

******16**

**MIC (μg/mL)**

**Telithromycin**

**Erythromycin**

**Clarithromycin**

**Azithromycin**

**Source: PROTEKT Studies  (Data on file)**

## Bactericidal Activity of Telithromycin Against Macrolide-Resistant S. pneumoniae

**Bactericidal Activity of Telithromycin Against Macrolide-Resistant *****S. pneumoniae***

***S. pneumoniae***** Strain 5467 *****mef*****(A)**
**MIC = 0.125 ****μ****g/mL**

***S.***** *****pneumoniae***** Strain 5991 *****erm*****(B)**** **
**MIC ******** 0.015 ****μ****g/mL**

**Hours**

**0 μg/mL**

**0.06**

**0.125**

**0.25**

**0.5**

**1**

**2**

**4**

**8**

**16**

**2**

**4**

**6**

**8**

**10**

**0**

**2**

**4**

**6**

**8**

**12**

**LOG****10**** ****cfu/mL**

**0**

**2**

**4**

**6**

**8**

**12**

**2**

**4**

**6**

**8**

**10**

**LOG****10**** ****cfu/mL**

**Hours**

## Decreased Propensity of Telithromycin to Induce or Select for Antibiotic Resistance

**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

## Summary of Microbiology Features of Telithromycin

**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

## Clinical Efficacy

**Bruno Leroy, MD**

**Senior Director, Clinical Development Anti-infectives, Aventis**

## Dosing Regimen and Study Design

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

## 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*

**Notes:**
Source data:  Y0000006x  25May2002

## 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

**Notes:**
Source data:  	CSR 2105    
	CSR 3107

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

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

**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**

**4003  *****vs***** CLA**

**89%**

**89%**

**92%**

_**142**_**159**

_**143**_**161**

_**134**_**146**

**[–9.7; 4.7] ****a,b**

**[–10.2; 4.3] ****a,c**

- 	b TEL (5 d) *vs* CLA

- 	c TEL (7 d) *vs* CLA

**Notes:**
Source data:  Y08/0000013x  26Apr2002

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

*	**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)

- 	Telithromycin	Comparators a

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

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

- a 	Study 3001: amoxicillin;  Studies 3006 and 4003: clarithromycin;  Study 3009: trovafloxacin

**Notes:**
Source data:	Y08/0000045t  14Jun2002
		Y08/0000017x  06May2002

## CAP: Bacteriological Eradication and Clinical Cure for S. pneumoniae Pathogens in TEL Subjects

- 	0.004	4/4	(100)	 4/4	(100)
- 	0.008	123/125	(98)	121/125	(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)

**PPb population at TOC (All Western studies)**

- NA = not available; a Data for MIC values of 0.015 and 0.016 μg/mL have been pooled

- 	Bact. Eradication	Clinical Cure

- n/N (%) Subjects

- MIC (μg/mL)

**Notes:**
Source data: q08/b200395t.lst, 6 Oct 2000
	x08/b20054t.lst, 17 Nov 2000
update lcw 26feb01:  v08/b200054t.lst 08jan01
2nd Update:
Y08/b200054t.lst  27 Jun 02

## CAP: Bacteriological Eradication and Clinical Cure for H. influenzae Pathogens in TEL Subjects

- 	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)

- n/N (%) Subjects

**PPb population at TOC (All Western studies)**

- NA = not available

- MIC (μg/mL)

**Notes:**
Source data: q08/b200395t.lst, 6 Oct 2000
	x08/b20054t.lst, 17 Nov 2000
update lcw 26feb01:  v08/b200054t.lst 08jan01
2nd Update:
Y08/b200054t.lst  27 Jun 02

## CAP: Clinical Cure for Resistant S. pneumoniae Isolates

- n/N (%) Subjects

**PPb population at TOC (All Western + Japanese studies)**

- PRSP = penicillin G-resistant (MIC 2.0 μg/mL) ERSP = macrolide (erythromycin A)–resistant (MIC 1.0 μg/mL)

- 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)

**Notes:**
Source data:	Y08/0000045t  14Jun2002
		CSR 2105
		CSR 3107

## CAP: Clinical Cure for Pneumococcal Bacteremia

- Blood culture positive
- 	All *S. pneumoniae*	74/82	(90)
- 		PRSP	5/7	(71)
- 		ERSP	8/10	(80)
- ERSP with urinary Ag positive only a	4/4	(100)

**PPb population at TOC (All Western Studies)**

- a Sputum positive, blood culture negative, *S. pneumoniae* urinary antigen positive (Binax test)

- n/N (%)Subjects

**Notes:**
Source data:	Y08/0000045t
For pneumococcal bacteremia.
Binax data: source unknown  (data came verbally from Bruno)

## CAP: Clinical Cure by Risk Factors for Morbidity

- 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)

- Controlled studies

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

- All CAP
- studies

**PPc population at TOC (Western Studies)**

- 	Telithromycin	Comparators	Telithromycin

- a PPb population

**Notes:**
Source data: 	Y08/0000056t  25May2002 = age
	Y/f010808c  13Jun2002 = others
	TEL controlled: Y08/0000192x 01Nov02
	(extra table generated by Christophe)

## Summary of Efficacy in CAP

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

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

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

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

## AECB: Phase III 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

**AECB: Phase III Studies**

**Notes:**
Source data: Y06/0000011x  25May2002

## AECB: Clinical Cure at TOC, PPc

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

**86%**

**86%**

**83%**

**82%**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

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

**3013 *****vs***** CLA**

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

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

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

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

**	**** ****[–6.4; 14.3] ****a**

**	**a 95% confidence intervals

**[–9.9; 3.1] ****a**

**86%**

**89%**

_**193**_**225**

_**206**_**231**

**[–5.8; 12.4] ****a**

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

**Notes:**
Source data:	Y08/0000020x  01May2002

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

- a Study 3003: amoxicillin-clavulanic acid, Study 3007: cefuroxime axetil; 3013: clarithromycin

- 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)

- 	Telithromycin (5 d) 	Comparators (10 d) a

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

**Notes:**
Source data:	Y08/0000047t  14Jun2002
	Y08/0000024x  06May2002

## AECB: Clinical Cure by Risk Factors for Morbidity

- 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 <60%	117/149	(79)	 129/157	(82)

- 	Telithromycin	Comparators

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

**PPc population at TOC**

**Notes:**
Source data:	Y08/0000056t  25May2002
	Y07/0000062x  06May2002
	Y/f0208a  07May2002

## 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)

## 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

**Notes:**
Source data:	v06/0000001x  09Jan2001

## 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:	v08/0000027x  17Jan2001

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

*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 (5 d)	TEL (10 d)	Comp (10 d)a

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

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

**PPb population at TOC**

- TEL = telithromycin, Comp = comparators
- a Study 3005: amoxicillin – clavulanic acid;  Study 3011: cefuroxime axetil

**Notes:**
Source data:     v08/0000049t  04Jan2001

## Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates (All Studies)

- PRSP	8/10	3/3	11/13
- ERSP	12/14	6/7	18/21

- n/N Subjects (TEL)

**PPb population at TOC**

- 	5 d	10 d	5+10 d

- PRSP = penicillin G resistant (MIC 2.0 μg/mL) ERSP = macrolide (erythromycin A)–resistant (MIC 1.0 μg/mL)

**Notes:**
Source data:    v08/0000049t  04Jan2001

## Acute Sinusitis: Clinical Cure in Subgroups of Interest

- 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)

- Controlled studies

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

- All AS
- studies

**PPc population at TOC**

- 	TEL (5 d)	Comp (10 d)	TEL (5 d)

- a PPb population; b According to investigator assessment at entry

**Notes:**
Source data: 	Y08/0000056t  25May2002 = age
	Y/f010808c  13Jun2002 = others
	TEL controlled: Y08/0000192x 01Nov02
	(extra table generated by Christophe)

## 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*

## 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

## Human Pharmacology

**Vijay Bhargava, PhD**

**Senior Director, Drug Metabolism ****and Pharmacokinetics, Aventis**

## 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)

## Pharmacokinetics in Healthy Subjects

- Single dose

- Repeated dose (7d)

- C24h (μg/mL)

- 0.03

- (72)

- AUC0-24h (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

-  Telithromycin 800 mg (oral)

**Notes:**
Source data: CSR 1008

## Tissue and Fluid Penetration in Subjects with RTIs

- Tissue

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

- 2h

- 24h

- Alveolar macrophages

- 69

- 162

- N = 6
- TEL = telithromycin

- Epithelial lining fluid

- 12h

- 14.9

- 0.8

- 3.3

- 318

- (76)

- (62)

- (51)

- (60)

- (59)

- (73)

**Notes:**
Source data: CSR 1043  Group A  (R2000CLN0263)

## Multiple Pathways of Elimination

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

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

**Renal excretion**

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

**GI tract/biliary**

**Hepatic excretion**

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

**	*****Total metabolized drug  (~70%)****

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

**First pass effect**

**Multiple Pathways of Elimination**

***(13%)***

***(37%)***

***(7%)***

***(33%)***

***Non-P450 mediated***

***CYP3A4-mediated***

***(~35%)***

- *	Telithromycin is not metabolized by CYP2D6

***(~35%)***

## 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

## Effect of Hepatic Impairment 

- N=13

- Healthy
- N=13

- 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

**Effect of ****Hepatic Impairment **

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

**Renal excretion**

**Hepatic ****excretion**

***Metabolites***

- Telithromycin 800 mg qd; 7-day repeated dose

**Notes:**
Source data: CSR 1060

## Effect of Renal Impairment

- 	N=9	N=8	N=8	N=8
- 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)

**Effect of ****Renal Impairment**

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

**Renal excretion**

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

- Study also investigated TEL 400 and 600 mg qd

- Telithromycin 800 mg qd; 5-day repeated dose

- Mean (%CV)

**Notes:**
Source data: CSR 1062

## Effect of CYP3A4 Inhibition

- Telithromycin
- N=11

- Telithromycin + Ketoconazole
- N=11

- Cmax (μg/mL)	2.0	(38)	3.1	(36)
- AUC(0-24 h) (μg.h/mL)	14.4	(39)	28.6	(31)
- t1⁄2,****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

**Effect of CYP3A4 Inhibition**

**First ****pass effect**

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

**Hepatic excretion**

***Metabolites***

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

***CYP3A4-mediated***

***~35%***

***~35%***

**Notes:**
Source data: CSR 1045

## Effect of Multiple Impairments (Renal + Ketoconazole) 

**First ****pass effect**

***Systemic bioavailability***

**Hepatic excretion**

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

***CYP3A4-******mediated******metabolites***

***~35%***

**Renal excretion**

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

***non-CYP3A4-******mediated******metabolites***

***~35%***

## Effect of Multiple Impairments (Renal + Ketoconazole) 

- Creatinine clearance (mL/min)	30-80
- Mean age (years)	74
- 	N=10

- 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

**Effect of Multiple Impairments ****(Renal + Ketoconazole) **

- Cmax,ss  (μg/mL)	3.6 (22)
- AUC(0-24h) (μg.h/mL)	33.4 (31)
- CLR (L/h)	6.1 (30)

- 	TEL + Keto

- Mean (CV%) exposure to TEL or CLA

**TEL = telithromycin**
**CLA = clarithromycin**
**Keto = ketoconazole**

**First ****pass effect**

***Systemic bioavailability***

**Hepatic excretion**

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

***CYP3A4-******mediated***
***metabolites***

**Renal excretion**

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

***non-CYP3A4-******mediated***
***metabolites***

***~35%***

***~35%***

## Effect of Multiple Impairments (Renal + Ketoconazole) 

- Creatinine clearance (mL/min)	30-80	30-80
- Mean age (years)	74	69
- 	N=10	N=6

- 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

**Effect of Multiple Impairments ****(Renal + Ketoconazole) **

- 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)

- 	TEL + Keto	CLA + Keto

- Mean (CV%) exposure to TEL or CLA

**First ****pass effect**

***Systemic bioavailability***

**Hepatic excretion**

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

***CYP3A4-******mediated***
***metabolites***

**Renal excretion**

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

***non-CYP3A4-******mediated***
***metabolites***

**TEL = telithromycin**
**CLA = clarithromycin**
**Keto = ketoconazole**

***~35%***

***~35%***

## Telithromycin and Clarithromycin Exposure in Subjects with Multiple Impairment

**AUC****0-24h,ss**** (****μ****g.h/mL)**

**0**

**50**

**100**

**150**

**N=**

**6**

**CLA +****Keto**
**Study**
**1063**

**10**

**TEL +****Keto**
**Study**
**1063**

**0**

**3**

**6**

**9**

**C****max,ss**** (****μ****g/mL)**

**N=**

**6**

**CLA +****Keto**
**Study**
**1063**

**10**

**TEL +****Keto**
**Study**
**1063**

**Telithromycin and Clarithromycin Exposure ****in Subjects with Multiple Impairment**

**TEL = telithromycin**
**CLA = clarithromycin**
**Keto = ketoconazole**

**CLA impaired**

**TEL impaired**

## Telithromycin and Clarithromycin Exposure in Subjects with Multiple Impairment

**AUC****0-24h,ss**** (****μ****g.h/mL)**

**0**

**50**

**100**

**150**

**N=**

**12**

**6**

**CLA +****Keto**
**Study**
**1063**

**CLA**
**van ****Haarst**
**et al. ***

**18**

**10**

**TEL**
**Study**
**1008**

**TEL +****Keto**
**Study**
**1063**

**0**

**3**

**6**

**9**

**C****max,ss**** (****μ****g/mL)**

**N=**

**12**

**6**

**CLA +****Keto**
**Study**
**1063**

**CLA**
**van ****Haarst**
**et al. ***

**18**

**10**

**TEL**
**Study**
**1008**

**TEL +****Keto**
**Study**
**1063**

**Telithromycin and Clarithromycin Exposure ****in Subjects with Multiple Impairment**

**TEL = telithromycin**
**CLA = clarithromycin**
**Keto = ketoconazole**

**CLA healthy**

**CLA impaired**

**TEL healthy**

**TEL impaired**

**x1.6**

**x2.2**

**x2.7**

**x3.3**

*** van Haarst et al. *****Clin Pharmacol Ther*****, 1998.**

## Summary of Exposures: Ratios of Impaired to Healthy Subjects

**Summary of Exposures: Ratios of ****Impaired to Healthy Subjects**

- Telithromycin exposure ratios

- Hepatic impairment	**1.0**	(0.8–1.2)	**1.0**	(0.8–1.1)
- Renal impairment a
- 	CLCR 50-80 mL/min	**1.3**	(1.0–1.8)	**1.4**	(1.0–1.9)
- 	CLCR 30-49 mL/min	**1.0**	(0.8–1.4)	**1.2**	(0.9–1.7)
- 	CLCR  30 mL/min	**1.5**	(1.1–2.0)	**2.0**	(1.5–2.8)
- CYP3A4 inhibition
- 	Ketoconazole	**1.5**	(1.1–2.0)	**1.9**	(1.5–2.5)
- 	Itraconazole	**1.2**	(1.0–1.4)	**1.5**	(1.4–1.7)
- Renal impairment + keto b
- 	CLCR 30-80 mL/min	**1.6****	****	****2.7**
- 	CLCR 30 mL/min	**3.1****	****	****4.5**

- Subjects with	**C****max**	(90% CI)	**AUC**	(90% CI)

## Comparison of Effects on CYP3A4 Substrate: Simvastatin

- 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.

- 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

- Fold increase in Exposure

- 	Simvastatin	Simvastatin acid

- 	Cmax	AUC 	Cmax	AUC

## Reduction of Simvastatin Interactionwith Different Time of Administration

- TEL = telithromycin
- a 	After 40 mg single dose of simvastatin, before and after telithromycin 800 mg qd for 5 days.  Data from Study 1065

- 		**Concomitant ****	**** 12 hours apart**
- 		N=14	N=14
- Simvastatin	Cmax	7.7 (6.3–9.5)	3.4 (2.8–4.2)
- 	AUC	8.4 (5.9–11.9)	3.8 (2.8–5.1)
- Simvastatin	Cmax	10.0 (8.3–12.1)	3.2 (2.6–3.8)
- acid	AUC	9.4 (7.4–11.9)	4.3 (3.3–5.4)

- Fold increase in exposure a
- (90% confidence interval)

## Effect of Telithromycin on Other CYP3A4 Substrates

- a Midazolam data from Gorski et al. *Clin Pharmacol Ther*, 1998.
- b Cisapride data from van Haarst et al. *Clin Pharmacol Ther*, 1998.

- Telithromycin	2.6	6.1	2.0	2.4
- Clarithromycin a,b	3	7	2.7	3.2

- Fold increase in midazolam / cisapride exposure

- 	Midazolam	Cisapride

- 	Cmax	AUC 	Cmax	AUC

## 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

## Clinical Safety

**Paul Lagarenne, MD**

**VP, Clinical Safety Analysis, ****Aventis Global Pharmacovigilance**

## 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

## Phase III Clinical Studies

## Most Frequent Adverse Events in Controlled Phase III Studies

- 	Telithromycin	Comparators
-  	N=2702	N=2139

- Subjects (%) with AEs 	1348	(49.9)	1035	(48.4)
- 	Diarrhea	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)

## Adverse Events Leading to Discontinuation and Serious Adverse Events in Controlled Phase III Studies

- 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)

- 	TEL	Comparators	N=2702	N=2139

- N (%) Subjects

- a No treatment-related deaths

- TEL = telithromycin

## 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

## 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)

## 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

## QTc vs Telithromycin Plasma Concentration in Phase III Studies 

**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)

## 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

## Large Comparative Study in Usual Care Setting (Study 3014)

## 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

## 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

## 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

## 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

## Study 3014:  Follow-up Status

- 			TEL	AMC	Total
- Treated	12,161	11,979	24,140
- Safety 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)

- Number (%) of subjects

- TEL = telithromycin, AMC = amoxicillin-clavulanic acid

## Study 3014: Most Frequent Adverse Events (AEs), AEs Leading to Discontinuation, and Serious AEs

- 	TEL	AMC
-  	N=12,159	N=11,978

- Total with AEs 	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	192	(1.6)	59	(0.5)
- AEs leading to discontinuation	467	(3.8)	557	(4.7)
- Serious AEs	155	(1.3)	133	(1.1)

- TEL = telithromycin, AMC = amoxicillin-clavulanic acid

- Number (%) of subjects

## Study 3014: Adverse Events in Subgroups

- 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	(23)

- TEL 	AMC

- n/N (%) subjects with AEs

- TEL = telithromycin, AMC = amoxicillin-clavulanic acid

## 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)

## 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)

## 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

## 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)billirubin 1.5x ULN a
- ALT 3x ULN and total	0/10864		1/10600bilirubin 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

## 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

## Study 3014: Cardiac AESIs in At-Risk Populations

- 	TEL	AMC

- n/N (%) of Subjects

- 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

## 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

## 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

## Post-marketing Experience

## 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

## 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

- 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

**Visual 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

- 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

**Cardiac Findings in ****Post-Marketing Experience**

## 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

## 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

## 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

## 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

## 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

## 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)

## Summary and Conclusions

**Paul Iannini, MD**

**Danbury Hospital, Danbury, Connecticut**

## 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

- Increased bacterial resistance to current antibiotics commonly used in the therapy of RTIs may shorten useful life

**There is a Medical Need for a New ****Anti-infective in Community-Acquired RTIs**

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

- atypicals
- penicillin-resistant *S. pneumoniae*
- β-lactamase positive *H. influenzae*
- Macrolides:
- macrolide-resistant* S. pneumoniae*
- Fluoroquinolones:
- not targeted to RTI pathogens

**Limitations of Current Therapy  ****in Community-Acquired RTIs**

##  Efficacy of Telithromycin

** ****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

## 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

##  Telithromycin

** ****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