# Presentation: 696688

## Anti-Infective Advisory CommitteeMarch 24, 2000

***ZYVOX******TM***** (linezolid)**
**Pharmacia and Upjohn**

## Pharmacia & Upjohn is Seeking Approval of Linezolid for:

- Nosocomial pneumonia
- Community-acquired pneumonia
- Complicated skin and skin structure infections
- Uncomplicated skin and skin structure infections
- Vancomycin-resistant *Enterococcus faecalis* and *Enterococcus faecium* infections

## Linezolid - Presentation Agenda

- Introduction 	W. Gary Tarpley, PhDMicrobiology 	VP, Discovery Research
- Clinical Pharmacology 	Barry Hafkin, MDClinical Trial Results 	Director, Clinical Research
- Early Pediatric Studies	Donald Anderson, MD 	CSO, Research & Development
- Conclusion	W. Gary Tarpley, PhD

## Most Common Nosocomial Blood Culture Isolates (US Hospitals)

- 	 Rank	Pathogen  (N=12,243)	%
- 	1	Coagulase-negative staph	32
- 	2	*S. aureus*	16
- 	3	*Enterococcus* spp	11
- 	4	*Candida* spp	8
- 	5	*E. coli*	6

- Edmond et al., *Clin Infect Dis.*1999;29:234-244.

- SCOPE Project

## Increasing Incidence of Resistance in the USMRSE, MRSA, VRE, PRSP, GISA   1980-1999

- 100

- 80

- 60

- 40

- 20

- 0

- 1980

- 1975

- 1985

- 1990

- 1995

- 2000

- 1997

**GISA****3**

**VRE****1**

**PRSP****2**

**MRSA****1**

**MRSE****1**

- Percentage of
- Pathogens
- Resistant to
- Antibiotics

**Increasing Incidence of Resistance in the US****MRSE, MRSA, VRE, PRSP, GISA   1980-1999**

- 1NNIS data
- 2TRUST2 project
- 3MMWR, July 11, 1997

## Limitations of Current Antibiotics for Serious Gm+ Infections

- Tolerability
- Formulation / route of administration
- Drug resistance

## New Antibacterials are Required to Treat Gm+ Bacterial Infections

- Novel mechanism of action
- Broad coverage of Gm+ bacteria
- Well-tolerated
- Flexible dosing

## Linezolid: First Antibacterial from a New Structural Class

**Morpholino group enhances pharmacokinetic profile & improves water solubility**

**Strategically located fluorine atom improves activity**

**C - 5 acylaminomethyl ****group essential**

**5 - (S) - configuration necessary**

**N - Aryl group required**

## Linezolid Profile

- Synthetic
- Broad Gm+ antibacterial spectrum
- Coverage of drug-sensitive bacteria and bacteria resistant to _any_ other drug class
- Unique Site of Action
- No pre-existing cross resistance

## Linezolid :  Unique Site of Action

- Initiation Factors

- 30S ribosome

- mRNA

- 50S ribosome

- 30S + mRNA

**fMet - tRNA**

- Elongation Factors

- 70S Initiation Complex

- Peptide Product

- Elongation

**Aminoglycosides**
**Macrolides    Streptogramins**

***Linezolid blocks formation of the initiation complex***

## Linezolid Profile (cont.) 

- 100% oral bioavailability
- Multiple dosage forms
- Solution for IV
- Tablets and suspension for oral
- IV/oral equivalent dosing
- Equal drug exposures after equal doses independent of formulation/route of administration

##  Efficacy - Phase III Studies in Adults

**55*** 	Complicated** **	**33*** 	Inpatient CAP 	**31** 	MRSA
**39A***	Uncomplicated**	****51***	Outpatient CAP	**54A***	VRE
**	****	****48A*****	**HAP

- * Pivotal trials

- 		Resistant
-          SST 	   Pneumonia 	Pathogens

## In Vitro Susceptibility Database

- 		 	  No. Isolates
- 	Streptococci	Staphylococci	Enterococci
- Preclinical Studies		2,985		4,589		2,169
- Sentry Study		630		6,276		1,417
-   (1998; >30 medical centers)
- Phase III Isolates		600		1,738		303
-            TOTAL		4,215		12,603		3,889

**In Vitro Susceptibility Database**

## Streptococci:  Preclinical Summary

- 	                                     	No.
- Species	Category2	Isolates	MIC50	MIC90
*S. pneumoniae*	 PSSP	303	0.6	1.0
- 	PISP	242	0.6	1.0
- 	 PRSP	266	0.6	0.9
*S. pyogenes*		181	1.1	2.2
*S. agalactiae*		164	1.9	2.0

- Average1

- 1 	Weighted average calculated for pooled studies.
- 2	NCCLS criteria

## S. pneumoniae Sentry and Phase III Data 

**Sentry  (N = 318)**

**Phase III  (N = 346)**

**Total N = 664**

***S. pneumoniae***** Sentry and Phase III Data **

- Linezolid MIC (μg/mL)

- % of Isolates

- 0

- 20

- 40

- 60

- 80

- 100

**<0.06**

**.12**

**.25**

**.50**

**1**

**2**

**4**

**8**

**16**

**32**

**>32**

## Staphylococci:  Preclinical Summary

- 		No.
- Species	Category2	Isolates	MIC50	MIC90
*S. aureus*	MSSA	916	1.8	2.5
- 	MRSA	973	1.7	3.2
- 	GISA	    8	2.0	2.0
*S. epidermidis*	MSSE	183	1.3	2.4
- 	MRSE	216	1.2	2.1
- 	GISE	    4	2.0	2.0

- Average1

- 1 	Weighted average calculated for pooled studies.
- 2	NCCLS criteria

## S. aureus Sentry and Phase III Data 

- 0

- 20

- 40

- 60

- 80

- 100

**<0.06**

**0.125**

**0.25**

**0.5**

**1**

**2**

**4**

**8**

**16**

**32**

**>32**

- Linezolid MIC (μg/mL)

- % of Isolates

- Sentry  (N = 4,498)

- Phase III  (N = 1,370)

- Total  N = 5,868

***S. aureus***** Sentry and Phase III Data **

## Enterococci:  Preclinical Summary

- 		                               	No.
- 	Species	Category2	Isolates	MIC50	MIC90
- 	*E. faecalis*	VSE	476	1.2	2.0
- 		VRE	148	1.7	3.1
- 	*E. faecium*	VSE	68	1.9	2.0
- 		VRE	252	1.3	2.4

- Average1

- 1 	Weighted average calculated for pooled studies.
- 2	NCCLS criteria

## Enterococcus spp  Sentry and Phase III Data 

- 0

- 20

- 40

- 60

- 80

- 100

**<0.06**

**0.125**

**0.25**

**0.5**

**1**

**2**

**4**

**8**

**16**

**32**

**>32**

- Linezolid MIC (μg/mL)

- % of Isolates

- Sentry  (N = 1,417)

- Phase III  (N = 303)

- Total  N = 1,720

***Enterococcus***** spp  ****Sentry and Phase III Data **

## Laboratory Prediction of Resistance Mechanism

- Low spontaneous mutation frequency
- 1 x 10-9
- Inability to derive resistant mutants by
- Chemical mutagenesis
- Serial passage through 2-fold drug concentrations
- Spiral-gradient, serial passage yielded two resistant strains
*S. aureus*
*E. faecalis*

## Characterization of Lab-derived Mutants

- Mutations identified in 23S rRNA gene
*S. aureus*, G2447U
*E. faecalis*, G2576U
- Gene exists in 5-6 copies in Gm+ bacteria
- MIC correlated with ratio of wild-type:mutant genes
- Significant increase in MIC required mutation in at least 2 of 6 gene copies

## Linezolid Efficaciousin Key Animal Models 

- Mouse systemic infection
- Oral, IV, SQ
- Mouse soft tissue infection
- Localized Group A streptococcal myonecrosis
- Pneumococcal pneumonia (neutropenic animals)
- Mouse thigh infection model

## Summary

- Broad Gm+ coverage
- Lack of inherent cross-resistance with marketed agents
- Therapy will be initiated principally in the hospital or institutional care setting
- Multiple dosage forms, equivalent IV/oral dosing provides treatment flexibility

## Linezolid - Presentation Agenda

- Introduction 	W. Gary Tarpley, PhDMicrobiology 	VP, Discovery Research
- Clinical Pharmacology 	Barry Hafkin, MDClinical Trial Results 	Director, Clinical Research
- Early Pediatric Studies	Donald Anderson, MD 	CSO, Research & Development
- Conclusion	W. Gary Tarpley, PhD

**Notes:**
1)	My goal today is to provide an overview of  Linezolid’s 	clinical pharmacology and pharmacokinetics 
2)	In addition I will review the data we have collected - in 	our phase 3 trials - to document the efficacy and safety 	of Linezolid in patients with Pneumonia and Skin and 	Skin Structures.

## Steady-State Plasma Concentrations Linezolid PO 600 mg BID (Mean  SD, N=16) 

**Steady-State Plasma Concentrations ****Linezolid PO 600 mg BID (Mean ******** SD, N=16) **

- Time After Dose, hours

- Plasma Conc,  μg/mL

**Staphylococcus**

**Enterococcus**

**Streptococcus**

- 0

- 2

- 4

- 6

- 8

- 10

- 12

- 0

- 4

- 8

- 16

- 20

- 24

- 28

- 12

- MIC90

**Notes:**
Our preclinical and early phase 1 studies suggested Linezolid would have an excellent pk profile. 
Easy to use twice daily either by the oral or IV route of administration.
The results of  a phase 1 trial investigating the plasma concentrations  over a 12 hr dosing interval are shown here.  
Peak concentration  after a  600 mg oral dose  is typically  16 to 20 g/ ml  with in an hour, at the end of the dosing interval the trough concentration is typically 4g/ml.

The three doted lines represent the MIC 90’s for Staph A,
Enterococci and Strep Pneumonia

## Linezolid Absolute Bioavailability After a Single IV or Oral 375 mg Dose (Mean  SD, N = 12)

**Linezolid Absolute Bioavailability After a Single IV or Oral 375 mg Dose**** ****(Mean ******** SD, N = 12)**

**IV (AUC - 50 μg h/mL)**

**Oral (AUC - 52 μg h/mL)**

**Time After Dose, Hours**

**Plasma Conc, μg/mL**

**16**

**12**

**8**

**4**

**0**

**0**

**2**

**4**

**6**

**8**

**12**

**10**

**Notes:**
This a concentration over time plot for patients receiving 375 mg  of LZD either by both the oral & IV route .  Although the peak of LZD experienced by the IV treated patients is higher at peak than that seen for the oral treatment , the AUC and Cmin at the end of dosing interval are very comparable.

## Clinical Pharmacology

- Oral bioavailibility	100% (based on AUC)
- Food effect	No effect on AUC	  Cmax (18%)
- Volume of distribution	50 liters
- Plasma protein binding	31%
- Elimination half-life 	~ 6 hours
- MAO enzyme	Weak, reversible inhibitor

**Notes:**
In addition to equivalent bioavailibility for oral and IV dosing. Food has minimal effect on the oral absorption of LZD with  the Cmax  dropping less than 20 % and no effect on the AUC. 
The Vd is equal to water
Plasma protein binding is low at 31%
Preclinical evaluation of the compound documented that LZD had the property of being a mild and reversible MAO inhibitor
The drug was non enzymatically oxidized but was not a substrate of or an inducer of human P450 systems

## Linezolid Metabolism

- Linezolid is not a substrate, inhibitor or inducer of P450
- Two primary metabolites
- Oxidation products of linezolid

**Notes:**
The half life of LZD is approximately 6 hrs,
35 % of the drug is eliminated as parent drug in the urine, the rest is eliminated as one of two primary metabolic products. Most via the urine but some via stool. There is no detectable drug in the stool.

These metabolites have no significant antibacterial activity and very little MAOI activity

## Linezolid Elimination

- Elimination
- 	~ 35% as parent compound in urine
- 	~ 50% as two primary metabolites in urine
- 	~ 10% as two primary metabolites in feces
- Primary metabolites accumulate in patientswith CLCR30 mL/min
- Linezolid and metabolites are dialyzable

**Notes:**
The half life of LZD is approximately 6 hrs,
35 % of the drug is eliminated as parent drug in the urine, the rest is eliminated as one of two primary metabolic products. Most via the urine but some via stool. There is no detectable drug in the stool.

These metabolites have no significant antibacterial activity and very little MAOI activity

## Clinical Pharmacology Summary

- No dosage adjustment for
- Route of administration
- Relationship to meals
- Gender or age
- Hepatic or renal impairment

**Notes:**
Absolute bioavailability - 100%
No significant effect of food, gender, age, hepatic or renal function  on drug exposure by AUC or by Concentration of the parent drug 
However in patients with very reduced Creatinine Cr ( a clearance < 30ml/min.... )
 the primary metabolites are not cleared as effectively and my accumulate.

## Linezolid Efficacy Data

##  Efficacy - Phase III Studies in Adults

**55*** 	Complicated** **	**33*** 	Inpatient CAP 	**31** 	MRSA
**39A***	Uncomplicated**	****51***	Outpatient CAP	**54A***	VRE
**	****	****48A*****	**HAP

- * Pivotal trials

- 		Resistant
-          SST 	   Pneumonia 	Pathogens

**Notes:**
 I’ve used this slide to aggregate study numbers and study titles by indication. 
 As you can see, we conducted studies in pneumonia, and SST infections.
 In addition, we conducted 2 pathogen driven studies, which permitted patients with  almost any site of infection due to either VRE or MRSA to be recruited and treated with LZD 600mg or a comparator agent
 I’ll begin with study 55, the largest single study we conducted, which enrolled hospitalized patients with complicated SST infection

## Complicated SST (55) 

- Randomized, double-blind, equivalence trial
- Dosing regimens:
- Linezolid 	600 mg BID IV ****** **PO
- Oxacillin 	2 g QID IV Dicloxacillin 	500 mg QID PO
- Concomitant aztreonam
- Treatment duration:	10-21 days
- Test of cure:	15-21 days PT
- Population:	819 inpatients

**Notes:**
 Study 55 was a randomized / db blind / equivalence trial 
 Patients in hospital with complicated skin and soft tissue infections were randomized to receive either LZD or oxacillin IV .... 
 Concomitant gram(-) coverage as needed with either aztreonam
 Typical diagnosis on admission  extensive cellulitis, traumatic wounds, abcesses & post-op infections  
 Necrotizing fasciitis & decubiti were excluded
 Treatment duration averaged 13 days -range 10 to 21 days
 TOC was 10 to 21 days post treatment
 A total of 819 patients were recruited

## Clinical Cure Complicated SST (55) 

_**259**_**300**

_**264**_
**291**

- 	**95% CI:**	**(2.4, 14.1) ****	****(–0.7,  9.5)****	**** (–3.5, 11.3)**
**	****Missing/Indet:****	****72  /  65****	****7  /  2****	****3  /  0**

_**279**_**328**

_**272**_**354**

_**126**_**140**

_**130**_**151**

**Notes:**
 Clinical cure rates for 3 study populations are shown here
 The ITT bars - patient outcomes-  receiving at least one dose of study medication 
The clinically evaluable (or CE) bars include all patients who met inclusion/exclusion criteria and who were cured after 5 or more days of therapy or who failed after at least 2 days of therapy
 The micro evaluable population (ME) includes all CE patients with baseline pathogens isolated
 For each of the 3 populations, ITT, CE & ME, LZD was at least equivalent to the comparator drug somewhat better in 2 of the populations – consistent and reliable results
Under each bar we report the confidence interval for the comparison made and below that 
the number of patients that are missing or indeterminate for each population

## Pathogen Eradication Rates Complicated SST (55)

- 	           Linezolid	              OX/DX
- Pathogen	n/N	%	n/N	%
*Staphylococcus aureus**	*85/93	91	87/103	85
*Streptococcus agalactiae**	*7/7	100	4/6	67
*Streptococcus pyogenes**	*23/29	79	27/32	84
- Other* Streptococcus *spp**	*10/11	91	5/5	100

- * Includes *S anginosus, S bovis, S canis, S mitis, *and* S intermedius*

**Notes:**
The comparable pathogen out comes for LZD and Oxacillin are shown here for Staph A, group A, group B and other strep sps.

## Uncomplicated SST (39A)

- Randomized, double-blind equivalence trial
- Dosing regimens:
- Linezolid	400 mg BID, PO
- Clarithromycin	250 mg BID, PO
- Treatment duration:	7-14 days
- Test of cure:	7-14 days PT
- Population:	753 outpatients

**Notes:**
 This study was a randomized / db blind / equivalence trial in outpatients treated orally 
 Patients were randomized to receive either LZD 400mg bid or clarithromycin 250mg bid
 These patients typically had cellulitis, burns, wounds, bites, or erysipelas
 Treatment duration averaged 12 days 
This study enrolled 753 patients in North America

## Clinical Cure Uncomplicated SST (39A)

_**262**_**301**

_**283**_**310**

- 	**95% CI:****	**** ****(–4.0, 7.2)****	****(–0.7, 9.2)****	****(–6.2, 9.3)**
**	****Missing/Indet:****	****39  /  48****	****4  /  8****	****1  /  5**

_**290**_**343**

_**268**_**323**

_**126**_**143**

_**122**_**141**

**Notes:**
 Clinical cure for each of the 3 study populations was statistically equivalent, 
 in the ITT population,
 in the CE population, and
 in the ME population

## Pathogen Eradication Rates Uncomplicated SST (39A)

- 	          Linezolid	         Clarithromycin
- Pathogen	n/N	%	n/N	%
*Staphylococcus aureus**	*82/91	90	91/108	84
*Streptococcus agalactiae**	*10/10	100	4/5	80
*Streptococcus pyogenes**	*5/5	100	11/12	92
- Other* Streptococcus *spp**	*9/10	90	2/3	67

- * Includes *S anginosus*, *S canis*, and *S intermedius, S mitis, and S sanguis*

**Notes:**
The comparable out comes for Staph A, group A, and group B streptococcus are shown here...

## Conclusions: SST

- Effective in
- Complicated SST
- Uncomplicated SSTdue to
*Staphylococcus aureus*
*Streptococcus pyogenes*
*Streptococcus agalactiae*

**Notes:**
 In conclusion, these  studies show  LZD is as effective as standard comparators in the treatment of uncomplicated or complicated SST infections due to:
 Staph aureus
 Strep pyogenes
 Strep agalactiae

##  Efficacy - Phase III Studies in Adults

**55*** 	Complicated** **	**33*** 	Inpatient CAP 	**31** 	MRSA
**39A***	Uncomplicated**	****51***	Outpatient CAP	**54A***	VRE
**	****	****48A*****	**HAP

- * Pivotal trials

- 		Resistant
-          SST 	   Pneumonia 	Pathogens

**Notes:**
The first pneumonia study I will review is protocol 33 , a study of CAP in patients requiring hospitalization.
I’ll then describe  our study of out patient CAP and finally our Nosocomial pneumonia study

## Patients Hospitalized with CAP (33)

- Randomized, open-label equivalence trial
- Dosing regimens:
- Linezolid	600 mg BID, IV **** POConcomitant aztreonam
- Ceftriaxone	1 gm BID, IVCefpodoxime	200 mg BID, PO
- Treatment duration:	7-14 days
- Test of cure:	15-21 days PT
- Population:	747 inpatients

**Notes:**
 Protocol 33 was a randomized, open-label equivalence trial
 Patients with CAP who required hospitalization for their treatment were randomized to receive either LZD or ceftriaxone IV
 LZD was given IV initially, followed by an optional switch to PO; concomitant AZT was allowed PRN
Treatment duration was typically  11 days
TOC was 15 to 21 days post-treatment
 A total of 747 patients were recruited

## Clinical Cure Patients Hospitalized with CAP (33)

_**225**_**254**

_**247**_**272**

_**81**_**93**

_**80**_**89**

- 	**95% CI:****	**** ****(0.3, 12.8)****	****(–3.0, 7.4)****	****(–6.5, 12.0)**
**	****Missing/Indet:****	****58  /  52****	****4  /  4****	****1  /  2**

_**268**_**323**

_**240**_**314**

**Notes:**
 Clinical Cure rates for patients with CAP in the hospital are  are shown here
Again, statistical equivalence was demonstrated for all three of the populations (ITT,CE,ME) considered in our trial.

## Pathogen Eradication Rates Hospitalized CAP (33)

- 	          Linezolid	        CTX/CPD
- Pathogen	n/N	%	n/N	%
*Streptococcus pneumoniae**	*63/71	89	62/69	90
*Staphylococcus aureus**	*18/20	90	13/17	77

**Notes:**
Microbiologic outcomes are excellent with both drugs for both Strep pneumonia & Staph A 

## Outpatients with CAP (51)

- Randomized, investigator-blind equivalence trial
- Dosing regimens
- Linezolid	600 mg BID, PO
- Cefpodoxime	200 mg BID, PO
- Treatment duration:	10-14 days
- Test of cure:	15-21 days PT
- Population:	540 outpatients

**Notes:**
 Protocol 51 was a randomized, INVESTIGATOR blind, equivalence trial
 Outpatients with CAP were randomized to receive either oral LZD or oral cefpodoxime
 Treatment duration was typically  11 days long
TOC was 15 to 21 days post-treatment
 A total of 540 patients were recruited

## Clinical Cure Outpatients with CAP (51) 

_**185**_**204**

_**182**_**203**

_**38**_**46**

_**45**_**50**

- 	**95% CI:****	**** ****(–10.3, 3.2)****	****(–6.8, 4.8)****	****(–6.4, 21.1)**
**	****Missing/Indet:****	****45  /  43****	****4  /  6****	****1  /  0**

_**188**_**229**

_**191**_**223**

**Notes:**
 For patients with outpatient CAP, clinical Cure rates for LZD  are  comparable for each  of the populations shown :  ITT, CE, ME
 Statistical equivalence was documented in the CE and the ME population

## Pathogen Eradication Rates Outpatient CAP (51)

- 	          Linezolid	        Cefpodoxime
- Pathogen	n/N	%	n/N	%
*Streptococcus pneumoniae**	*25/27	93	19/21	91
*Staphylococcus aureus**	*11/12	92	11/12	92
*Haemophilus influenzae**	*10/12	83	13/15	87
*Moraxella catarrhalis**	*3/3	100	1/1	100
*Streptococcus pyogenes**	*1/1	100	1/1	100

**Notes:**
Pathogen specific microbiological outcomes for Strep Pneumonia, Staph A, & Hflu were very similar....

## Nosocomial Pneumonia (48A)

- Randomized, double-blind equivalence trial
- Dosing regimens:
- Linezolid	600 mg BID, IV
- Vancomycin	1 gm BID, IV
- Concomitant aztreonam
- Treatment duration:	7-21 days
- Test of cure:	15-21 days PT
- Population:	396 inpatients		including 229 with ventilator- 		associated pneumonia

**Notes:**
 Protocol 48A was a randomized / db blind / equivalence trial
 Patients in the hospital with nosocomial pneumonia were randomized to receive either IV LZD or IV vancomycin, with concomitant gram(-) coverage as needed
 Treatment duration was typically  9 to 10 days
 TOC was 15 to 21 days post-treatment
 396 inpatients were recruited, of whom, more than  half (58%) had ventilator-associated pneumonia 

## Clinical CureNosocomial Pneumonia (48A)

_** **__**26 **_
**38**

_** **__**37 **_
**53**

_** **__**62 **_
**91**

_** **__**71 **_
**107**

-  	**95% CI:****	**** ****(–10.0, 12.6)****	****(–14.9, 11.3)****	****(–17.9, 20.7)**
**	****Missing/Indet:****	****42  /  51****	****1  /  5****	****1  /  2**

_** **__**86     **_**161**

_** **__**74 **_**142**

**Notes:**
 Clinical cure rates for all three study populations are shown here
 In each comparison, for each population, results are quite similar and quite comparable for LZD and vancomycin

## Pathogen Eradication Rates Nosocomial Pneumonia (48A)

- 	          Linezolid	        Vancomycin
- Pathogen	n/N	%	n/N	%
*Streptococcus pneumoniae**	*9/9	100	9/9	100
*Staphylococcus aureus**	*25/41	61	15/23	65

**Notes:**
Pathogen specific micro out comes for Strep pneumonia and Staph are quite comparable.

## Conclusions: Pneumonia

- Effective in
- Community-acquired pneumonia
- Nosocomial pneumoniadue to
*Streptococcus pneumoniae *
*Staphylococcus aureus*

**Notes:**
We have demonstrated good efficacy in patients with CAP  and or HAP due to staph a or strep pneumo

##  Efficacy - Phase III Studies in Adults

**55*** 	Complicated** **	**33*** 	Inpatient CAP 	**31** 	MRSA
**39A***	Uncomplicated**	****51***	Outpatient CAP	**54A***	VRE
**	****	****48A*****	**HAP

- * Pivotal trials

- 		Resistant
-          SST 	   Pneumonia 	Pathogens

**Notes:**
Next I describe the results of our two pathogen driven studies, one designed to recruit patients with MRSA or the occasional invasive Coag Neg Staph infection. The other designed to recruit patients with VRE infections

## Methicillin-Resistant Staphylococcus (31)

- Randomized, open-label equivalence trial
- Dosing regimens:
- Linezolid	600 mg BID, IV **** PO
- Vancomycin	1 gm BID, IV
- Concomitant aztreonam
- Treatment duration:	7-28 days
- Population:	460 patients

**Notes:**
460 patient’s presumed to be infected with a methicillin resistant  staph were recruited into this study....
Patients were randomized to receive either LZD or Vanco
Gram negative coverage was permitted
Blinding of the study wasn’t possible since the patient could be started on oral LZD when the physician though appropriate. 

## Primary Source of Infection (31)

- Source	Patients
- SST Infection	230
- Pneumonia	99
- Bacteremia 	 50
- UTI	27
- Other	54
- Total	460

**Notes:**
Half of the patients recruited had by our inclusion / inclusion criteria complicated SST,
and almost 100 patients had nosocomial pneumonia

## Clinical Cure - All Patients (31) 

_**  **__**87**_**117**

_**  **__**94**_**122**

_**109**_**192**

_**  **__**93**_**169**

_**46**_
**64**

_**45**_
**62**

** ****	****95% CI:****	**** ****(–8.5, 12.0)****	****(–8.2, 13.6)****	****(–16.3, 14.9)**
**	****Missing/Indet:****	****48  /  51****	****2  /  13****	****0  /  8**

**Notes:**
Taking the results of treatment for all sites of infection LZD treatment is comparable to Vanco for all populations.

## Clinical Cure - Complicated SST (31) 

_**51**_**66**

_**56**_**68**

_**64**_**99**

_**54**_**87**

_**30**_
**37**

_**26**_
**35**

** ****	****Missing/Indet:****	****23  /  21****	****2  /  8****	****0  /  4**

**Notes:**
On this slide I have only the results for complicated SST, for this population we have good comparability as well.... For the ITT,CE, and ME patients.

## Clinical Cure -Nosocomial Pneumonia (31) 

_**14**_**19**

_**17**_**22**

_**20**_
**39**

_**16**_
**32**

_** **__**9 **_
**12**

_**12**_
**16**

** ****	****Missing/Indet:****	****11  /  17****	****0  /  2****	****0  /  1**

**Notes:**
When we examine the results for the patients treated with HAP we see the same comparability as we do in the SST and the overall analysis.

## MRSA Pathogen Eradication (31)

- 	          	           Linezolid	        Vancomycin
- 		n/N	%	n/N	%
- ME patients withSST due to MRSA	22/34	65	18/31	58
- ME patients with *	*HAP due to MRSA*	*8/12	67	12/17	71
- Total with MRSA	34/56	61	36/57	63

**Notes:**
When we review the pathogen specific results for MRSA we see the same pattern of comparability for LZD and Vancomycin outcomes

## VRE Study Design Considerations

- No standard therapy, no acceptable comparators
- Dose-comparison study using 600 mg BID vs 200 mg BID (based on PK and animal models)
- Site of infection:  pneumonia, SST, UTI, intra-abdominal infections, bacteremia

**Notes:**
When we began to plan the VRE study there was no acceptable standard of therapy for VRE, no drug was available or indicated for the treatment of VRE infections
Since a study of LZD 600mg twice daily vs either high dose ampicillin or chloro was not acceptable to our investigators we offered another study design, the 600mg dose of LZD used in our phase 3 trials and a second  dose based on our human pk studies, and animal models
Our investigators urged us to utilize patients with various sites of  infection

## VRE (54A, 54)

- Randomized, double-blind, superiority trial
- Dosing regimens
- Linezolid	600 mg BID, IV **** PO
- Linezolid	200 mg BID, IV ****** **PO
- Concomitant aztreonam or aminoglycosides
- Treatment duration:	7-28 days
- Population:	54A:	145	 patients	54:		 82 of 186 patients

**Notes:**
	I have the results of one fully analysed study - study 54a with 145 patients and one incomplete study - with 82 patient outcomes to share.  The inclusion  criteria in the studies  and the treatments offered the patients were the same. 
 Patients with VRE infection were treated with either 600mg or 200 mgs twice daily. 
Gram neg coverage with AZTM or aminoglycoside was permitted.

## VRE - Primary Infection Source

- Bacteremia	20%
- Intra-abdominal infections	21%
- UTI 	37%
- SST 	18%
- Pneumonia	 4%

**Notes:**
The site of VRE infection for patients  in both of our studies followed this pattern
More observations with UTI and intrabd infections in transplant patients than expected...

## Clinical Cure VRE (54A)

_**28**_**38**

_**39**_**44**

_**22**_**29**

_**30**_**35**

_**42**_**63**

_**28**_**52**

- 	**P-values:****	****0.1609****	****0.0807****	****0.3148**
**	****Missing/Indet:****	****16  /  14****	****4  /  2****	****1  /  0**

**Notes:**
For the larger study of 145 patients the results obtained with 600 mg twice daily for each of the populations studied were better. The study is underpowered but the trend is consistent.

## Clinical Cure - Interim Results VRE (54)

- LZD 600 mg

- LZD 200 mg

_**16**_**22**

_**18**_**24**

_**15**_**18**

_**15**_**18**

_**18**_**29**

_**18**_**36**

** ****	****Missing/Indet:****	****5  /  12****	****1  /  3****	****1  /  1**

**Notes:**
For the second cohort of patients - we see a suggestion of the same pattern.  Results of 600mg twice daily are some what better

## Clinical Cure (CE) by DiagnosisVRE (54A)

- 	Linezolid	 Linezolid
- 	600 mg BID	200 mg BID

- Source of Infection	n/N†	% 	n/N†	%
- Intra-abdominal infections 	 8/8	100	 6/10	60
- Bacteremia	9/12	75	 3/3	100
- UTI	12/13	92	13/19	68
- SST	8/9	89	 6/6	100
- Pneumonia	2/2	100	NA

- † Excludes indeterminate and missing.

**Notes:**
When we consider the site of infection we have an even stronger sense of improved outcome with the 600mg dose for the first study of 145 pts.
Intrabd infections equal peritonitis, liver abcess, or intrab abcess.
Positive results were seen in both groups but were better with 600mg twice /day

## Clinical Cure (CE) by Diagnosis - Interim Results VRE (54)

- 	Linezolid	 Linezolid
- 	600 mg BID	200 mg BID

- Source of Infection	n/N†	% 	n/N†	%
- Intra-abdominal infections 	 4/5 	80	 4/5	80
- Bacteremia	5/5	100	 4/5	80
- UTI	8/11	73	6/7	86
- SST	1/2	50	2/5	40
- Pneumonia	0/1	0	NA

- † Excludes indeterminate and missing.

**Notes:**
The results of the second cohort to be treated with these doses of LZD are shown here - again a trend toward better out comes with the higher dose

## Microbiologic Outcome (ME) in VRE (54A)

- 	Linezolid	Linezolid
- 	600 mg BID	200 mg BID
- 	N=36	N=29

- Assessment	n	%†	n	%†
- Microbiological success*	30	86	17	59
- Microbiological failure	5	14	12	41
- * p=0.0146

- † Percentages exclude indeterminate and missing.

**Notes:**
When we consider the microbiologic outcome we have superiority of the 600mg dose over the 200mg dose.

## Compassionate Use (25)

- Open-label treatment in patients for whom no alternative was available
- Dosing regimen
- Linezolid	600 mg BID, IV **** PO
- Concomitant antibiotics were permitted
- Treatment duration:	up to 3 months
- Population:	230 patients (30Jun99)
- 		750 patients (01Mar00)

**Notes:**
Results for our Compassionate Use program are supportive of the results of the comparative trial for VRE.
The patient’s treated in this program had no other choice for therapy - they had failed other treatments and had nothing to lose....

## Clinical Cure (CE) Compassionate Use (25)

- 	Linezolid

- Site of Infection	n/N‡	%
- Intra-abdominal infections, peritonitis, other	24/26	92
- Bacteremia	19/21	90
- Complicated SST 	7/9	78
- Nosocomial pneumonia	1/1	100
- UTI	1/1	100

- ‡ 	Excludes indeterminate and missing.

**Notes:**
The sites of infection and the outcomes of those  clinically evaluable   patients are similar to the patients recruited into protocol 54

## Conclusions:  VRE

- Linezolid 600 mg BID is effective in the treatment of vancomycin-resistant *Enterococcus* (VRE)
- Clinical and microbiologic outcomes were better in patients randomized to 600 mg BID
- Compassionate use experience supports results in dose-comparative VRE study

**Notes:**
Linezolid is effective in the treatment of VRE infections, our clinical trails indicate that 600 mg twice daily is the best dose
The results seen in patients treated with LZD in our  compassionate use program are similar to the results seen in our dose comparative trials

## Efficacy Conclusions

- Linezolid was effective in the treatment of
- Complicated skin and skinstructure infections
- Uncomplicated skin and skinstructure infections
- Community-acquired pneumonia
- Nosocomial pneumonia
- MRSA and VRE infections

**Notes:**
LZD is effective therapy in patients with skin and soft tissue infection due to gram + organisms,
LZD is effective therapy in patients with pneumonia  due to gram + organisms as well 
LZD is effective in the treatment  of  infections due to both MRSA and VRE

## Resistance Surveillance

- No resistant *Staphylococcus* or *Streptococcus* isolates in more than 3,000 patients treated with linezolid in Phase II/III studies
- Resistance developed in 15 of 832 patients treated with linezolid for enterococcal infections in Phase III and compassionate use

**Notes:**
	Surveillance for the development of resistance to a new drug is quite easy within a phase 3 program.
	All organisms isolated at base line and at follow up  are referred to a central micro lab and intra - laboratory differences are avoided
Thousands of patients with Staph A and Strep sps were treated with LZD  - no resistant isolates were reported
We have treated 832 patients with VRE infection todate in all of our compassionate use and controlled trials, 15 patients had enterococcal isolates with a 4 fold  in MIC

## Resistance Development

- 			 ResistantProtocol	Patients	Enterococcal Isolates
- 54A	145	1
- 54	186	5
- 25	501	9
- Probable factors in development of resistance:
- Avascular nidus of infection
- Extended duration of treatment
- Randomized to 200 mg BID

**Notes:**
We saw most of our resistance develop  when an infected and indwelling device complicated treatment
We saw other patients fail with un-drained intra-abdominal  abcesses even with 3 to 4 weeks of therapy
When protocol 54 and 54a is considered most of the failures were present in patients randomized to the low dose arm of 200mgs twice daily

## Linezolid Safety Data

## Early Development Issues

- Mild, reversible inhibition of monoamine oxidase (MAO) enzyme
- Mild, transient increases in hepatic enzymes (3- to 5-fold increase in ALT, AST)
- Mild, transient hematopoietic suppression

**Notes:**
Dr Tarpley reviewed the extensive work of discovery in modifying the oxazlidinone platform in the development of LZD...
As a result of our screening we - identified the mild reversible MAOI activity of LZD early on...
We knew that at the highest doses and for the longest period of treatment LZD can produce  transient, &  mild LFT and hematopoetic effect 

## Drug Interactions with MAOIs

- Potent, irreversible MAOIs
- Interaction with serotonergic agents results in serotonin syndrome (cognitive dysfunction, fever, diaphoresis)
- Interaction with adrenergic agents resultsin significant hypertension
**In contrast**
**Linezolid is a weak, reversible MAOI**

**Notes:**
Drugs that have the potential strongly  inhibit MAO enzymes have few direct clinically significant effects,  BP
When given concomitantly with a serotonergic  agent such as dextromethorphan, SSRI - fever, confusion, diaphoresis is occasionally reported
When given concomitantly with an adrenergic agent hypertension may be seen
LZD is not a strong or irreversible MAOI

## Phase I MAOI Studies

- Dextromethorphan (serotonergic agent) - no change: body temp, cognitive function, sedation, BP, or pulse
- Tyramine coadministration with LZD required 100 mg to raise SBP by 30 mmHg - no food restrictions
- Blood pressure increases seen with phenylpropanolamine and pseudoephedrine (adrenergic agents) potentiated by LZD coadministration

**Notes:**
In this phase 1 trial we recruited healthy volunteers and treated them with both LZD and dextromethorphan.  We saw no change in BP, Pulse, temperature, or sign of CNS depression. 

## Linezolid - Phenylpropanolamine Systolic BP Effects 

- 	Mean Maximum Change 	Range 	from Baseline (mmHg)	(mmHg)
- Placebo	8  7	103-158
- Linezolid	11  7	107-135
- Phenylpropanolamine	14  11	106-139
- Linezolid + 	Phenylpropanolamine	 38  20	129-176

**Notes:**
In another phase 1 trial we treated volunteers with a common adrenergic agent - phenylpropanolamine and we showed that LZD alone doesn’t increase or decrease BP
and that LZD with PPA will produce a detectable  in BP
 Extent of BP  was moderate  and length of BP response was about 2 to 4 hrs

When volunteers were treated with LZD and oral crystal  tyramine it took at least 100 mg of tyramine to produce a predictable BP response.  Recall that blue cheese, red wine and beer will typically have 1 to 2 mg of tyramine....
When Nardil - the MAOI antidepressant was tested in a similar study it required only 15 mg of tyramine to produce a detectable  BP response....

## Phase II Analysis of PotentialMAOI-Related Drug Interactions

**A total of 247 of 867 patients (28%) took potentially interacting drugs**

**Drug Categories****	****	****       LZD pts with Concomitant Use**
- sympathomimetic bronchodilators		165
- selected analgesics			57
- vasopressors			9
- cyclic and misc antidepressants			27
- indirect-acting sympathomimetics		14
- SSRI antidepressants			17
- selected antitussive			12
- amphetamines and related stimulants		4
- serotonin receptor agonists			3

**Notes:**
The following classes of non-investigational medications were considered in the analysis:  sympathomimetic bronchodilators, selected analgesics, vasopressors, cyclic and miscellaneous  antidepressants, indirect-acting sympathomimetics, SSRI antidepressants, selected antitussive, amphetamines and related stimulants, and serotonin receptor agonists.

Nearly 3000 patients from Phase II and Phase III trials treated with linezolid were included in this pooled analysis.  These patients were classified into groups based on whether they received any of the defined medications from the selected classes known to potentiate MAOI agents.

Approximately 900 patients received both linezolid and a concomitant potentiator of MAOI effects.     
 247 patients in phase 2

Approximately 2000 patients received linezolid without any medications known to potentiate MAOI drugs.

## Phase II MAOI Experience

- No adverse events attributable tolinezolid MAOI effect
- Food restrictions were lifted for Phase III
- Restrictions regarding potentially MAO interacting drugs were modified

## Phase III Analysis of PotentialMAOI-Related Drug Interactions

**Drug Categories****	****	****       LZD pts with Concomitant Use**
- sympathomimetic bronchodilators		417
- selected analgesics			111
- vasopressors			68
- cyclic and misc antidepressants			66
- indirect-acting sympathomimetics		64
- SSRI antidepressants			52
- selected antitussive			32
- amphetamines and related stimulants		4
- serotonin receptor agonists			3

**A total of 632 of 2046 patients (31%) took potentially interacting drugs**

**Notes:**
The following classes of non-investigational medications were considered in the analysis:  sympathomimetic bronchodilators, selected analgesics, vasopressors, cyclic and miscellaneous  antidepressants, indirect-acting sympathomimetics, SSRI antidepressants, selected antitussive, amphetamines and related stimulants, and serotonin receptor agonists.

Nearly 3000 patients from Phase II and Phase III trials treated with linezolid were included in this pooled analysis.  These patients were classified into groups based on whether they received any of the defined medications from the selected classes known to potentiate MAOI agents.

Approximately 900 patients received both linezolid and a concomitant potentiator of MAOI effects.
632 patients received LZD and concomitant MAOI potentiators

Approximately 2000 patients received linezolid without any medications known to potentiate MAOI drugs.

## Phase III MAOI Experience

- 632 patients were treated with linezolid and potentially interacting drugs
- 13 patients had hypertension as an AE
- In only 1 patient was hypertension judged to be drug-related by the investigator

**Notes:**
In our phase 3 program we identified  each patient that experienced an adverse event called HBP - for those patients who received either LZD or the Comparator antibiotic and no potentially interacting drug  we found 22 patients with HBP as an AE , and 4 in the comparator group.
The baseline BP and range of BP’s in both groups are similar

## Blood Pressure Measurements in Phase III Patients with Concomitant MAOI Potentiators

**Blood Pressure Measurements in Phase III Patients with Concomitant MAOI Potentiators**

**Pre***

**Mean********SD **

** **

**Post ****†**

**Mean********SD **

**Range ****‡**

**(min – max)**

**Systolic BP (mmHg)**

**Linezolid**

- 129.9  29.2

- 130.1  22.8

- 80 – 184

**Comparator**

- 127.2 24.4

- 124.4  23.6

- 77 – 189

**Diastolic BP (mmHg)**

**Linezolid**

- 66.5 14.9

- 65.7  12.6

- 36 – 95

**Comparator**

- 66.9 13.7

- 34 – 98

- *

- n = 81 and 93 for linezolid and

- comparator respectively

- †

- n = 76 and 92 for linezolid and

- comparator respectively

- ‡

- Ranges of post-dose vital signs

**Notes:**
We also identified all the LZD and comparator agent treated patients that had HBP as an AE in the CRF.
The baseline and highest treatment value for the LZD and concomitant potentially interactive drug are similar.  The treating physicians did not associate the in BP with LZD in 12 of the cases, and continued LZD RX without problem
The single case of  BP associated by an investigator to LZD was a patient on Prozac - Prozac and LZD might be expected in the worse case to cause a serotonin syndrome not a tyramine response.

## MAOI Conclusions

- Preclinical and Phase I
- Weak, reversible MAOI effect
- Phase II and III
- 879 patients received linezolid and a potentially interacting medication
- 1 episode of attributed hypertension
- Benefit vs risk

##  Safety - Phase III Comparator-Controlled Studies

**55** 	Complicated** **	**33** 	Inpatient CAP 	**31** 	MRSA
**39A**	Uncomplicated**	****51**	Outpatient CAP
**39****	**Uncomplicated**	****48A****	**HAP
- Total Patients Treated with Linezolid	2,046
- Total Patients Treated with Comparators*	2,001
- *vancomycin, ceftriaxone, cefpodoxime, clarithromycin, oxacillin, dicloxacillin

- 		Resistant
-          SST 	   Pneumonia 	Pathogens

**Notes:**
For the remainder of the safety analysis I have used all of the phase 3 comparator controlled studies all together we have 2046 pts treated with LZD and 2001 pts treated with comparator agents

## All AEs  2% (1 of 2) Phase III Comparator-Controlled Studies

- 	All Linezolid	All Comparators
- 	N=2046	N=2001

- MET	n	%	n	%
- Diarrhea	 170 	 8.3	126	6.3
- Headache	134	6.5	110	5.5
- Nausea	127	6.2	92	4.6
- Vomiting	75	3.7	41	2.0
- Insomnia	52	2.5	35	1.7

## All AEs  2% (2 of 2) Phase III Comparator-Controlled Studies

- 	All Linezolid	All Comparators
- 	N=2046	N=2001

- MET	n	%	n	%
- Constipation	44	2.2	42	2.1
- Trauma	43	2.1	36	1.8
- UTI	43	2.1	27	1.3
- Rash	40	2.0	44	2.2
- Dizziness	41	2.0	38	1.9
- Fever	 33 	1.6	42	2.1

**Notes:**
Continuing the  AE’s seen in our trials the  rates  for both groups are very similar. 

## Drug-Related AEs  1% Phase III Comparator-Controlled Studies

- 	All Linezolid	All Comparators
- 	N=2046	N=2001

- MET	n	%	n	%
- Diarrhea	 89	 4.3	65	3.2
- Nausea	69	3.4	46	2.3
- Headache	44	2.2	27	1.3
- Taste alteration	24	1.2	14	0.7
- Vag. moniliasis	24	1.2	13	0.6
- Vomiting	23	1.1	8	0.4
- Abnormal LFTs	21	1.0	7	0.3

**Notes:**
I have the Drug related AE’s listed on this table - once again the AE’s are typical for Antibiotic trials and similar in frequency for both groups

I will review the frequency of abnormal LFT’s again in just a few moments with a more quantitative approach to the data

## Most Common Serious AEs Phase III Comparator-Controlled Studies

- 	All Linezolid	All Comparators
- 	N=2046	N=2001

- MET	n	%	n	%
- Pneumonia	26	1.3	24	1.2
- Sepsis	19	0.9	19	0.9
- Resp. failure	18	0.9	17	0.8
- CHF	11	0.5	8	0.4
- Multi-organ failure	10	0.5	8	0.4
- Dyspnea	10	0.5	7	0.3
- Septic shock	9	0.4	6	0.3

**Notes:**
The  most Common SAE’s in our trial are as you can see the progression of the patient’s underlying illness. The rates are comparable for both groups of patients.

## Laboratory Assessments

- Mean changes in laboratory assay values
- Substantially abnormal laboratory assay values were assessed by
- Regression analysis
- Hazard function analysis
- Extreme outlier analysis

**Notes:**
	We compared the changes in safety lab assay values in many ways 
the mean changes for the LZD and the comparator groups were both  within normal limits for both groups
we also looked at the patient safety labs with regression analysis and found no significant difference between the treatment groups
And finally we used an analysis of extreme outliers to demonstrate the effect of treatment on lab test results

## Percent of Patients with Chemistry Assays  2 Times Upper Limit of Normal

- 	All Linezolid	All Comparators

- Assay	n/N	%	n/N	%
- ALT (U/L)	145/1959	7.4	139/1919	7.2
- AST (U/L)	80/1959	4.1	102/1920	 5.3
- Creatine kinase (U/L)	103/2017	5.1	65/1976	3.3
- Lipase (U/L)	79/2018	3.9	74/1976	3.7
- Amylase (U/L)	36/2024	1.8	30/1983	1.5
- Total bilirubin (mg/dL)	14/2021	0.7	16/1981	0.8

- Studies 31, 33, 39A, 39, 48A, 51, 55

**Notes:**
Comparing the % of patients with abnl biochemical values X2  the ULN  in the LZD group and Comparator group we see no real difference 
This approach doesn’t allow us to be certain though - so in the next few slides I’d like to show you a bit more of the safety analysis we performed for almost all the analytes collected on patients in our trials

## Cumulative Percentage Over Time - Patients With at Least One Substantially High ALT Value 

**Cumulative Percentage Over Time - Patients ****With at Least One Substantially High ALT Value **

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**22**

**24**

**Time in Days**

**Percent Substantially High**

**Notes:**
This is a hazard analysis we used to determine the risk of having a substantially high ALT value with treatment.
The blue line is the LZD treated patient population
the red line is the comparator population
There is no difference in the risk of developing an abnormal ALT using this analysis either

## ALT Values for Linezolid-TreatedPatients with Substantially High Values

**Notes:**
On this graph I have plotted the ALT results for  all of the patients who had developed who had abnormal results documents over the period of treatment with LZD  and followup 

## ALT Values for Comparator-TreatedPatients with Substantially High Values

**Notes:**
This is the graph of the comparator experience.... Very similar to the LZD group

## Percent of Patients with Hematology Assays < 75% of Lower Limit of Normal*

- 	All Linezolid	All Comparators

- Studies 31, 33, 39A, 39, 48A, 51, 55
- *  50% of LLN for neutrophils

- 	Assay	n/N	%	n/N	%
- 	Hemoglobin (g/dL)	110/2020	5.4	95/1974	4.8
- 	RBC (x 106/mm3)	83/2019	4.1	73/1973	3.7
- 	Hematocrit (%)	78/2016	3.9	65/1973	3.3
- 	WBC (x 103/mm3)	33/2020	1.6	21/1974	1.1
- 	Neutrophils (x 103/mm3)	15/1954	0.8	17/1909	0.9
- 	Platelets (x 103/mm3)	48/2010	2.4	30/1966	1.5

**Notes:**
Similar to the analysis of biochemistry results for patients treated in our trials - similar freq of abnormal hematopoetic results for LDZ and comparators...
the one hazard and  outlier analysis I’d like show you  is our analysis of  platelet count - if we have the time I’ll be happy to review any of the others....

## Cumulative Percentage Over Time - Patients With at Least One Substantially Low Platelet Count

**Cumulative Percentage Over Time - Patients With ****at Least One Substantially Low Platelet Count**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**22**

**24**

**Time in Days**

**Percent Substantially Low**

**Notes:**
Using the hazard analysis - LZD treated patients are noted in light blue and comparator treated patients in red.  There is a 1% increased risk of developing a low platelet count if treated with LZD
the next slides will show the actual change in platelet count over time for individual patients

## Platelet Counts for Linezolid-TreatedPatients with Substantially Low Values

**Notes:**
On this slide we’ve graphed the change of platelet count over time for those pts that ended up with a 50% drop in count from base line.  Note that more than half of the pt’s in this group have low platelets at baseline, the rate of change is slow, and for those who’s counts drop - they normalize rapidly....
No one had problems with hemostasis

## Platelet Counts for Comparator-TreatedPatients with Substantially Low Values

**Notes:**
This is the comparator group... qualitatively similar to the LZD group ... 

## Platelet Conclusions

- Risk factors for decreased platelet counts
- Low baseline values
- >2 weeks of therapy
- Decreases are mild and reversible
- Not associated with clinical consequences

## Safety Conclusions

- Linezolid is well-tolerated in adults treated with 600 mg BID for up to 28 days
- Most common drug-related AEs were diarrhea (4%), nausea (3%), and headache (2%)
- No clear association between adverse events and use of concomitant medications
- Changes in platelet counts were mild and transient

**Notes:**
Through out our comparative trials both LZD and comparators were well tolerated - LZD was use d for up to 28 days and was well tolerated.
AE’s attributed to LZD were typical for anibiotic trials
AE’s weren’t attributed to the drugs MAOI effect
Safety Laboratory results suggest that no special safety issue exists in using LZD

## Linezolid - Presentation Agenda

- Introduction 	W. Gary Tarpley, PhDMicrobiology 	VP, Discovery Research
- Clinical Pharmacology 	Barry Hafkin, MDClinical Trial Results 	Director, Clinical Research
- Early Pediatric Studies	Donald Anderson, MD 	CSO, Research & Development
- Conclusion	W. Gary Tarpley, PhD

## Linezolid Pediatric Drug Development

- P&U commitment to early pediatric development
- Unmet medical need is equally urgent for children
- PRSP, MRSA, MRSE & VRE are major pathogens in children
- Few safe & effective therapeutic options exist
- Alternative therapeutic agents are needed for serious infections in healthy and high risk pediatric populations, including neonates

## Linezolid - Pediatric Use Development Program

- Pharmacokinetics (3 mos to 17 yrs)
- PK in neonates - planned
- Safety, Efficacy, PK/PD
- Focus on pneumococcal disease
- Community Acquired Pneumonia
- Acute Otitis Media
- Experience with VRE bacteremia
- Currently being planned

- Phase II

- Phase III

- Compassionate Use in Children

- Phase I

## Linezolid - Pediatric Use Clinical Pharmacokinetics

- Clearance adjusted by body weight is inversely proportional to age
- Higher clearance in very young patients; further PK analysis planned for patients < 5 years old
- Children  5 years old given 10 mg/kg oral BID had CL, Vd and t1⁄2 at steady state similar to adults

## Linezolid - Pediatric UsePhase II Study Design

- 		Hospitalized CAP	Acute Otitis Media
- 		Study 45, N=78	Study 49, N=65
- 	Age:	12 mos - 17 yrs*	12 mos - 6 yrs
- 	Route:	IV, oral	oral only
- 	Dose:	10 mg/kg BID	10 mg/kg BID
- 	Duration:	7 - 28 days	7 - 10 days
- 	Design:	        Open-label, uncontrolled
- 	Safety:	       AEs, lab assays, vital signs
- * 95% age 12 mos - 6 yrs

## Linezolid - Pediatric UseMost Common Drug-Related Adverse Events

- Diarrhea	13	9.1
- Vomiting	6	4.2
- Loose Stools*	5	3.5
- Rash	4	2.8
- Neutropenia	3	2.1

- * Not elsewhere specified

- 	Adverse Event		Linezolid
- 	MET 	 	ITT N=143
- 		n		%

## Linezolid - Pediatric UseAll Reported Serious Adverse Events

- Bronchiolitis	1	0.7
- Convulsions	1	0.7
- Neutropenia	1	0.7
- Pneumothorax	1	0.7
- Vomiting	1	0.7

- 			Linezolid
- 	 Adverse Event 	 	ITT N=143
- 	 MET 	n		%

## Linezolid - Pediatric UseConclusions

- Safety & efficacy findings in children are promising
- Additional safety and efficacy studies are being planned and implemented, including pivotal studies
- Preliminary pharmacokinetic data suggests a dosing regimen of 10 mg/kg BID for children  5 years old
- More definitive pharmacokinetic studies in neonates and other pediatric age groups are planned or in progress

## Linezolid - Presentation Agenda

- Introduction 	W. Gary Tarpley, PhDMicrobiology 	VP, Discovery Research
- Clinical Pharmacology 	Barry Hafkin, MDClinical Trial Results 	Director, Clinical Research
- Early Pediatric Studies	Donald Anderson, MD 	CSO, Research & Development
- Conclusion	W. Gary Tarpley, PhD

## Linezolid Conclusions

**Linezolid Conclusions**

- Addresses unmet medical need
- Broad Gm+ coverage
- Effective treating Gm+ infections withadded advantages:
- PK profile
- Convenience/flexibility
- Well-tolerated

## Pharmacia & Upjohn is Seeking Approval of Linezolid for:

- Nosocomial pneumonia
- Community-acquired pneumonia
- Complicated skin and skin structure infections
- Uncomplicated skin and skin structure infections
- Vancomycin-resistant *Enterococcus faecalis* and *Enterococcus faecium* infections