cardio-renal advisory committee meeting extraneal™ (7.5% icodextrin) peritoneal dialysis solution...

CARDIO-RENALAdvisory Committee Meeting

EXTRANEAL™ (7.5% Icodextrin)

Peritoneal Dialysis SolutionNDA 21-321

Orphan Drug Designation 97-1056

August 9, 2001

Baxter Healthcare Corporation

2

Baxter Participants Marsha Wolfson, M.D.

Vice President, Global Clinical Affairs Salim Mujais, M.D.

Vice President, Global Medical Affairs Frank Ogrinc, Ph.D.

Clinical Statistician Leo Martis, Ph.D.

Vice President, Solution Development James Moberly, Ph.D.

Director, Solutions R&D Richard Newman, Ph.D.

Vice President, Global Product Development Mary Kay Rybicki

Associate Director, Regulatory Affairs

3

Consultants John Burkart, M.D.

Professor of Internal Medicine/Nephrology, Bowman Gray School of Medicine

Allan Collins, M.D. Professor of Medicine,

University of Minnesota, Director Nephrology Analytical Services, Minneapolis Medical Research Foundation

Marc DeBroe, M.D., Ph.D. Dept. of Nephrology &

Hypertension, University Hospital of Antwerp

Ram Gokal, M.D. Consultant Nephrologist,

University of Manchester

Karl Nolph, M.D. Curator Professor Emeritus,

University of Missouri, Columbia William Frishman, M.D.

Chairman & Professor of Medicine, New York Medical College, Department of Medicine

Peter O’Brien, Ph.D. Professor of Biostatistics, Mayo

Medical School, Department of Health Sciences Research

Robert Stern, M.D. Carl J. Herzog Professor of

Dermatology, Beth Israel Deaconess Medical Center

Jeff Trotter, M.M. President, Ovation Research Group

4

Extraneal Development Milestones

First market approval UK 1992 by ML Labs

Licensed by Baxter 1996

Marketing approval in 31 countries ~8200 patients currently treated worldwide

30% of PD patients in Europe

US clinical trials began 1997

Orphan Drug designation granted 1997

NDA submitted December 2000

5

Proposed Indication

Extraneal is indicated for a single daily exchange for the long (8-16 hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of chronic renal failure.

6

Topics Identified in FDA Briefing Document & Questions

Dialysis Efficacy

Quality of Life

Size of Database

Safety Profile Mortality

Rash

Peritonitis

Membrane Transport Characteristics

7

AGENDACardio-Renal Advisory Committee

NDA 21-321 Extraneal (7.5% icodextrin)

Introduction and Rationale for ExtranealSalim Mujais, M.D., Vice President Global Medical Affairs,

Baxter  

Clinical Trial Experience with ExtranealMarsha Wolfson, M.D., Vice President Global Clinical Affairs,

BaxterFrank Ogrinc, Ph.D., Clinical Statistician, Baxter

 Conclusions Salim Mujais, M.D., Vice President Global Medical Affairs,

Baxter 

8

Icodextrin: A Polymer of Glucose

Main chain 1 4 linkage

O

CH2OH

O

CH2OH

O

CH2

O

CH2OH

O O O

O

CH2OH

O

O

CH2OH

O

9

Composition of Extraneal

DIANEAL EXTRANEAL

Dextrose (g/dL) 1.5, 2.5, 4.25 ---

Icodextrin (g/dL) --- 7.5

Sodium (mEq/L) 132.0 132.0

Chloride (mEq/L) 96.0 96.0

Calcium (mEq/L) 3.5 3.5

Magnesium (mEq/L) 0.5 0.5

Lactate (mEq/L) 40.0 40.0

Osmolality (mOsm/kg) 346-485 282-285

pH 5.2 5.2

10

Clinical Rationale for Extraneal

Unmet clinical need

Limitations of fluid management in PD

Limitations of current osmotic agents

Necessity of the long dwell

Kinetics of peritoneal ultrafiltration

Extraneal as a new osmotic agent

Kinetics matching clinical requirement

11

Unmet Clinical NeedLimitations of Current Fluid Management

in PD Symptomatic fluid retention occurs in 25% of

all PD patients1. In these patients:

Lower extremity edema 98.6%

Pleural effusions 76.1%

Pulmonary congestion 80.3%

Similar clinical observations have been reported from Japan2, the Netherlands3 and Sweden4

1Tzamaloukas et al. JASN 1995; 2Kawaguchi et al. Kidney Int 1997;3Ho-dac-Pannekeet et al. Perit Dial Int 1997; 4Heimbürger et al. Perit Dial Int 1999

12

Limitations of Fluid Management in PD Hampered by Inflexibility

Complexity of dietary counseling Hampered by compliance issues

May complicate management

Constrained renal excretion1

Gradual decline to anuria

Diuretic resistance

Peritoneal Ultrafiltration Challenge of the long dwell

1 Medcalf et al, Kidney International 59:1128, 2001

13

The long dwell: an integral component of PD

Dwell3

Dwell2

Dwell4

Dwell1

Long dwell

AP

D

nighttime period daytime period

Long dwellday

dwellday

dwellday

dwell

CA

PD

Extraneal Use

Extraneal Use

14

Rationale for the long dwell in PD: Intersection of two imperatives

Toxin removal imperative:

Small solutes removal fluid flow dependent

Middle and large molecular weight toxins are time dependent

Continuously wet abdomen required for therapy success

Realistic therapy imperative

Logistic burden and compliance

15

Limitations of Current Osmotic Agents Dextrose Kinetics in PD: Rapid Dissipation

Mujais et al, Peritoneal Dialysis Int. 2001

0%

20%

40%

60%

80%

100%

120%

0 1 2 3 4 5

Dwell time (hr)

% D

ex

tro

se

re

ma

inin

g

+ 2SD

Mean

-2 SD

16

Limitations of Current Osmotic Agents Balance of opposing forces

-600

-400

-200

0

200

400

600

800

-30 0 30 60 90 120 150 180 210 240

Time (min)

Cu

mu

lati

ve

tra

ns

po

rt (

ml)

Absorption Transcapillary UF Net UF

Mactier et al, J Clinical Invest 80:1311, 1987Removal from peritoneum

17

Limitations of Current Osmotic Agents:Temporal Decline

-800

-600

-400

-200

0

200

400

600

800

1000

1200

0 2 4 6 8 10 12 14 16

Time (hr)

Ne

t U

F (

ml)

2.5% Dextrose

4.25% Dextrose

1.5% Dextrose

Negative UltrafiltrationHo-Dac-Pannekeet et al, Kid Int 1996; 50:979-86 Douma et al, Kid Int 1998; 53:1014-21

18

Limitations of Current Osmotic AgentsGlycemic Effect of 4.25% Dextrose

orali.p.

Delarue et al, Kidney Int. 45:1147, 1994

19

Limitations of Current Osmotic AgentsHyperinsulinemic Effect of 4.25%

Dextrose orali.p.

Delarue et al, Kidney Int. 45:1147, 1994

20

Contrasting Dextrose vs. Icodextrin Peritoneal Kinetics

0%

20%

40%

60%

80%

100%

120%

0 2 4 6 8 10 12 14

Dwell time (hr)

Pe

rce

nt

rem

ain

ing

Dextrose Icodextrin

Dextrose data from Mujais et al, PDI 2001; Icodextrin data from RD-99-CA-060

21

Plasma Levels of Total Icodextrin & Maltose

Extraneal 035 Study – APD

0

1000

2000

3000

4000

5000

6000

7000

Baseline Week 1 Week 6 Week 12 Week 13 Week 14

Pla

sm

a le

ve

l (m

g/L

)

IcodextrinMaltose

22

Contrasting Dextrose vs. Icodextrin Net UF Profile

Temporal Decline vs. Sustained Effect

-800

-600

-400

-200

0

200

400

600

800

1000

1200

0 2 4 6 8 10 12 14 16

Time (hr)

Ne

t U

F (

ml)

2.5% Dextrose

4.25% Dextrose

7.5% Icodextrin

1.5% Dextrose

Negative UltrafiltrationHo-Dac-Pannekeet et al, Kid Int 1996; 50:979-86 Douma et al, Kid Int 1998; 53:1014-21

23

Plasma Glucose and Insulin During an Extraneal Dwell

(060 Study)

0

20

40

60

80

100

0 2 4 8 12 16

Time (hr)

Pla

sma

Insu

lin

(U

U/m

l)

0

2

4

6

8

10

Plasm

a Glu

cose

(mm

ol/L

)Insulin

Glucose

24

Rationale for Extraneal

Fluid management in PD is constrained by the consequences of the underlying disease resulting in a necessary high reliance on peritoneal ultrafiltration.

With dextrose-based solutions a long dwell can compound the difficulties with fluid management

There is an unmet need in fluid management in PD

Extraneal is uniquely suited for successful ultrafiltration during the long dwell, and can contribute significantly to fluid management in these critically ill patients

Clinical Trial Experience with Extraneal

Efficacy and Safety

Marsha Wolfson, MD, FACP

VP, Global Clinical Affairs

Francis G. Ogrinc, Ph.D.

Clinical Statistician

26

Presentation Plan

Efficacy of Extraneal Net Ultrafiltration

Peritoneal Clearance

Special Assessments in Study 131

Safety Profile of Extraneal Database

Observational Mortality Data

Adverse Events

Laboratory Values

27

Key Studies

Study Control

(n)

Extraneal

(n)

Study Length/PD Therapy

Dwell Time/ Duration

Study Design

RD-97-CA-130 (2.5% dextrose)

85 90 1 month

CAPD

8-16 hrs Double Blind

Pro-Renal-REG-035 (2.5% dextrose)

19 20 4 mos.

APD

12-16 hrs Open

ML/IB/001 (MIDAS) (1.5% and 2.5/ 4.25% dextrose

103 106 6 mos.

CAPD

8,12 hrs Open

TOTAL EFFICACY 207 216

RD-97-CA-131 (2.5% dextrose)

112 175 12 mos.

APD/CAPD

8-16 hrs Double Blind

28

Supportive Studies

Study Control Extraneal Study Length/ PD Therapy

Dwell Time Study Design

ML/IB/011 DIANA

19 19 2 years APD

12-16 hrs Open

Ml/IB/020 (DELIA)

9 10 20 weeksAPD

14-16 hrs Open

ML/IB/004 (MIDAS-2)

0 48 45 monthsCAPD

8-12 hrs Open

ML/IB/014(S-5)

0 12 5 weeksCAPD

8-12 hrs Open

RD-99-CA-060 0 13 N/A Single Exchange-

PK

Open

TOTAL PATIENTS

28 102

29

Age, Gender and RaceIntegrated Summary of Safety — Baseline

Demographics for All Studies

0

10

20

30

40

50

60

70

80

MEAN AGE

Control

Extraneal

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MALE FEMALE

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

AGE GENDER RACE

30

Primary Renal DiagnosisIntegrated Summary of Safety — Baseline

Demographics for All Studies

0% 5% 10% 15% 20% 25%

Other

Autoimmune Disease

Obstructive Nephropathy

Interstitial Nephritis

Polycystic Kidney Disease

Glomerulonephritis

Hypertensive Nephropathy

Diabetic Nephropathy

ExtranealControl

31

Efficacy Endpoints

Primary Endpoint Net Ultrafiltration

Secondary Endpoints Peritoneal Creatinine Clearance

Peritoneal Urea Clearance

Special Assessments from Study 131 Edema

Body weight

QoL

32

Ultrafiltration Extraneal 130 Study — CAPD

8-16 hour Dwell, Mean Net UF – Change from Baseline

*significant within (p<0.001) and between (p<0.01) groups

**

Mea

n N

et U

F (

ml)

0

50

100

150

200

250

300

350

400

Week 2 Week 4

Control (2.5%)

Extraneal

33

Ultrafiltration Extraneal 035 Study — APD

12-16 Hour Dwell, Mean Net UF – Change from Baseline

Mea

n N

et U

F (

ml)

**

*significant within (p<0.001) and between (p<0.001) groups

*

-100

0

100

200

300

400

500

600

Week 1 Week 6 Week 12 Follow-up

Control (2.5%)

Extraneal

34

Ultrafiltration Extraneal MIDAS Study — CAPD

8 & 12-Hour Dwell 1.5% Dextrose, Mean Net UF – Change from Baseline

*significant within (p<0.001) and between (p<0.001) groups

Mea

n N

et U

F (

ml)

* * *

0

100

200

300

400

500

600

Week 4 Week 13 Week 21

* **

8 HOUR DWELL 12 HOUR DWELL

0

100

200

300

400

500

600

Week 3 Week 12 Week 20

Control

Extraneal

35

Ultrafiltration Extraneal MIDAS Study — CAPD

8 & 12-Hour Dwell 4.25% Dextrose, Mean Net UF – Change from Baseline

*significantly different from baseline

Mea

n N

et U

F(m

)

*

8 HOUR DWELL 12 HOUR DWELL

-400

-200

0

200

400

600

800

Week 4 Week 13 Week 21

Control

Extraneal

-400

-200

0

200

400

600

800

Week 3 Week 12 Week 20

Control

Extraneal

36

Percentage of Patients with Negative Net UF

Extraneal 130 Study — CAPD8-16 Hour Dwell

0%

10%

20%

Baseline Week 2 Week 4

Control (2.5%)

Extraneal

% p

atie

nts

wit

h N

egat

ive

Net

UF

**

* significant between treatment groups (p<0.005)

37

%

Pa

tie

nts

wit

h N

eg

ati

ve

Ne

t U

FPercentage of Patients with Negative Net

UF Extraneal 035 Study — APD

12-16 Hour Dwell

0%

10%

20%

30%

40%

50%

60%

70%

80%

Baseline Week 1 Week 6 Week 12 Follow-up

Control (2.5%)Extraneal

** *

*significant between treatment groups (p<0.001)

38

Percentage of Patients with Negative Net UF

Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 1.5% Dextrose

0%

10%

20%

30%

40%

50%

Baseline Week 3 Week 12 Week 20

% P

ati

en

ts w

ith

Ne

ga

tiv

e N

et

UF

* * * 0%

10%

20%

30%

40%

50%

Baseline Week 4 Week 13 Week 21

Control

Extraneal

8-HOUR DWELL 12-HOUR DWELL

* * *

* significant between treatment groups (p<0.001)

39

Percentage of Patients with Negative Net UF

Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 4.25% Dextrose

0%

10%

20%

30%

40%

50%

Baseline Week 3 Week 12 Week 20

% P

ati

en

ts w

ith

Ne

ga

tiv

e N

et

UF

0%

10%

20%

30%

40%

50%

Baseline Week 4 Week 13 Week 21

Control

Extraneal

8-HOUR DWELL 12-HOUR DWELL

40

Efficacy Endpoints

Primary Endpoint Net Ultrafiltration

Secondary Endpoints Peritoneal Creatinine Clearance

Peritoneal Urea Clearance

Special Assessments from Study 131 Edema

Body weight

QoL

41

Clearance of Creatinine & Urea Extraneal 130 Study — CAPD

Cle

aran

ce (

mL

/min

) fo

r th

e L

on

g D

wel

l

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Week 2 Week 4

Control (2.5%)

Extraneal

p<0.001 p=0.001

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Week 2 Week 4

Cle

aran

ce (

mL

/min

) fo

r th

e L

on

g D

wel

l

p=0.005 p=0.004

CREATININE UREA

** *

*

42

Special Assessments from Long-term Study 131

Edema

Body Weight

Quality of Life

43

Peripheral Edema Assessment Extraneal 131 Study — CAPD & APD

Usually assessed by same individual

0 - 3+ - Recorded on CRF

4+ - Recorded as Adverse Event

44

Adverse Events for Edema Extraneal 131 Study — CAPD & APD

COSTART Term ControlN=112

ExtranealN=175

Peripheral Edema (p=0.002)

17.9% 6.3%

Other Edema 13.4% 10.3%

45

Special Assessments from Study 131

Edema

Body Weight

Quality of Life

46

Body Weight

Important parameter in ESRD

Assesses:

Fluid balance - short term

Body composition - long term

47

Body Weight – Before Drain Extraneal 131 Study — CAPD & APD

(N=47 Control, N=88 Extraneal)

Extraneal patients - maintained body weight at 52 weeks (mean change -0.03 kg)

Control patients - average increase of 2.33 kg at 52 weeks

(p=0.022 at 52 weeks)

48

Special Assessments from Long-term Study 131

Edema

Body Weight

Quality of Life

49

Quality of Life — KDQoL Extraneal 131 Study — CAPD & APD

Patients completing both Baseline and Week 52 (N=25 Control, 41 Extraneal):

Queried on 35 kidney-specific symptoms/problems

Short Form 36

50

Quality of Life — KDQoL Results - SF36

Change in SF-36 Score: Baseline to Week 52Patients with Baseline and Week 52 Forms

-25

-20

-15

-10

-5

0

5

PF RP BP GH VT SF RE MH

Mea

n C

han

ge

in S

core

Extraneal

Control

**

* clinically significant result favoring Extraneal, ** favoring Dianeal

*

**

*

51

Quality of Life — KDQOL Extraneal 131 Study — CAPD & APD

For patients completing both Baseline and Week 52 (N=25 Control, N=41 Extraneal):

35 Symptoms/Problems: 10 favored Extraneal, 5 favored Dextrose

Short Form 36 Domains: 4 favored Extraneal, 1 favored Dextrose

Health Transition Summary:

30% of Extraneal patients vs 4% of Control patients reported their health was much better as compared to one year ago (p=0.032)

52

Extraneal Efficacy Conclusions

Superior UF compared to 1.5% or 2.5% Dextrose and comparable to 4.25% Dextrose

Significantly reduced number of patients with negative net UF compared to both 1.5% and 2.5% Dextrose and comparable to 4.25% Dextrose

Significantly increased peritoneal clearance of urea and creatinine compared to 2.5% Dextrose

Potential benefit in preventing weight gain and edema, and improving quality of life

53

Safety Profile of Extraneal

Database

Observational Mortality Data

Adverse Events

Laboratory Values

Membrane Transport Characteristics

54

Extraneal Clinical Database

840 Total Patients 347 Control, 493 Extraneal

Exposure Control 174.3 days average

Extraneal 232.5 days average215 (43.6%) Extraneal patients exposed greater

than 6 months

155 (31.4%) Extraneal patients exposed greater than 12 months

55

Patient Disposition (Withdrawals/Completions, All Studies)

CONTROL N=347

EXTRANEAL N=493

Completed 70.9% 65.5%

Prematurely Discontinued 29.1% 34.5%

Transplantation 6.1% 8.5%

Adverse Event 11.8% 13.4%

Deaths 3.2% 3.7%

Protocol Violations 3.2% 1.4%

Other 4.9% 7.5%

56

Safety Profile of Extraneal

Database

Observational Mortality Data

Adverse Events

Laboratory Values

Membrane Transport Characteristics

57

Observational MortalityExtraneal 131 Study: Original Data

Collection Each patient was followed until drop out or completion of 12 months. Once a patient discontinued (early drop out or completer), he was

observed for an additional 30 days to collect adverse events, including death.

Based on these data collection methods:

Treatment Group Number of Patients

Deaths

N %

Control 112 5 4.5

EXTRANEAL 175 13 7.4

58

Observational Mortality Extraneal 131 Study: Additional Data

Collection Additional information on 13-month status (dead or alive 395 days

after enrollment) was obtained for the patients who had not died and had not completed the 12-month study.

Treatment Group

Number of Patients

Number of Deaths

12-Month Mortality Rate@

Control 112 9 7.2%

EXTRANEAL 175 20 11.7%

@ From Kaplan-Meier estimation (Not Sig.)

Treatment Group

Number of Patients

Number of Deaths

12-Month Mortality Rate@

Control 112 9 7.2%

EXTRANEAL 175 20 11.7%

59

0 25 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400Days Until Death or Censor

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Pro

po

rtio

n S

urv

ivin

g

Treatment Group:ControlExtraneal

p=0.301 from the Log-Rank Test

All Follow-Up Time for Mortality Extraneal Study 131: Long-Term Safety Study in APD

and CAPD Patients

60

Observational MortalityAll Studies (Other Than MIDAS-2)

Because of the limited database in Study 131, mortality results from all studies, other than MIDAS-2, were combined to describe the overall mortality.

Intent-to-treat methods were applied and all deaths were included. Some of these were after study participation.

Treatment Group

Number of Patients

Number of Deaths

Total Follow-Up Time (Patient-Yrs)

Deaths per 1000 Pt-Year

Control 285 20 189 106

EXTRANEAL 366 26 244 107

61

Observational MortalityAll Studies (Other Than MIDAS-2)

Estimated Death Rates from the Kaplan-Meier Methods

Month Control EXTRANEALRatio of

Death Rates

12 7.9% 10.4% 1.32

18 47.4% 17.3% 0.36

24 54.0% 27.6% 0.51

62

100 200 300 400 500 600 700 800Time to Death (Days)

00

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Pro

po

rtio

n S

urv

ivin

g

Treatment Group:ControlExtraneal

p=0.929 from Log-Rank Test

Kaplan-Meier Survival Curves for Time to Death

Using All Mortality From ISS Except MIDAS-2 (Uncontrolled)

63

Observational MortalitySummary

Mortality information from all clinical studies was combined to better describe the experience for Extraneal.

There were 366 Extraneal patients in this integrated safety database.

These provide 244 patient-years of experience with Extraneal.

Survival times were comparable for Control and Extraneal Hazard Ratio: 1.03

90% Confidence Interval: [0.63, 1.68]

64

Safety Profile of Extraneal

Database

Observational Mortality Data

Adverse Events

Laboratory Values

Membrane Transport Characteristics

65

Extraneal All StudiesSafety - Adverse Events

Control (N=347)

Extraneal (N=493)

p-Value

Pct. of Patients with at least one AE

84.1% 87.0% 0.240

Most Related AE to Treatment

NoneRelatedNot Reported

41.1%25.7%33.2%

40.1%28.2%31.7%

0.250

Most Severe AE MildModerateSevereNot Reported

20.2%39.4%38.7%1.7%

16.6%40.6%39.4%3.5%

0.339

Pct. Of Patients with at least one Serious AE

31.2% 31.7% 0.290

66

Adverse Events

Peritonitis

Rash

67

Adverse Events

Peritonitis most frequent adverse event Control – 25.4%

Extraneal – 26.4%

Peritonitis most frequent serious adverse event - resulting in hospitalization Control - 8.6%

Extraneal - 5.3%

(p=0.013)

68

Adverse Events

Of all adverse events, only Rash showed greater than 5 percentage points difference between groups

69

Total Skin EventsIncidence Rates – All Studies, Unrelated and Related

AEs

COSTART Code Control (N=347)

Extraneal (N=493)

All SKIN EVENTS

RASH

22.5%

4.6%

27.0%

10.1%

DERM EXFOL 0.3% 1.8%

70

Total Skin EventsIncidence Rates – All Studies, Related AEs

COSTART Code Control(N=347)

Extraneal (N=493)

All SKIN EVENTS 4.0% 9.9%

RASH 1.7% 5.5%

DERM EXFOL 0.0% 1.6%

71

Outcomes for Rash in Clinical Trials

6 patients withdrew/discontinued for rash, 1 for exfoliative dermatitis

All were in the Extraneal Group

No patient was hospitalized for rash

All rash events resolved

No anaphylaxis

No Stevens-Johnson Syndrome

72

Safety Profile of Extraneal

Database

Observational Mortality Data

Adverse Events

Laboratory Values

Membrane Transport Characteristics

73

Laboratory Value ChangesAt Last Visit, Between Groups

INCREASED:

Alkaline Phosphatase (130, 131 and 035 studies)

DECREASED:

Amylase-Assay Interference

Sodium

Chloride

74

Serum Alkaline Phosphatase (U/L)

(130, 131 and 035 Studies)

Mean change +4.039 Control

+19.073 Extraneal

Patients above normal range (31.0 - 115.0 U/L)

23.6% Control

33.5% Extraneal

Adverse Events for increased Alk. Phos. 1.7% Control

2.8% Extraneal

75

Serum Sodium (mmol/L)All Studies

Mean change -0.272 Control -2.771 Extraneal

Patients below normal range (135-148 mmol/L) 15.8% Control 32.5% Extraneal

Adverse Events for Hyponatremia 2.0% Control 2.2% Extraneal

76

Serum Chloride (mmol/L)All Studies

Mean change +0.610 Control -2.003 Extraneal

Patients below normal range (96-112 mmol/L) 32.9% Control 51.7% Extraneal

Adverse Events for hypochloremia 0.9% Control 1.6% Extraneal

77

Safety Profile of Extraneal

Database

Observational Mortality Data

Adverse Events

Laboratory Values

Membrane Transport Characteristics

78

Membrane Transport CharacteristicsMTAC for Creatinine, Urea and Glucose

*significantly different from baseline within group‡ significantly different between groups

0

10

20

Baseline Week 26 Week 52

Control

Extraneal

0

10

20

Baseline Week 26 Week 52

Control

Extraneal

0

10

20

Baseline Week 26 Week 52

Control

Extraneal

** ‡

CR

EA

TIN

INE

(m

L/m

in)

UR

EA

(m

L/m

in)

GL

UC

OS

E(m

L/m

in)

79

Summary of Clinical Trial Results

EFFICACY Increased Ultrafiltration

Reduced percentage of patients with negative net UF

Increased peritoneal creatinine and urea clearance

Potential benefit in preventing weight gain and edema, and improving quality of life

SAFETY Safety profile comparable to

current therapy

Rash most frequent related AE

Increases in alkaline phosphatase, decreases in sodium and chloride, with no known clinical relevance

80

ExtranealOverall Summary

Patients on PD have limited therapy options for fluid management

Extraneal provides patients and their physicians a new dialysis solution that expands these options by sustaining effective ultrafiltration during the long dwell

The enhanced efficacy of the new solution is coupled with a safety profile comparable to existing solutions

81

Proposed Indication

Extraneal is indicated for a single daily exchange for the long (8-16 hour) dwell during continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for the management of chronic renal failure.