CARDIORENAL Advisory Committee Meeting

1
CARDIO-RENALAdvisory Committee Meeting

• EXTRANEAL (7.5 Icodextrin)
• Peritoneal Dialysis Solution
• NDA 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 RD
• 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 OBrien, 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

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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.

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Topics Identified in FDA Briefing Document
Questions

• Dialysis Efficacy
• Quality of Life
• Size of Database
• Safety Profile
• Mortality
• Rash
• Peritonitis
• Membrane Transport Characteristics

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AGENDACardio-Renal Advisory CommitteeNDA
21-321 Extraneal (7.5 icodextrin)

• Introduction and Rationale for Extraneal
• Salim Mujais, M.D., Vice President Global
  Medical Affairs, Baxter
•   
• Clinical Trial Experience with Extraneal
• Marsha Wolfson, M.D., Vice President Global
  Clinical Affairs, Baxter
• Frank Ogrinc, Ph.D., Clinical Statistician,
  Baxter
•  
• Conclusions
• Salim Mujais, M.D., Vice President Global
  Medical Affairs, Baxter
•  
•  

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Icodextrin A Polymer of Glucose
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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

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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

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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
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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 591128,
2001
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The long dwell an integral component of PD
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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

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Limitations of Current Osmotic Agents Dextrose
Kinetics in PD Rapid Dissipation
Mujais et al, Peritoneal Dialysis Int. 2001
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Limitations of Current Osmotic Agents Balance of
opposing forces
Mactier et al, J Clinical Invest 801311, 1987
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Limitations of Current Osmotic AgentsTemporal
Decline
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Limitations of Current Osmotic AgentsGlycemic
Effect of 4.25 Dextrose
Delarue et al, Kidney Int. 451147, 1994
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Limitations of Current Osmotic AgentsHyperinsulin
emic Effect of 4.25 Dextrose
Delarue et al, Kidney Int. 451147, 1994
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Contrasting Dextrose vs. Icodextrin Peritoneal
Kinetics
Dextrose data from Mujais et al, PDI 2001
Icodextrin data from RD-99-CA-060
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Plasma Levels of Total Icodextrin
MaltoseExtraneal 035 Study APD
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Contrasting Dextrose vs. Icodextrin Net UF
Profile Temporal Decline vs. Sustained Effect
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Plasma Glucose and Insulin During an Extraneal
Dwell (060 Study)
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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

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Clinical Trial Experience with Extraneal
Efficacy and Safety

• Marsha Wolfson, MD, FACP
• VP, Global Clinical Affairs
• Francis G. Ogrinc, Ph.D.
• Clinical Statistician

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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

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Key Studies
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Supportive Studies
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Age, Gender and RaceIntegrated Summary of
Safety Baseline Demographics for All Studies
AGE
GENDER
RACE
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Primary Renal DiagnosisIntegrated Summary of
Safety Baseline Demographics for All Studies
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Efficacy Endpoints

• Primary Endpoint
• Net Ultrafiltration
• Secondary Endpoints
• Peritoneal Creatinine Clearance
• Peritoneal Urea Clearance
• Special Assessments from Study 131
• Edema
• Body weight
• QoL

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Ultrafiltration Extraneal 130 Study CAPD8-16
hour Dwell, Mean Net UF Change from Baseline
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Ultrafiltration Extraneal 035 Study APD12-16
Hour Dwell, Mean Net UF Change from Baseline
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Ultrafiltration Extraneal MIDAS Study CAPD 8
12-Hour Dwell 1.5 Dextrose, Mean Net UF
Change from Baseline
significant within (p(p 35
Ultrafiltration Extraneal MIDAS Study CAPD 8
12-Hour Dwell 4.25 Dextrose, Mean Net UF
Change from Baseline
36
Percentage of Patients with Negative Net UF
Extraneal 130 Study CAPD8-16 Hour Dwell
patients with Negative Net UF


significant between treatment groups (p 37
Percentage of Patients with Negative Net UF
Extraneal 035 Study APD12-16 Hour Dwell
Patients with Negative Net UF



significant between treatment groups (p 38
Percentage of Patients with Negative Net UF
Extraneal MIDAS Study CAPD 8-Hour Dwell
12-Hour Dwell 1.5 Dextrose
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Percentage of Patients with Negative Net UF
Extraneal MIDAS Study CAPD 8-Hour Dwell
12-Hour Dwell 4.25 Dextrose
8-HOUR DWELL
12-HOUR DWELL
Patients with Negative Net UF
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Efficacy Endpoints

• Primary Endpoint
• Net Ultrafiltration
• Secondary Endpoints
• Peritoneal Creatinine Clearance
• Peritoneal Urea Clearance
• Special Assessments from Study 131
• Edema
• Body weight
• QoL

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Clearance of Creatinine Urea Extraneal 130
Study CAPD
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Special Assessments from Long-term Study 131

• Edema
• Body Weight
• Quality of Life

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Peripheral Edema Assessment Extraneal 131 Study
CAPD APD

• Usually assessed by same individual
• 0 - 3 - Recorded on CRF
• 4 - Recorded as Adverse Event

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Adverse Events for Edema Extraneal 131 Study
CAPD APD
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Special Assessments from Study 131

• Edema
• Body Weight
• Quality of Life

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Body Weight

• Important parameter in ESRD
• Assesses
• Fluid balance - short term
• Body composition - long term

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Body Weight Before Drain Extraneal 131 Study
CAPD APD (N47 Control, N88 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
• (p0.022 at 52 weeks)

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Special Assessments from Long-term Study 131

• Edema
• Body Weight
• Quality of Life

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Quality of Life KDQoL Extraneal 131 Study
CAPD APD

• Patients completing both Baseline and Week 52
  (N25 Control, 41 Extraneal)
• Queried on 35 kidney-specific symptoms/problems
• Short Form 36

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Quality of Life KDQoL Results - SF36
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Quality of Life KDQOL Extraneal 131 Study
CAPD APD

• For patients completing both Baseline and Week
  52 (N25 Control, N41 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 (p0.032)

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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

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Safety Profile of Extraneal

• Database
• Observational Mortality Data
• Adverse Events
• Laboratory Values
• Membrane Transport Characteristics

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Extraneal Clinical Database

• 840 Total Patients
• 347 Control, 493 Extraneal
• Exposure
• Control 174.3 days average
• Extraneal 232.5 days average
• 215 (43.6) Extraneal patients exposed greater
  than 6 months
• 155 (31.4) Extraneal patients exposed greater
  than 12 months

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Patient Disposition (Withdrawals/Completions,
All Studies)
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Safety Profile of Extraneal

• Database
• Observational Mortality Data
• Adverse Events
• Laboratory Values
• Membrane Transport Characteristics

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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

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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.

_at_ From Kaplan-Meier estimation (Not Sig.)
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All Follow-Up Time for Mortality Extraneal Study
131 Long-Term Safety Study in APD and CAPD
Patients
p0.301 from the Log-Rank Test
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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.

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Observational MortalityAll Studies (Other Than
MIDAS-2)
Estimated Death Rates from the Kaplan-Meier
Methods
62
Kaplan-Meier Survival Curves for Time to Death
Using All Mortality From ISS Except MIDAS-2
(Uncontrolled)
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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

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Safety Profile of Extraneal

• Database
• Observational Mortality Data
• Adverse Events
• Laboratory Values
• Membrane Transport Characteristics

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Extraneal All StudiesSafety - Adverse Events
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Adverse Events

• Peritonitis
• Rash

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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
• (p0.013)

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Adverse Events

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

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Total Skin EventsIncidence Rates All Studies,
Unrelated and Related AEs
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Total Skin EventsIncidence Rates All Studies,
Related AEs
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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

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Safety Profile of Extraneal

• Database
• Observational Mortality Data
• Adverse Events
• Laboratory Values
• Membrane Transport Characteristics

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Laboratory Value ChangesAt Last Visit, Between
Groups

• INCREASED
• Alkaline Phosphatase (130, 131 and 035 studies)

• DECREASED
• Amylase-Assay Interference
• Sodium
• Chloride

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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

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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

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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

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Safety Profile of Extraneal

• Database
• Observational Mortality Data
• Adverse Events
• Laboratory Values
• Membrane Transport Characteristics

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Membrane Transport CharacteristicsMTAC for
Creatinine, Urea and Glucose
CREATININE (mL/min)
UREA (mL/min)


GLUCOSE (mL/min)
significantly different from baseline within
group significantly different between groups
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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

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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

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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.