# Presentation: 415698

## CARDIO-RENALAdvisory Committee Meeting

- EXTRANEALTM (7.5% Icodextrin)
- Peritoneal Dialysis Solution
- NDA 21-321
- Orphan Drug Designation 97-1056
- August 9, 2001
- Baxter Healthcare Corporation

## 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

## 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

## 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

## 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.

## Topics Identified in FDA Briefing Document & Questions

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

## AGENDACardio-Renal Advisory CommitteeNDA 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*

## Icodextrin: A Polymer of Glucose

## 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

## 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

## Unmet Clinical NeedLimitations 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

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

## 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**

## The long dwell: an integral component of PD

## 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

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

**Mujais et al, Peritoneal Dialysis Int. 2001**

## Limitations of Current Osmotic Agents Balance of opposing forces

**Mactier et al, J Clinical Invest 80:1311, 1987**

## Limitations of Current Osmotic Agents:Temporal Decline

## Limitations of Current Osmotic AgentsGlycemic Effect of 4.25% Dextrose

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

## Limitations of Current Osmotic AgentsHyperinsulinemic Effect of 4.25% Dextrose

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

## Contrasting Dextrose vs. Icodextrin Peritoneal Kinetics 

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

## Plasma Levels of Total Icodextrin & MaltoseExtraneal 035 Study – APD

## Contrasting Dextrose vs. Icodextrin Net UF Profile Temporal Decline vs. Sustained Effect

## Plasma Glucose and Insulin During an Extraneal Dwell (060 Study)

## 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

## 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

## 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 |

## 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 weeks
APD | 14-16 hrs | Open |
| ML/IB/004 
(MIDAS-2) | 0 | 48 | 45 months
CAPD | 8-12 hrs | Open |
| ML/IB/014
(S-5) | 0 | 12 | 5 weeks
CAPD | 8-12 hrs | Open |
| RD-99-CA-060 | 0 | 13 | N/A | Single Exchange-PK | Open |
| TOTAL PATIENTS | 28 | 102 |  |  |  |

##  Age, Gender and RaceIntegrated Summary of Safety — Baseline Demographics for All Studies

**AGE**

**GENDER**

**RACE**

## Primary Renal DiagnosisIntegrated Summary of Safety — Baseline Demographics for All Studies

## Efficacy Endpoints

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

## Ultrafiltration Extraneal 130 Study — CAPD8-16 hour Dwell, Mean Net UF – Change from Baseline

- Ultrafiltration Extraneal 130 Study — CAPD8-16 hour Dwell, Mean Net UF – Change from Baseline

## Ultrafiltration Extraneal 035 Study — APD12-16 Hour Dwell, Mean Net UF – Change from Baseline

## 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**

## Ultrafiltration Extraneal MIDAS Study — CAPD 8 & 12-Hour Dwell 4.25% Dextrose, Mean Net UF – Change from Baseline

## Percentage of Patients with Negative Net UF Extraneal 130 Study — CAPD8-16 Hour Dwell 

**% patients with Negative Net UF**

- *

- *

*** significant between treatment groups (p<0.005)**

## Percentage of Patients with Negative Net UF Extraneal 035 Study — APD12-16 Hour Dwell

- Percentage of Patients with Negative Net UF Extraneal 035 Study — APD12-16 Hour Dwell

- *

- *

- *

*******significant between treatment groups (p<0.001)**

## Percentage of Patients with Negative Net UF  Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 1.5% Dextrose

## Percentage of Patients with Negative Net UF  Extraneal MIDAS Study — CAPD 8-Hour Dwell & 12-Hour Dwell 4.25% Dextrose

**% Patients with Negative Net UF**

**8-HOUR DWELL**

**12-HOUR DWELL**

## Efficacy Endpoints

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

## Clearance of Creatinine & Urea Extraneal 130 Study — CAPD 

- Clearance of Creatinine & Urea Extraneal 130 Study — CAPD

## Special Assessments from Long-term Study 131

- Edema
- Body Weight
- Quality of Life

## Peripheral Edema Assessment Extraneal 131 Study — CAPD & APD

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

## Adverse Events for Edema Extraneal 131 Study — CAPD & APD

| COSTART Term | Control
N=112 | Extraneal
N=175 |
| --- | --- | --- |
| Peripheral Edema (p=0.002) | 17.9% | 6.3% |
| Other Edema | 13.4% | 10.3% |

## Special Assessments from Study 131

- Edema
- Body Weight
- Quality of Life

## Body Weight

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

## 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)

## Special Assessments from Long-term Study 131

- Edema
- Body Weight
- Quality of Life

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

- 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

## Quality of Life — KDQoL Results - SF36

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

- 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)**

## 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

## Safety Profile of Extraneal

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

## 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

## 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% |

## Safety Profile of Extraneal

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

## Observational MortalityExtraneal 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 |

## 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% |

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

**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

## Observational MortalityAll 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 |

## Observational MortalityAll Studies (Other Than MIDAS-2)

- Estimated Death Rates from the Kaplan-Meier Methods

| 
Month | 
Control | 
EXTRANEAL | Ratio of Death Rates |
| --- | --- | --- | --- |
| 12 | 7.9% | 10.4% | 1.32 |
| 18 | 47.4% | 17.3% | 0.36 |
| 24 | 54.0% | 27.6% | 0.51 |

## Kaplan-Meier Survival Curves for Time to Death Using All Mortality From ISS Except MIDAS-2 (Uncontrolled)

- Kaplan-Meier Survival Curves for Time to Death Using All Mortality From ISS Except MIDAS-2 (Uncontrolled)

## Observational MortalitySummary

- 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]

## Safety Profile of Extraneal

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

## Extraneal All StudiesSafety - 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 | None
Related
Not Reported | 41.1%
25.7%
33.2% | 	40.1%
	28.2%
	31.7% | 0.250 |
|  |  |  |  |  |
| Most Severe AE | Mild
Moderate
Severe
Not 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 |

## Adverse Events

- Peritonitis
- Rash

## 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)

## Adverse Events

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

## Total Skin EventsIncidence 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% |
|  |  |  |

## Total Skin EventsIncidence 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% |

## 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

## Safety Profile of Extraneal

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

## Laboratory Value ChangesAt Last Visit, Between Groups

- INCREASED:
- Alkaline Phosphatase (130, 131 and 035 studies)

- DECREASED:
- Amylase-Assay Interference
- Sodium
- Chloride

## 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

## 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

## 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

## Safety Profile of Extraneal

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

## Membrane Transport CharacteristicsMTAC for Creatinine, Urea and Glucose

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

- *

- * ‡

**CREATININE **
**(mL/min)**

**UREA **
**(mL/min)**

**GLUCOSE**
**(mL/min)**

## 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

## ExtranealOverall 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

## 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.