Updated: 二○○三年十一月二十五日星期二

Haemoglobin-Based Oxygen Carriers for Anaemia:An Overview

Bing Lou Wong, Ph.D.CEO, Advantek Biologics Limited

Contents

• History of Blood Transfusion• Categories of Blood Substitutes• HBOCs in Development• Approval Status• Investigational Indications• Compassionate Uses• Side Effects

History of Blood Transfusion

1600s - 2001

Oxyglobin® approved by US FDA for anaemia in dogs

1998

Oxyglobin® approved by EU EMEA for anaemia in dogs

1999

Hemopure® approved in South Africa for acute anaemia in surgery

2001

Fluosol approved by US FDA but pulled off in 19931989

Blood typing introduced1901

First successful human-to-human transfusion1795

Sheep’s blood for wounded soldiers1600s

Categories of Blood Substitutes

Biologics Vs Chemicals

• Stroma-free heamoglobin– Liquid– Encapsulated– Polymerized

• Perfluorocarbons– Liquid– Emulsions

HBOCs in Development

Preoperative Intraoperative

EPO• Repeated office visits• Failure rate @ 5%• Iron

Preoperative AutologousDonation (PAD)

• Collection• Transport• Risk of errors• Old RBCs (>15 Days)• Certain conditions

precluded; HIV, hepC• 45% wasted

• Extra time • Risk of anemia

Cell Salvage• Equipment• Disposable• Technician• Small recovery vol.

Why HBOCs?

Acute Normovolemic

Hemodilution (ANH)

General Benefitsof HBOCs

• No prior planning• Faster & better O2 Del• Ready to use• No waste• No equipment• Long shelf life• No refrigeration• Universally compatible• No clerical errors• Immediately offloads

oxygen (No 2,3-DPG)• Can use Jehovah’s

patients

Leading HBOCs

Source

Shelf-life

Half-life

Approved oxygen therapeutics

Biopure Northfield Hemosol

BovineHgb

3 years

18-22 hours

2

Outdated human RBCs

1 year

24 hours

0

Outdated human RBCs

1 year

14 hours

0

Storage Room Temperature RefrigeratedRefrigerated/Room Temp

HRC-101PolyHeme ®Hemopure ®

Oxyglobin ®Product Name

Severe AnemiaAnemia

treatment

Occupying Plasma Space

NORMAL BLOOD FLOW HBOCsANEMIC BLOOD FLOW

Mechanism of Action

Stabilized hemoglobin circulates in plasma• Greater distribution throughout the body than RBCs

• Causes greater extraction of O2 from RBCs

Approval Status

Hemopure® [hemoglobin glutatmer-250 (bovine)] and Oxyglobin® [hemoglobin glutamer-200 (bovine)] are registered trademarks of Biopure Corporation

Hemopure® (Human Use)Approved for treatment of acute anemia in surgery2001 - South Africa

Marketing application for treatment of acute anemia in elective orthopedic surgery 2002 – filed in United States2003 – mid-year response from FDA

Oxyglobin® (Veterinary Use)Approved for treatment of anemia in dogs1998 – United States1999 – European Union

Biopure: The Front-Runner

Hemopure® PolymerizationNative Hb

Stabilized Tetramer

Polymer (Hemopure®) (Oxyglobin®)

Hemoglobin®Red Blood Cells (Bovine Derived)

tetramer 64 kD dimer 32 kD

64 kD

Average 250 kD

+

Hemopure® Stability: MetHb

2- 8°C

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

Tim e ( M os.)

% M

etH

b

H 8C 003 (2- 8 °C )

H 8C 005 (2- 8 °C )

H 8C 006 (2- 8 °C )

Spe c ific a tio n

RT

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

%M

etH

b

H 8C 003 (RT)

H 8C 005 (RT)

H 8C 006 (RT)

Spe c ific a tio n

40°C

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

% M

etH

bH 8C 003 (40 °C )

H 8C 005 (40 °C )

H 8C 006 (40 °C )

Spe c ific a tio n

Hemopure® Stability: MW

2-8 °C

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

Tim e (Mos.)

% M

etH

b H8C003 (2- 8 °C)

H8C005 (2- 8 °C)

H8C006 (2- 8 °C)

Spec if ic at ion

RT

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

% 6

5 k

D H8C003 (RT )

H8C005 (RT )

H8C006 (RT )

Spec if ic at ion

40 °C

0

2

4

6

8

10

12

0 5 10 15 20 25 30 35 40

% 6

5 k

D

H8C003 (40 °C)

H8C005 (40 °C)

H8C006 (40 °C)

Spec if ic at ion

Attribute Infused HBOC-201 Transfused Red Cells

Onset of action Immediate 2,3-DPG dependent

Oxygen affinity Red cell 2,3 DPG not required for oxygen release

Red cell 2,3 DPG required for oxygen release

Oxygen transport Red cells plus plasma Red cells only

Risk of disease transmission

Sterile pharmaceutical; no leukocyte exposure

Risk minimized by improved donor selection; leukocyte exposure

Storage Room temperature; no loss of efficacy

Refrigeration required; progressive loss of efficacy

Shelf life 36 months 42 days

Compatibility Universal Type-specific

Preparation Ready to use Requires typing and cross-matching

Viscosity Low High

Duration of action Maximum of 3 days Estimated 60 to 90 days

HBOCs Vs RBCs

Tissue pO2 (torr)

0

10

20

30

Horn EP, Standl TG, Wilhelm S, et al. Bovine hemoglobin increased skeletal muscle oxygenation during 95% artificial arterial stenosis. Surgery (1997);121:411-18.

NORMAL FLOW95% STENOSIS

Hemopure’s small size and low viscosity enables penetration to areas of restricted flow

ADD HEMOPURE

Hemopure® Reversing Hypoxia Due to Arterial Stenosis

Adapted from Page TC et al. Microvas Rrs 1198;55:54-64.

Hemopure® Oxygen Release

Adapted from Standl TG et al. Can J Anaesth 1196;43:714-723.

MEAN OBSERVED GROUP VALUES: 50% Tissues pO2 (mmHg)

Hemopure® Tissue pO2

Investigational Indications

SURGERY

TRAUMA

General (S Africa)Orthopedic (US)Orthopedic (EU)Cardiopulmonary BypassAortic Aneurysm Recon.

ISCHEMIA

Emergent

Phase II Phase III Regulatory Filing

Regulatory Approval

Product Sales

Leading HBOC

Cardiac CNS

Phase I

CANCERAdjunct to Radiotherapy

Clinical Development

Hemopure®

Hemopure®

Hemopure®

Hemopure®

Hemopure®

PolyHeme®

Hemopure®

Hemopure®

Hemopure®

Hemopure®Depth of Clinical Experience

# Studies# Studies TypeType HemopurePatients (n)HemopurePatients (n)

Control Patients (n)

Control Patients (n)

Maximum Total Dose(g Hemopure)

Maximum Total Dose(g Hemopure)

4

4

3

6

1

4

22

Healthy Volunteers

Non-Surgery

Surgery with ANH*

General Surgery

Military Surgery Trial

Major Surgery Trials

64

34

31

120

26

531

806**

29

14

36

70

25

487

661

45-140

43-1230

36-98

27-245

300

120-300

27-1230

* ANH = Acute Normovolemic Hemodilution** Total does not include compassionate use patients treated under emergency INDs

Note: Not including >250 post clinical trials applications in South Africa

PolyHeme®Depth of Clinical Experience

Exception from informed consent(21 CFR 50.24 federal regulations on clinical research in emergency settings)

• Ethics:

Improved survival• Endpoint:Standard of care (Ringers Lactate)• Control:700+ patients expected• Size: 20 Level I trauma centers• Scale:

•Ongoing Phase III

Phase IIVASCULAR

Phase IICARDIAC

Phase IIIGENERAL

Phase IIIORTHOPEDIC

≤ 6 days≤ 6 days≤ 7 units ≤ 7 units

≤ 6 days≤ 6 days≤ 10 units≤ 10 units

≤ 4 days≤ 4 days≤ 4 units≤ 4 units

≤ 3 days≤ 3 days≤ 3 units≤ 3 units

Hemopure®: % Patients Avoiding RBC’s

Pivotal trialefficacy endpoint

≥35%

43%

27%34%

59%

98 Patients 72 Patients 160 Patients 593 Patients

Compassionate Uses

Dying for Lack of Blood• Emily Gruszka was dying for lack of blood in 1999

despite 45 days of continuous RBC transfusion• Kidneys stopped working; on the verge of multi

organ failure• But blood couldn’t save her because of severe

autoimmune hemolytic anemia • Her doctor read about Oxyglobin in a pet magazine,

then requested Biopure for 11 units of Hemopure• Hours after first transfusion, she stabilized and was

maintained for 8 days until immune system was controlled

• She survived at a hematocrit of 3%+ • New Engl J Med. 2000;342(22):1638-1643

Severe AnemiaAnemia

treatment

Occupying Plasma Space

Critical Level of Oxygen

Deprivation

Tiss

ue O

xyge

natio

n

Days0%

100%

“Oxygen Bridge”“Oxygen Bridge”

Acts as Oxygen Bridge™

Side Effects

Hemopure®: Clinical Side Effects

• GI symptomsSymptomSymptom HBOC (%)

N 797HBOC (%)

N 797Control (%)

N 661Control (%)

N 661p valuep value

141 (17%)

48 (6%)

125 (16%)

63 (8%)

52 (7%)

49 (7%)

7 (1%)

127 (19%)

32 (5%)

14 (2%)

Hemopure®: Clinical Side Effects

• GI symptoms• Blood pressure response• Lipase and AST changes

SymptomSymptom HBOC (%) N 799

HBOC (%) N 799

Control (%)N 661

Control (%)N 661

p valuep value

Lipase Increased

Amylase Increased

AST

ALT

48 (6%)

15 (2%)

34 (4%)

20 (3%)

12 (2%)

13 (2%)

12 (2%)

10 (2%)

.0001

1.000

.0098

.1992

Source: ISS AE Com. 1

Hemopure®: Clinical Side Effects

• GI symptoms• Blood pressure response• Amylase and AST changes• Skin/Sclera discoloration

SymptomSymptom HBOC (%) N 797

HBOC (%) N 797

Control (%)N 661

Control (%)N 661

p valuep value

161 (20%) 6 (1%)

Number of SubjectsHemopure

(n=421 patients)

Deaths

Other Serious AEs*

Overall Incidence of AEs

Comparators **(n=298 patients)

3%

21%

90%

3%

19%

84%

* Prolongation of hospitalization; requires intervention; persistent significant disability or congenital abnormality or death

** 149 subjects red blood cell controlled; 149 subjects colloid or crystalloid controlled

Source: South Africa Regulatory Submission

(Integrated data from 19 studies, not including pivotal Phase III trial)

Hemopure®: Treatment-Emergent Adverse Events

PolyHeme®: Treatment-Emergent Adverse Events

No organ toxicitiesNo systemic hypertension No pulmonary hypertension

• Side effects:

300+ patients• Size:

5 trials• Scale:

Previous Trials*

* In 2001, US FDA rejected BLA with a “Refusal to File” letter

Acknowledgements

• Hong Kong Association of Blood Transfusion and Haematology

• Hong Kong Red Cross Blood Transfusion Service

• Biopure Corporation• Northfield Laboratories Inc.

Air Force Link

Hemopure, made with bovine hemoglobin, may make the difference in future life or death situations far from any emergency room. Since it adjusts to all blood types and needs norefrigeration, field hospitals and pararescuemen, like those from the California Guard’s 129th Rescue Wing, Moffett Federal Air Field, might have to put the artificial blood product to good use.

by Master Sgt. Tim Barela

Hemopure®: Clinical Side Effects

• GI symptoms• Blood pressure response

Statistic HBOC-201 (n = 350)

RBC (n =338)

P-value*

Pre-treatment

Highest Value Post-treatment

Largest Increase

Pre-treatment

Highest Value Post-treatment

Largest Increase

Systolic Blood Pressure

Mean SE

136.5 1.2

159.8 1.1

23.9 1.3

137.0 1.3

150.7 1.0

14.0 1.4

< 0.0001

Median 136.0 160.0 23.0 136.0 150.0 12.0 Range 90-206 106-234 -33-90 95-222 110-221 -79-110 Diastolic Blood Pressure

Mean SE

76.5 0.7

89.2 0.6

12.5 0.8

77.1 0.8

83.9 0.5

6.9 0.9

< 0.0001

Median 78.0 90.0 11.0 78.0 82.0 8.0 Range 50-110 55-131 - 20-46 48-120 60-114 -44-50 Mean Arterial Pressure

Mean SE

96.5 0.7

110.7 0.6

14.4 0.8

97.0 0.8

104.2 0.6

7.3 0.9

< 0.0001

Median 96.7 110.0 14.0 96.0 103.7 6.7 Range 63.3-136.7 75.3-150.0 -18.3-

53.3 66.7-150.0 77.3-143.3 -56.0-

56.7

Source: HEM 115 Study Report