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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
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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
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Categories of Blood Substitutes
Biologics Vs Chemicals
• Stroma-free heamoglobin– Liquid– Encapsulated– Polymerized
• Perfluorocarbons– Liquid– Emulsions
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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
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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Outdated human RBCs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Outdated human RBCs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
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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
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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
+
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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
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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
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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
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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®
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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
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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
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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
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Critical Level of Oxygen
Deprivation
Tiss
ue O
xyge
natio
n
Days0%
100%
“Oxygen Bridge”“Oxygen Bridge”
Acts as Oxygen Bridge™
Side Effects
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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%)
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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%)
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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
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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
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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