Contents - The Federation of Medical Societies of Hong Kong

Haemoglobin-Based
Oxygen Carriers for
Anaemia:
An Overview
Bing Lou Wong, Ph.D.
CEO, Advantek Biologics Limited
Updated: 二○○三年十一月二十五日星期二
Contents
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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
1600s
Sheep’s blood for wounded soldiers
1795
First successful human-to-human transfusion
1901
Blood typing introduced
1989
Fluosol approved by US FDA but pulled off in 1993
1998
Oxyglobin® approved by US FDA for anaemia in
dogs
1999
Oxyglobin® approved by EU EMEA for anaemia in
dogs
2001
Hemopure® approved in South Africa for acute
anaemia in surgery
Categories of Blood Substitutes
Biologics Vs Chemicals
• Stroma-free heamoglobin
– Liquid
– Encapsulated
– Polymerized
• Perfluorocarbons
– Liquid
– Emulsions
HBOCs in Development
Why HBOCs?
Preoperative
EPO
• Repeated office visits
• Failure rate @ 5%
• Iron
Preoperative Autologous
Donation (PAD)
• Collection
• Transport
• Risk of errors
• Old RBCs (>15 Days)
• Certain conditions
precluded; HIV, hepC
• 45% wasted
General Benefits
of HBOCs
Intraoperative
Cell Salvage
• Equipment
• Disposable
• Technician
• Small recovery vol.
Acute Normovolemic
Hemodilution (ANH)
• Extra time
• Risk of anemia
•
•
•
•
•
•
•
•
•
•
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
Biopure
Northfield
Hemosol
Source
Bovine
Hgb
Outdated
human RBCs
Outdated
human RBCs
Shelf-life
3 years
1 year
1 year
Storage
Room
Temperature
Refrigerated
Refrigerated/
Room Temp
Half-life
18-22 hours
24 hours
14 hours
2
0
0
Hemopure ®
Oxyglobin ®
PolyHeme ®
HRC-101
Approved oxygen
therapeutics
Product Name
Occupying Plasma Space
Severe
Anemia
Anemia
treatment
Mechanism of Action
NORMAL BLOOD FLOW
ANEMIC BLOOD FLOW
Stabilized hemoglobin circulates in plasma
•
Greater distribution throughout the body than RBCs
•
Causes greater extraction of O2 from RBCs
Approval Status
HBOCs
Biopure: The Front-Runner
Hemopure®
(Human Use)
ƒ Approved for treatment of acute anemia in surgery
2001 - South Africa
ƒ Marketing application for treatment of
acute anemia in elective orthopedic surgery
2002 – filed in United States
2003 – mid-year response from FDA
Oxyglobin®
(Veterinary Use)
ƒ Approved for treatment of anemia in dogs
1998 – United States
1999 – European Union
Hemopure® [hemoglobin glutatmer-250 (bovine)] and Oxyglobin® [hemoglobin glutamer-200 (bovine)]
are registered trademarks of Biopure Corporation
Hemopure® Polymerization
Native Hb
Red Blood Cells
Hemoglobin®
+
(Bovine Derived)
tetramer 64 kD
dimer 32 kD
Stabilized Tetramer
64 kD
Polymer
(Hemopure®)
(Oxyglobin®)
Average 250 kD
Hemopure® Stability: MetHb
12
10
8
% MetHb
4 0 °C
H 8 C 0 0 3 ( 4 0 °C )
6
H 8 C 0 0 5 ( 4 0 °C )
H 8 C 0 0 6 ( 4 0 °C )
4
S p e c ific a t io n
2
0
0
5
10
15
20
25
30
35
40
12
10
%MetHb
RT
H 8 C 0 0 3 ( RT)
8
H 8 C 0 0 5 ( RT)
6
H 8 C 0 0 6 ( RT)
S p e c ific a t io n
4
2
0
0
5
10
15
20
25
30
35
40
12
% MetHb
10
2 - 8 °C
8
H 8 C 0 0 3 ( 2 - 8 °C )
6
H 8 C 0 0 5 ( 2 - 8 °C )
H 8 C 0 0 6 ( 2 - 8 °C )
4
S p e c ific a t io n
2
0
0
5
10
15
20
25
30
35
40
T im e ( M o s .)
Hemopure® Stability: MW
4 0 °C
% 65 kD
12
10
H8C 003 (40 °C )
8
H8C 005 (40 °C )
6
H8C 006 (40 °C )
4
S p e c ific a t io n
2
0
0
5
10
15
20
25
30
35
40
RT
% 65 kD
12
10
H8C 003 (RT )
8
H8C 005 (RT )
6
H8C 006 (RT )
4
S p e c if ic a t io n
2
0
0
5
10
15
20
25
30
35
40
2 - 8 °C
% MetHb
12
H8C 003 (2- 8 °C )
10
H8C 005 (2- 8 °C )
8
6
H8C 006 (2- 8 °C )
4
S p e c ific a t io n
2
0
0
5
10
15
20
Tim e (M o s .)
25
30
35
40
HBOCs Vs RBCs
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
Hemopure® Reversing Hypoxia
Due to Arterial Stenosis
ADD HEMOPURE
NORMAL
FLOW
95% STENOSIS
30
Tissue
pO2 (torr)
20
10
0
Hemopure’s small size and low viscosity
enables penetration to areas of restricted flow
Horn EP, Standl TG, Wilhelm S, et al. Bovine hemoglobin increased skeletal muscle oxygenation during 95% artificial arterial stenosis.
Surgery (1997);121:411-18.
Hemopure® Oxygen Release
Adapted from Page TC et al. Microvas Rrs 1198;55:54-64.
Hemopure® Tissue pO2
MEAN OBSERVED GROUP VALUES: 50% Tissues pO2 (mmHg)
Adapted from Standl TG et al. Can J Anaesth 1196;43:714-723.
Investigational Indications
Clinical Development
Phase I
Phase II
Phase III
Regulatory
Filing
Regulatory
Approval
Product
Sales
Leading
HBOC
SURGERY
General (S Africa)
Hemopure®
Orthopedic (US)
Hemopure®
Orthopedic (EU)
Hemopure®
Cardiopulmonary Bypass
Hemopure®
Aortic Aneurysm Recon.
Hemopure®
TRAUMA
Emergent
PolyHeme®
CANCER
Adjunct to Radiotherapy
ISCHEMIA
Cardiac
CNS
Hemopure®
Hemopure®
Hemopure®
Hemopure®
Depth of Clinical Experience
## Studies
Studies
Type
Type
Hemopure
Hemopure
Patients
Patients (n)
(n)
4
Healthy Volunteers
64
29
45-140
4
Non-Surgery
34
14
43-1230
3
Surgery with ANH*
31
36
36-98
6
General Surgery
120
70
27-245
1
Military Surgery Trial
26
25
300
4
Major Surgery Trials
531
487
120-300
806**
661
27-1230
22
Control
Control
Patients
Patients (n)
(n)
Maximum
Maximum Total
Total Dose
Dose
(g
(g Hemopure)
Hemopure)
* 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
•Ongoing Phase III
• Scale:
20 Level I trauma centers
• Size:
700+ patients expected
• Control:
Standard of care (Ringers Lactate)
• Endpoint:
Improved survival
• Ethics:
Exception from informed consent
(21 CFR 50.24 federal regulations
on clinical research in emergency
settings)
Hemopure®: % Patients Avoiding RBC’s
59%
43%
34%
≥35%
27%
≤≤ 33 units
units
≤≤ 44 units
units
≤≤ 77 units
units
≤≤ 10
10 units
units
≤≤ 33 days
days
≤≤ 44 days
days
≤≤ 66 days
days
≤≤ 66 days
days
CARDIAC
VASCULAR
GENERAL
ORTHOPEDIC
Phase III
Phase III
Phase II
Phase II
98 Patients
72 Patients
160 Patients
593 Patients
Compassionate Uses
Pivotal trial
efficacy
endpoint
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
Occupying Plasma Space
Severe
Anemia
Anemia
treatment
Acts as Oxygen Bridge™
100%
Tissue Oxygenation
“Oxygen Bridge”
0%
Days
Side Effects
Critical Level
of Oxygen
Deprivation
Hemopure®: Clinical Side Effects
• GI symptoms
Symptom
Symptom
pp value
value
HBOC
HBOC (%)
(%)
Control
Control (%)
(%)
N
N 797
797
N
N 661
661
141 (17%)
49 (7%)
<.0001
48 (6%)
7 (1%)
<.0001
125 (16%)
127 (19%)
.0820
Diarrhea
63 (8%)
32 (5%)
.0190
Flatulence
52 (7%)
14 (2%)
<.0001
Abd Discomfort
Dysphagia
Constipation
Source: ISS AE Com. 1
Hemopure®: Clinical Side Effects
• GI symptoms
• Blood pressure response
Symptom
Symptom
BP Increase
Source: ISS AE Com. 1
HBOC
HBOC (%)
(%)
Control
Control (%)
(%)
N
N 799
799
N
N 661
661
168 (21%)
64 (10%)
pp value
value
<.0001
Hemopure®: Clinical Side Effects
• GI symptoms
• Blood pressure response
• Lipase and AST changes
Symptom
Symptom
pp value
value
HBOC
HBOC (%)
(%)
Control
Control (%)
(%)
N
N 799
799
N
N 661
661
Lipase Increased
48 (6%)
12 (2%)
.0001
Amylase Increased
15 (2%)
13 (2%)
1.000
AST
34 (4%)
12 (2%)
.0098
ALT
20 (3%)
10 (2%)
.1992
Source: ISS AE Com. 1
Hemopure®: Clinical Side Effects
•
•
•
•
GI symptoms
Blood pressure response
Amylase and AST changes
Skin/Sclera discoloration
Symptom
Symptom
Discoloration
(Jaundice)
Source: ISS AE Com. 1
HBOC
HBOC (%)
(%)
Control
Control (%)
(%)
N
N 797
797
N
N 661
661
161 (20%)
6 (1%)
pp value
value
<.0001
Hemopure®: Treatment-Emergent
Adverse Events
(Integrated data from 19 studies, not including pivotal Phase III trial)
Number of Subjects
Hemopure
(n=421 patients)
Comparators **
(n=298 patients)
Deaths
3%
3%
Other Serious AEs*
21%
19%
Overall Incidence of AEs
90%
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
PolyHeme®: Treatment-Emergent
Adverse Events
Previous Trials*
• Scale:
5 trials
• Size:
300+ patients
• Side effects:
No organ toxicities
No systemic hypertension
No pulmonary hypertension
* 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 no
refrigeration, 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
Pretreatment
HBOC-201
(n = 350)
Highest
Value Posttreatment
Largest
Increase
Pretreatment
RBC
(n =338)
Highest
Value Posttreatment
P-value*
Largest
Increase
Systolic
Blood Pressure
Mean
SE
Median
Range
136.5
1.2
136.0
90-206
159.8
1.1
160.0
106-234
23.9
1.3
23.0
-33-90
137.0
1.3
136.0
95-222
150.7
1.0
150.0
110-221
14.0
1.4
12.0
-79-110
< 0.0001
Diastolic
Blood Pressure
Mean
SE
Median
Range
76.5
0.7
78.0
50-110
89.2
0.6
90.0
55-131
12.5
0.8
11.0
- 20-46
77.1
0.8
78.0
48-120
83.9
0.5
82.0
60-114
6.9
0.9
8.0
-44-50
< 0.0001
Mean
Arterial Pressure
Mean
SE
Median
Range
96.5
0.7
96.7
63.3-136.7
110.7
0.6
110.0
75.3-150.0
14.4
0.8
14.0
-18.353.3
97.0
0.8
96.0
66.7-150.0
104.2
0.6
103.7
77.3-143.3
7.3
0.9
6.7
-56.056.7
< 0.0001
Source: HEM 115 Study Report