ANNUAL REPORT 2002
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Item 1. Business
Biopure develops, manufactures and markets oxygen therapeutics, a new class of pharmaceuticals that
are administered intravenously into the circulatory system to increase oxygen transport to the body's tissues.
Using its patented and proprietary technology, the Company has developed and manufactures two products:
Hemopure [hemoglobin glutamer — 250 (bovine), or HBOC-201] for human use, and Oxyglobin [hemoglobin
glutamer — 200 (bovine), or HBOC-301] for veterinary use.
Hemopure is a first-in-class product that is approved in South Africa for the treatment of adult surgical
patients who are acutely anemic, and for the purpose of eliminating, delaying or reducing the need for
allogenic red blood cells in these patients. On July 31, 2002, Biopure submitted a biologic license application
(BLA) to the U.S. Food and Drug Administration seeking regulatory approval to market Hemopure in the
United States for a similar indication in patients undergoing orthopedic surgery. The FDA has accepted and is
reviewing this application.
Biopure is also developing Hemopure for potential use in trauma and other medical applications. In
September 2002, the U.S. Department of the Army awarded Biopure a $908,900 grant for a standard therapy
controlled, Phase II clinical trial evaluating the safety and tolerability of the product in trauma patients. The
Company has identified trauma as its next clinical development priority and is working with a committee of
independent civilian and military trauma experts to broaden its trauma program.
Oxyglobin is the only product of its kind approved in the United States and the European Union, where it
is indicated for the treatment of anemia in dogs, regardless of the cause of the anemia.
During 2002 Biopure also completed plant expansions designed to increase the Company's design
capacity to approximately 75,000 Hemopure units or 262,000 Oxyglobin units. Upon future validation and
regulatory approval of a newly installed product fill process, these expanded facilities will be designed to
produce up to approximately 100,000 Hemopure units or 350,000 Oxyglobin units per year, or any
combination of the two products. Biopure also signed a lease, contingent upon financing, in December 2002 for
a proposed manufacturing facility that, when constructed, is designed to produce up to 500,000 Hemopure
units per year.
Biopure was incorporated in Delaware in 1984. Biopure maintains a website at the following Internet
address: www.biopure.com. Through a link to a third-party content provider, this corporate website provides
free access to Biopure's annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on
Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the
Securities Exchange Act of 1934 as soon as reasonably practicable after electronic filing with the Securities
and Exchange Commission.
Biopure®, Hemopure®, and Oxyglobin® are registered trademarks of Biopure.
Scientific Overview
Oxygen is indispensable to the life of all of the body's tissues. Hemoglobin, a protein normally contained
within red blood cells, is the molecule responsible for carrying and releasing oxygen to the body's tissues.
Hemoglobin's protein structure is similar in many different animal species, including humans. Under normal
conditions, hemoglobin contained within red blood cells carries approximately 98 percent of the body's oxygen
and the remaining two percent is dissolved in the plasma, the fluid part of blood.
As the heart pumps blood, hemoglobin within red blood cells takes up oxygen in the lungs and carries it to
various parts of the body. Blood travels through progressively smaller blood vessels to the capillaries, some of
which are so narrow that red blood cells can only pass through in single file. Most of the oxygen release occurs
in the capillaries. Blood then returns to the lungs to reload the red blood cells with oxygen. Adequate blood
pressure and red blood cell counts are crucial to this process. Oxygen deprivation, even for several minutes,
can result in cell damage, organ dysfunction and, if prolonged, death.
The causes of inadequate tissue oxygenation generally can be classified into three categories:
- anemia — insufficient hemoglobin, reducing the oxygen-carrying capacity of the blood. Blood loss from
injury, surgery or disorders that affect red blood cell production or maintenance, such as bone marrow
disease, can cause anemia;
- ischemia — localized, inadequate red blood cell flow. Obstructed or constricted blood vessels can result
in ischemia. Ischemia can lead to stroke, heart attack or other organ or tissue dysfunction; and
- cardiopulmonary failure — impaired function of the heart or lungs. The heart's inability to pump
sufficient quantities of blood to meet the needs of the tissues or the failure of the lungs to oxygenate
blood adequately can cause tissue damage.
A red blood cell transfusion is the standard therapy for anemia resulting from blood loss. Sources of red
blood cells for transfusions include stored supplies of donated blood or of the recipient's own pre-donated
blood. Health care professionals also may use medications that stimulate red blood cell production if anemia is
anticipated, for example, as a result of planned surgery.
Red blood cell transfusions have certain risks and limitations. As HIV, hepatitis, West Nile Virus and
other pathogens have contaminated portions of the world's blood supply, the need for a purified, pharmaceutical
quality blood product has become increasingly apparent. There is currently no 100 percent effective
method for detecting blood-borne diseases or for sterilizing donated blood. As a result, the risk of disease
transmission from donated blood is an ongoing concern to physicians and patients. Handling errors in typing
and cross-matching blood, as well as the inadvertent introduction of pathogens, can also have significant
medical consequences. Blood typing and handling requirements, particularly refrigeration, limit the feasibility
of using red blood cell transfusions in pre-hospital emergency treatment situations. Shortages of certain types
of blood can occur due to seasonal factors or disasters. Donated red blood cells are available for use in
transfusions for only 42 days after collection and this limitation affects the ability to stockpile red blood cell
supplies. Although freezing can extend the life of red blood cells, the freezing and thawing processes require
chemical treatment of the red blood cells and reduce the efficacy of those red blood cells. Finally, the longer
red blood cells are stored, the longer it takes them to reach their maximum oxygen-releasing capacity and the
more they break down, limiting their effectiveness in delivering oxygen. Red blood cells lose approximately
75 percent of their immediate oxygen-releasing ability after eight days of storage. Blood banks generally
release the longest stored blood first to prevent outdating after 42 days.
Red blood cell transfusions generally are not effective for ischemic conditions caused by blockage. In
such situations, an obstructed or constricted blood vessel that is too narrow to permit the normal passage of red
blood cells can prevent oxygen from reaching the body's tissues. Similarly, red blood cell transfusions are
generally not effective in overcoming poor oxygenation due to impaired heart or lung function.
In trauma situations, victims may experience massive bleeding resulting in rapid loss of blood volume and
oxygen-carrying capacity. Existing alternatives to red blood cell transfusions are limited. In an effort to
stabilize trauma patients, emergency caregivers typically administer commonly used intravenous fluids, such
as Ringer's lactate or saline. Ringer's lactate consists of water and electrolytes and generally is administered to
patients who have lost substantial amounts of bodily fluids as a result of bleeding, vomiting or diarrhea. Both
Ringer's lactate and saline restore blood volume, but do not carry oxygen.
For anemia in non-acute situations, there are currently two biological products on the market. Both of
these products are formulations of a protein called erythropoietin. Erythropoietin stimulates the body's ability
to produce red blood cells. In a surgical setting, these products are administered in anticipation of blood loss
during surgery, thereby potentially reducing the need for red blood cell transfusions. However, erythropoietin
does not deliver oxygen to the body's tissues and does not act as a blood volume expander. As a result, these
products are not effective in treating acute blood loss and are generally not used in cases of unplanned
surgeries or emergency need. In addition, the labels on these products caution against their use in patients
undergoing cardiac surgery.
Biopure's Oxygenation Technology
Biopure has two proprietary oxygen therapeutic products that are identical except for their molecular size
distributions. Biopure defines its products as therapeutics because they remediate oxygen deprived tissues.
One administers these products intravenously. Biopure's products are made from hemoglobin that has been
extracted from bovine red blood cells and then purified, chemically modified and cross-linked for stability. The
resulting hemoglobin solutions do not contain red blood cells and are formulated in a balanced salt solution
similar to Ringer's lactate for the final product.
The average Hemopure molecule is less than 1/1000th the size of a red blood cell. Once infused into a
patient, the Hemopure molecules disperse throughout the entire plasma space and are in continuous contact
with the blood vessel wall where oxygen transport to tissues takes place.
Upon infusion into the bloodstream, Hemopure immediately turns the plasma into an oxygen-delivering
substance. Plasma containing Hemopure flows everywhere that blood ordinarily flows and can also bypass
partial blockages or pass through constricted vessels that impede the normal passage of red blood cells.
In addition, introducing Hemopure into the bloodstream may enable red blood cells to release more
oxygen to the tissues than they otherwise would. In addition to delivering oxygen to tissues, Hemopure also
acts as a blood volume expander and may support the body's ability to produce red blood cells.
Hemopure molecules hold the same amount of oxygen as the hemoglobin molecules in red blood cells on
a gram-for-gram basis. Hemopure molecules, however, are chemically modified to have less affinity for oxygen
than red blood cells, enabling Hemopure to take up oxygen from the lungs and release it to tissues more
efficiently than red blood cells. Human hemoglobin, unlike bovine hemoglobin, depends on the action of 2,3
diphosphoglycerate, or 2,3 DPG, a substance found in high concentrations only within the red blood cell, for
optimal onloading and offloading of oxygen to tissues. The 2,3 DPG breaks down rapidly in stored blood
causing red blood cells to lose approximately 75 percent of their ability to immediately release oxygen after
eight days of storage. The 2,3 DPG breakdown reduces the oxygen offloading efficiency of transfused red blood
cells until 2,3 DPG levels are restored, a process that can require hours. Biopure's bovine hemoglobin permits
the efficient offloading of oxygen in the absence of 2,3 DPG, thereby allowing Hemopure to be at its optimal
oxygen offloading effectiveness immediately upon infusion.
Hemoglobin molecules in different species have demonstrated low antigenicity, which means that they do
not readily elicit an immune or allergic response. Biopure has confirmed Hemopure's low antigenicity, as
indicated by the absence of certain effects, through studies in the laboratory, not involving living beings, and in
living animals and humans.
The following chart lists Hemopure's characteristics in comparison to transfused red blood cells:
| Characteristic |
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Hemopure |
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Transfused Stored Red Blood Cells |
| Onset of action |
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Immediate Ì not 2,3 DPG-dependent |
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Initially limited Ì 2,3 DPG dependent |
| Oxygen affinity |
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More efficient oxygen release to tissue |
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Less efficient oxygen release to tissue |
| Oxygen transport |
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Red blood cells and Hemopure molecules in plasma |
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Red blood cells; plasma a minor contributor |
| Risk of disease transmission |
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Product purity maintained through raw material controls and a reproducible and controllable pharmaceutical manufacturing process that is validated to remove potential pathogens; no leukocyte, or white blood cell, exposure |
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Risk minimized by testing, donor selection and administration protocols and ongoing surveillance for emerging pathogens; leukocyte exposure |
| Storage |
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Room temperature; no loss of efficacy |
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Refrigeration required; loss of efficacy |
| Shelf life |
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36 months |
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42 days |
| Compatibility |
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Universal |
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Type-specific |
| Preparation |
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Ready-to-use |
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Requires typing and cross-matching |
| Viscosity |
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Low |
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High |
| Raw material source |
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Controlled |
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Not controlled |
| Duration of action (time the product remains active in the body) |
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One to three days, depending on dose |
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Estimated 60 to 90 days |
In addition to Hemopure's use as an alternative to red blood cell transfusions in surgery, human clinical
testing and preclinical studies suggest that Hemopure also could be a readily available therapeutic with other
potential applications. These applications may include the treatment of trauma and ischemic conditions, such
as stroke and heart attack. Hemopure may also improve the effectiveness of radiation and chemotherapy
against malignant hypoxic tumors.
Hemopure has a 36-month shelf life without refrigeration (2º to 30º centigrade), is universally
compatible and can be stocked well in advance of anticipated use. Consequently, when blood is not available,
Hemopure could be used to maintain a patient until the needed type and quantity of red blood cells arrive,
until the patient can be transported to a hospital or until a patient's body replenishes its own red blood cells.
We refer to use in these contexts as an Oxygen Bridge™. Hemopure may be particularly well suited for this
Oxygen Bridge function because the duration of action of an infusion of a single unit is between one and two
days with 50 percent of the Hemopure molecules retained in the circulatory system for 19 to 24 hours
following administration. In clinical trial data, Biopure observed that dosing with more than one unit or the
redosing of Hemopure over several days can prolong Hemopure's "Oxygen Bridge" effect.
Transfused red blood cells have some advantages when compared to Hemopure. Transfused red blood
cells have a longer duration of action and can persist in the body for an estimated 60 to 90 days. Hemopure, on
the other hand, has a half-life of up to one day and, depending on the amount infused, may require repeat
administration. In addition, it is anticipated that Hemopure will be more expensive to use than transfused red
blood cells.
Strategy
Biopure intends to develop, manufacture and market oxygen therapeutics through the following strategy:
- Develop and Commercialize Hemopure as a Treatment for Acute Anemia in Patients Undergoing
Surgery. Biopure's advanced clinical trials have demonstrated Hemopure's efficacy as an alternative
to red blood cell transfusions in the treatment of acute anemia in patients undergoing elective
orthopedic surgery. While Biopure does not anticipate that Hemopure will replace all red blood cell
transfusions, the Company believes that Hemopure's use in orthopedic surgery and its use in other
types of surgery in South Africa demonstrates the product to be a safe and effective oxygen
therapeutic.
- Pursue Marketing Approvals. Biopure will seek to register its oxygen therapeutics internationally.
- Pursue Approvals of Hemopure for Additional Therapeutic Applications. Because of Hemopure's
unique physical and clinical characteristics, Biopure intends to develop it for multiple medical
applications, including trauma, ischemic conditions such as stroke and heart attack, and as an adjunct
therapy for malignant hypoxic tumors.
- Increase Market Awareness of Hemopure. Biopure intends to increase market awareness of
Hemopure by identifying the issues and benefits of oxygen therapeutics in patient management and
implementing professional education programs targeted at the medical community.
Biopure's Products
Our two products are oxygen therapeutics. Hemopure is our product for human use. In fiscal year 2002,
we filed an application with the FDA seeking regulatory approval to market Hemopure in the United States
for the treatment of the signs and symptoms of acute anemia in adult patients undergoing orthopedic surgery,
and for the purpose of eliminating or reducing the need for red blood cells in these patients. The FDA and the
European Commission have approved the use of Oxyglobin, our veterinary product, for the treatment of
anemia in dogs, regardless of cause. Oxyglobin is marketed and sold to veterinary hospitals in the United
States and Europe. We have tested Hemopure in clinical trials involving more than 1450 humans, of whom
more than 800 were administered Hemopure. On a "compassionate use" basis, Hemopure has been
administered as an Oxygen Bridge to more than 40 human patients with life threatening anemia when
compatible red blood cells were unavailable or unacceptable. Hemopure and Oxyglobin have been tested in
180 completed preclinical studies involving animals from 10 species. Commercial sales of Oxyglobin have
resulted in thousands of administrations in animals. The overall incidence of adverse events reported in the
United States and Europe for Oxyglobin is less than 0.05 percent.
Hemopure
We believe Hemopure can be developed for several indications. As described below, the first indication
we are seeking is for the treatment of acute anemia in surgery patients undergoing orthopedic surgery, as an
alternative to red blood cell transfusions. Preclinical studies and observations from completed trials show that
general surgery, trauma, ischemic conditions such as stroke and heart attack, and malignant hypoxic tumors
might be possible additional indications for clinical development.
Red Blood Cell Transfusion Alternative
Hemopure serves as an alternative to red blood cell transfusions by providing a temporary Oxygen Bridge
until suitable red blood cells become available or are produced by the body. We do not expect Hemopure to
replace all red blood cell transfusions. However, Hemopure's oxygen-carrying properties, storage and infusion
advantages address many of the limitations associated with red blood cell transfusions.
Biopure's clinical trials have demonstrated Hemopure's efficacy as an alternative to red blood cell
transfusions in patients undergoing elective orthopedic surgery as measured by the avoidance of red blood cell
transfusions. In all of Biopure's advanced clinical trials, Hemopure's efficacy as an oxygen therapeutic was
evaluated by determining, within the context of a written set of guidelines known as a protocol, the percentage
of patients given Hemopure who did not require a subsequent transfusion of red blood cells. In these trials,
Hemopure was administered only to patients who needed a red blood cell transfusion. Trial design limited the
amount of Hemopure that could be infused and the number of post-operative days during which it could be
infused. Under this protocol, Hemopure's clinical trials that have been completed and analyzed demonstrate
clinically significant elimination of red blood cell transfusions. Elimination was deemed to occur if the patient
did not require a subsequent red blood cell transfusion. Elimination was deemed not to occur if the patient was
administered a red blood cell transfusion for any reason.
The following chart summarizes the advanced clinical trials that Biopure has completed for Hemopure as
an alternative to red blood cell transfusions. The column labeled "Results" lists efficacy results.
U.S. Phase III Orthopedic Surgery Trial. Biopure's application to the FDA for approval to market
Hemopure includes two Phase III trials. The U.S. Phase III trial was in elective orthopedic surgery. Elective
orthopedic surgery includes non-emergency surgery involving bones and joints, including spinal surgery and
the repair of orthopedic fractures in stabilized trauma patients. The primary efficacy objective of this trial was
the avoidance of red blood cell transfusions for six weeks after orthopedic surgery. The safety objective of the
U.S. Phase III trial is that patients treated with Hemopure have outcomes no worse than patients treated with
red blood cells per the statistical methodology defined in the study analysis plan. Biopure designed this
randomized, red blood cell controlled, multi-center study to enroll a total of 640 patients in the United States,
Europe, Canada and South Africa, of whom approximately one-half would be in the Hemopure treatment
group and the other half would receive red blood cells. Final enrollment was 688 patients. Up to 300 grams of
hemoglobin, or ten units of Hemopure, could be infused before, during or after surgery for a total of up to six
treatment days. The efficacy objective of this trial, the elimination of red blood cell transfusions in at least
35 percent of the patients who received Hemopure, was achieved.
Non-U.S. Phase III Non-cardiac Surgery Trial. Biopure completed a Phase III trial in Europe and
South Africa in 1998 in non-cardiac surgery. Non-cardiac surgery refers to surgery that does not involve the
heart and can include surgery of the digestive or urinary tract as well as orthopedic surgery. The primary
objective of this trial was the avoidance of red blood cell transfusions for 28 days after non-cardiac surgery.
This randomized, red blood cell controlled, multi-center study enrolled 160 patients, 83 of whom were infused
with Hemopure. Up to 210 grams of hemoglobin, or seven units of Hemopure, were permitted during a six-day
treatment period. The trial resulted in the clinically significant elimination of red blood cell transfusions in
43 percent of the patients who received Hemopure in the intent-to-treat population.
U.S. Phase II Post-Cardiopulmonary Bypass Surgery Trial. A randomized, double-blind, red blood cell
controlled, multi-center study in post-cardiopulmonary bypass surgery patients was completed in 1997. During
cardiopulmonary bypass surgery, patients are connected to a heart and lung machine that replaces functions of
the heart and lungs during surgery. The primary objective of this trial was the avoidance of red blood cell
transfusions for 28 days after surgery. The study treated 98 patients, 50 of whom were infused with Hemopure.
Up to 120 grams of hemoglobin, or four units of Hemopure, were administered over a three-day treatment
period following surgery. The trial resulted in the clinically significant elimination of red blood cell
transfusions in 34 percent of the patients that received Hemopure. In this study, 100 percent of the patients
who received Hemopure did not require any red blood cells during the day of surgery.
Additionally, we observed that the hematocrit, which is a measure of the packed red blood cell volume as
a percentage of total blood volume, of the patients treated with Hemopure recovered to a degree that was
similar to the red blood cell treated patients at both six and 28 days post-surgery. This trial was reported in the
Journal of Thoracic and Cardiovascular Surgery, July 2002.
U.S. Phase II Aortic Aneurysm Reconstruction Surgery Trial. In 1998, Biopure completed a randomized,
red blood cell controlled, multi-center trial in abdominal aortic aneurysm reconstruction surgery. Aortic
aneurysm reconstruction surgery involves repairing a damaged segment of the aorta, the body's principal
artery. This study treated 72 patients, 48 of whom were infused with Hemopure. The maximum dosage was
150 grams of hemoglobin, 30 grams more than the post cardiopulmonary bypass trial. Usually aortic aneurysm
reconstruction surgery involves much more blood loss than post cardiopulmonary bypass surgery. In this trial,
Hemopure was used during the surgery in contrast to the post cardiopulmonary bypass trial, where use began
after surgery. The trial resulted in the clinically significant elimination of red blood cell transfusions in
27 percent of the patients that received Hemopure. The trial was reported in the Journal of Vascular Surgery,
February 2000.
In these four red blood cell controlled trials, adverse events that occurred in the Hemopure-treated group
of patients (n=531) at greater than or equal to 5 percent increased incidence versus the control group
(n=487) were anemia (low red blood cell count), abdominal pain, dysphagia (difficulty swallowing), nausea,
vomiting, jaundice (transient yellow skin discoloration not generally associated with liver dysfunction),
increased lipase (metabolic enzyme), oliguria (low urine output), hypertension (mild to moderate increase in
blood pressure) and tachycardia (rapid heart rate).
Trauma
We believe that Hemopure could be infused at the site of a crash, potentially extending the time that a
trauma patient could be supported awaiting hospital care. Hemopure is also a blood volume expander, a
common therapy used to stabilize trauma patients. To facilitate a clinical development program for Hemopure
in trauma, we conducted a Phase II trial in non-cardiac surgery patients. This 51-patient trial was conducted
at the University of Texas at San Antonio Health Service Center, Brooke Army Medical Center and Wilford
Hall Air Force Hospital. In this controlled and randomized study, investigators infused patients on a
randomized basis with Hemopure, or Ringer's lactate, the control treatment, based on the estimated amount
of blood the patient had lost. Biopure has convened a panel of experts, including experts in the U.S. military,
to advise us in the design of a trauma program and study.
Preclinical animal studies performed in academic and military research laboratories have shown the
benefit of using Hemopure in situations involving severe trauma, hemorrhagic shock, hemorrhagic shock with
tissue injury and resuscitation from cardiac arrest resulting from severe hemorrhage.
An abstract published in the The Journal of Trauma in January 2000 and presented at the 30th Annual
Scientific Meeting of the Western Trauma Association on March 1, 2000 described a preclinical study using a
pre-hospital hemorrhagic shock model designed to simulate what happens to humans after an accident. The
study demonstrated that resuscitation using small volumes of Hemopure can restore and sustain brain
oxygenation, blood pressure and cardiac output following severe hemorrhagic shock.
Ischemia
The ability of Hemopure molecules to circumvent partial occlusions could potentially benefit patients
suffering from ischemic conditions by supplying oxygen to tissues that are receiving inadequate numbers of red
blood cells. Inadequate tissue oxygenation due to partial vessel blockage or constriction can cause heart
attack, angina and transient ischemic attack, which is a precursor to stroke. In these situations, treatment with
red blood cell transfusions would not be effective because red blood cells are too large to navigate around
blockages. Biopure has completed preclinical studies with results supporting these potential indications. One
preclinical study demonstrated that Hemopure sustained heart tissue oxygenation and heart function during
90 percent constriction of a coronary artery.
Cancer Therapy Adjunct
Radiation therapy and many types of chemotherapy depend on the adequate oxygenation of tumors to kill
cancer cells. Malignant cancer tumors, such as brain, breast, prostate and other solid tumors, are dense tumors
which often outgrow their blood supply, leaving much of the tumor without oxygen. Consequently, they resist
chemotherapy and radiation treatment. We collaborated with the Dana-Farber Cancer Institute in Boston to
develop a patented method for oxygenating oxygen deficient tumor cells, referred to as "hypoxic" that
potentially could increase the tumor-killing effects of radiation and chemotherapy. Studies in animals have
shown the feasibility of this application. In 1999, Biopure initiated clinical development of this indication,
specifically the treatment of brain tumor (glioblastoma). Enrollment in a Phase I clinical trial of patients
diagnosed with glioblastoma was completed in 2001. Biopure has identified further cancer trials as its next
priority after trauma.
Oxyglobin
Oxyglobin is identical to Hemopure except for its molecular size distribution. The FDA Center for
Veterinary Medicine approved Oxyglobin in 1998 and the European Commission approved Oxyglobin in 1999,
in both cases for the treatment of canine anemia, regardless of the cause of the anemia. Anemia in dogs often
results from blood loss, disease or ineffective red blood cell production. Oxyglobin sales were $2.0 million in
fiscal 2002, $3.5 million in fiscal 2001 and $3.1 million in fiscal 2000. The decline in 2002 sales is attributable
to the Company's expansion of manufacturing capacity and resultant need for regulatory approval to ship
product manufactured at its facilities post-expansion.
As of December 31, 2002, we had $1.3 million in backorders, believed to be firm, for Oxyglobin. There
was no backlog as of December 31, 2001. All of the backlog is expected to be filled in fiscal year 2003.
Manufacturing
We use proprietary and patented purification and polymerization processes in the manufacture of our
oxygen therapeutic products. Biopure's scientific and engineering team has designed and built much of its
large-scale critical equipment. Proprietary computer logic controls operate and monitor most aspects of this
process. Biopure has produced both Hemopure and Oxyglobin since 1991.
Raw Material Source
Our products consist of bovine hemoglobin that has been purified, chemically modified and cross-linked
for stability. Controlled herds of U.S. cattle raised for meat provide the raw material, bovine hemoglobin, used
in our products. Cattle must meet the requirements of a herd management program we have in place to
confirm origin, health, feed and quality of the cattle to be used as a raw material source. These safety
standards are not and cannot be established for donated human blood. Suppliers to Biopure contract to
maintain traceable records on animal origin, health, feed and care to assure the use of known, healthy animals.
The U.S. Department of Agriculture, or USDA, deems the United States to be free of pathogens associated
with "mad cow disease."
Raw Material Collection
We collect bovine whole blood into individual presanitized containers at an abattoir. We then transport
the containers to a separation facility. Prior to collection, the animals undergo live inspection. Then, following
blood collection, the animal carcass undergoes USDA inspection for use as beef for human consumption. If an
animal carcass is retained for further inspection for final disposition by the USDA veterinarian, we reject the
corresponding container of whole blood.
Safety
Our patented purification and manufacturing process has been validated to remove potential pathogens, if
present, including bacteria, viruses such as those leading to hepatitis and AIDS, and the transmissible
spongiform encephalopathies (TSE) that cause rare neurological disorders such as "mad cow disease" and its
human equivalent. Health and regulatory authorities have given guidance directed at three factors to control
these diseases: source of animals, nature of tissue used and manufacturing process. We comply with, and
believe we exceed, all current guidelines regarding such risks for human pharmaceutical products. Our source
is controlled, U.S. source bovine red blood cells do not carry BSE and our process has been shown to remove
all measurable quantities of prions, were they present. Bovine red blood cells do not contain prions, the
proteins necessary for transmissible spongiform encephalopathies. In addition, in fiscal 2001 the European
Directorate for the Quality of Medicines (EDQM) granted a "Certification of Suitability of Monographs of
the European Pharmacopoeia" for our veterinary product, Oxyglobin. This certification is required for all
human and veterinary medicinal products that are manufactured from ruminant materials and marketed in the
European Union, and it represents the Council of Europe's official acknowledgment of the acceptability of
Oxyglobin with regard to transmissible spongiform encephalopathy agents.
Manufacturing Processes
A cell washing filtration process removes plasma proteins in the bovine blood. Washed cells are next
placed in a centrifuge that separates the red blood cells from other, remaining blood components. The
hemoglobin is extracted from the red blood cells and is then diafiltered to remove red blood cell wall debris
and other contaminants. The resulting material is a cell-free hemoglobin intermediate. A semi-continuous
purification process involving a high performance liquid chromatography process purifies the hemoglobin
intermediate. Next, the purified hemoglobin is polymerized, or linked, by the addition of a cross-linking agent.
Polymerized and stabilized material is placed into a physiologic solution, then fractionated if required, and
concentrated. The final product is filtered into sterilized batch holding tanks until it is sterile filled into bags.
Marketing
Hemopure
Biopure expects to market Hemopure initially to hospitals. Biopure recognizes that it is crucial to
establish a core understanding among opinion leaders that Hemopure fills an important medical need and that
systematic development of opinion leader advocacy is necessary for capturing and maintaining a leadership
position. Biopure expects to use publications and educational forums, such as seminars and presentations at
meetings of medical specialists. Biopure has engaged a distributor for sales in South Africa. Biopure has
trained approximately 400 doctors and nurses in South Africa in the use of the product and is continuing to
train individuals there who wish to use it.
Biopure will explore various means of selling Hemopure elsewhere. Among other options, the Company
may seek to enter into licensing or co-marketing agreements for parts or all of the world. Alternatively, it could
engage "contract" sales organizations from vendors, contract pharmaceutical companies that supply sales
services or recruit and train its own marketing and sales force.
Oxyglobin
Biopure estimates that there are at least 15,000 small animal veterinary practices in the United States,
another 4,000 mixed animal practices treating small and large animals in the United States and approximately
22,000 small animal practices in Europe. Biopure believes that the average veterinary practice treats only a
small percentage of canine anemia cases with a red blood cell transfusion. The remainder receive either cage
rest or a minimally effective treatment such as fluid administration, iron supplements, nutritional supplements
or inspired oxygen.
Biopure sells Oxyglobin to veterinarians in the United States through veterinary product distributors Ì
one national and seven regional. Orders are drop shipped by Biopure directly. In Europe, Oxyglobin is
imported by a pharmaceutical company that releases each lot through its quality assurance personnel. It is
then purchased by distributors and wholesalers and resold to veterinarians.
Marketing programs in both the United States and Europe have included advertising, direct mail,
educational seminars, conference calls, lectures at congresses and attendance at trade shows. Biopure has
established a core group of veterinary practices in the United States and Europe that use the product regularly.
These veterinarians are effective advocates of the product when interacting with other veterinarians.
Competition
Hemopure will compete with traditional therapies and with other oxygen delivery pharmaceuticals.
Comparisons with traditional therapies, including red blood cell transfusions, are described under "Ì Scientific
Overview," "Ì Biopure's Oxygenating Technology" and "Ì Biopure's Products." In addition, cost may
be a competitive factor in traditional therapies.
Oxygen therapeutics under development fall into two categories:
- hemoglobin-based oxygen carriers, including Hemopure and Oxyglobin, consist of natural hemoglobin
from an animal or human or genetically engineered source that has been modified to improve stability,
efficacy and safety; and
- perfluorocarbon emulsions are chemicals administered intravenously. Perfluorocarbon emulsions are
effective principally under conditions of high oxygen partial pressure to assist in oxygen delivery by
forcing dissolved oxygen into the plasma space.
We believe that the competitive factors for our oxygen therapeutics will be efficacy, safety, ease of use
and cost. We believe that we have significant advantages as compared to our competitors' pharmaceuticals,
including:
- patents covering our processes, our products and their uses;
- larger molecule size than competitor's hemoglobin based oxygen carriers, resulting in longer duration
of action than some other products under development;
- long-term room temperature stability;
- operational large-scale manufacturing facility;
- ample, controlled raw material source;
- marketing approval in South Africa;
- FDA acceptance for review of a marketing application; and
- FDA and European Commission approvals of Oxyglobin and the facilities that produce it and usage by
veterinarians.
Some of our competitors and potential competitors have greater financial and other resources to develop,
manufacture and market their products. Existing competitors in the development of hemoglobin-based oxygen
therapeutics use outdated human red blood cells or recombinant human hemoglobin as their raw material. We
are aware of two human hemoglobin-based products currently in a pivotal, U.S. Phase III clinical trial or with
applications for approval pending. We are not aware of any competitor that has completed a pivotal,
U.S. Phase III clinical trial of a product as an alternative to red blood cell transfusions in surgery. Biopure
believes that its use of bovine red blood cells is an advantage over products made from outdated donated
human red blood cells because of the availability, abundance, ability to control source, cost and relative safety
of bovine red blood cells. However, the use of bovine derived blood products may encounter resistance from
physicians and patients. Among other things, public perceptions about the risk of "mad cow disease" may
affect market acceptance of Hemopure. We also believe that competitors may find it difficult to make or offer
a hemoglobin-based oxygen carrier product having the product characteristics of Hemopure without infringing
on one or more of our patents. In addition, the relatively low viscosity of Hemopure is a potential advantage for
patients with low blood pressure resulting from blood loss.
Biopure knows of no companies developing oxygen products intended to compete with Oxyglobin in the
veterinary market.
Intellectual Property
Patents, trademarks, trade secrets, technological know-how and other proprietary rights are important to
Biopure's business. We actively seek patent protection both in the United States and abroad. We filed our
initial patent in 1986 in the United States. Five U.S. patents have been issued from this filing. These patents
describe and claim ultra-pure semi-synthetic blood substitutes and methods for their preparation.
In total, we have 21 U.S. patents granted and 11 applications pending relating to our oxygen therapeutics.
Our granted U.S. patents include:
- three patents covering an ultra-purification process for hemoglobin solutions, regardless of the source of
hemoglobin, two of which expire in 2006 and one of which expires in 2014; two patents covering the
ultra-pure oxygen therapeutic solutions produced by this process expiring in 2009; and one patent
covering the chromatography purification of the hemoglobin solution, expiring in 2015;
- three patents regarding compositions having improved stability, of which two expire in 2015 and the
third expires in 2016, and one patent covering processes for producing these compositions which
expires in 2016;
- three patents, two of which expire in 2015 and one of which expires in 2016, covering improvements in
preservation of such hemoglobin solutions;
- two patents, which expire in 2015 and 2016, covering improved methods for separating polymerized
from unpolymerized hemoglobin;
- one patent, which expires in 2015, covering methods of oxygenating tissue affected by inadequate red
blood cell flow;
- one patent, which expires in 2016, covering the removal of pathogens, if present, from Biopure's source
material; and
- three patents, which expire in 2011, 2014 and 2015, covering methods for treating tumors; and
- one patent, which expires in 2010, covering a sample valve for sterile processing.
We believe that it is not economically practicable to determine in advance whether our products, product
components, manufacturing processes or the uses of our products infringe the patent rights of others. It is
likely that, from time to time, we will receive notices from others of claims or potential claims of intellectual
property infringement or we may be called upon to defend a customer, vendee or licensee against such thirdparty
claims. Responding to these kinds of claims, regardless of merit, could consume valuable time, result in
costly litigation, which in turn could harm our business. Responding to these claims also could require us to
enter into royalty or licensing agreements with the third parties claiming infringement. Such royalty or
licensing agreements, if available, may not be available on terms acceptable to us.
Employees
As of January 9, 2003, we employed 249 persons. None of our employees are covered by a collective
bargaining agreement. We believe our relations with our employees are good.
Government Regulation
New Drug or Biologic Approval for Human Use
Governmental authorities in the United States and other countries extensively regulate the testing,
manufacturing, labeling, advertising, promotion, export and marketing, among other things, of Biopure's
oxygen therapeutic products. Any oxygen therapeutic product administered to human patients is regulated as a
drug or a biologic drug and requires regulatory approval before it may be commercialized.
In the United States, Hemopure is regulated as a human biologic.
The steps required before approval of a biologic for marketing in the United States generally include:
- preclinical laboratory tests and animal tests;
- the submission to the FDA of an Investigational New Drug, or IND, application for human clinical
testing, which must become effective before human clinical trials may lawfully commence;
- adequate and well-controlled human clinical trials to establish the safety and efficacy of the product;
- the submission to the FDA of a biologic license application;
- FDA review of the biologic license application; and
- satisfactory completion of an FDA inspection of the manufacturing facilities at which the product is
made to assess compliance with current good manufacturing practices, which include elaborate testing,
control, documentation and other quality assurance procedures.
The testing and approval process requires substantial time, effort and financial resources. After approval
is obtained, a supplemental approval generally is required for each proposed new indication, often accompanied
by data similar to that submitted with the original biologic license application.
Preclinical studies include laboratory evaluation of the product and animal studies to assess the safety and
potential efficacy of the product. The results of the preclinical studies, together with manufacturing
information and analytical data, are submitted to the FDA as part of the IND. The IND automatically
becomes effective in 30 days unless the FDA, before that time, raises concerns or questions and imposes a
"clinical hold." In such a case, the IND sponsor, in our case Biopure, and the FDA must resolve any
outstanding concerns before the trial can proceed. Once trials have commenced, the FDA may stop the trials,
or particular types of trials, by imposing a clinical hold because of concerns about, for example, the safety of
the product being tested or the adequacy of the trial design.
Clinical trials involve the administration of investigational products to healthy volunteers or patients
under the supervision of a qualified principal investigator consistent with an informed consent. An independent
institutional review board, or IRB, or ethics committee must review and approve each clinical trial at each
institution at which the study will be conducted. The IRB or ethics committee will consider, among other
things, ethical factors, the safety of human subjects and the possible liability of the institution.
Clinical trials typically are conducted in three sequential phases, but the phases may overlap. In Phase I,
the initial introduction of the drug into human subjects, the drug is usually tested for safety or adverse effects,
dosage tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics. Phase II clinical
trials usually involve studies in a limited patient population to evaluate the efficacy of the drug for specific,
targeted indications, determine dosage tolerance and optimal dosage and identify possible adverse effects and
safety risks. Phase III clinical trials generally further evaluate clinical efficacy and test further for safety within
an expanded patient population and at multiple clinical sites. Phase IV clinical trials are conducted after
approval to gain additional experience from the treatment of patients in the intended therapeutic indication. If
the FDA approves a product, additional clinical trials may be necessary. A company may be able to use the
data from these clinical trials to meet all or part of any Phase IV clinical trial requirement. These clinical trials
are often referred to as Phase III/IV post-approval clinical trials.
We believe that our completed Phase III clinical trials are consistent with the FDA's guidance on the
design and efficacy and safety endpoints required for approval of products such as Hemopure. However, the
FDA could change its view or require additional data or even further clinical trials prior to approval of
Hemopure.
The results of the preclinical studies and clinical trials, together with detailed information on the
manufacture and composition of the product, are submitted to the FDA in the application requesting approval
to market the product. Before approving a biologic license application, the FDA will inspect the facilities at
which the product is manufactured and will not approve the product unless the manufacturing facility is in
compliance with current good manufacturing practices. The FDA may delay or deny approval of a biologic
license application if applicable regulatory criteria are not satisfied or may require additional testing or
information, and/or require postmarketing testing and surveillance to monitor safety, purity or potency of a
product. It may also limit the indicated uses for which an approval is given.
New Drug Approval for Veterinary Use
New drugs for companion animals must receive New Animal Drug Application, or NADA, approval
prior to being marketed in the United States. The requirements for approval are similar to those for new
human drugs. Obtaining NADA approval requires preclinical studies and clinical field trials and the
submission of an Investigational New Animal Drug Application, which becomes effective upon acceptance for
filing.
Pervasive and Continuing Regulation
Any product approvals that are granted remain subject to continual FDA review, and newly discovered or
developed safety or efficacy data may result in withdrawal of products from the market. Moreover, if and when
FDA approval is obtained, the manufacture and marketing of our products remain subject to extensive
regulatory requirements administered by the FDA and other regulatory bodies, including continuing compliance
with current good manufacturing practices, adverse event reporting requirements and the FDA's general
prohibitions against promoting products for unapproved or "off-label" uses. We are subject to inspection and
market surveillance by the FDA for compliance with these requirements. Failure to comply with the
requirements can, among other things, result in warning letters, product seizures, recalls, fines, injunctions,
suspensions or withdrawals of regulatory approvals, operating restrictions and criminal prosecutions. Any such
enforcement action could have a material adverse effect on us. Unanticipated changes in existing regulations
or the adoption of new requirements also could have a material adverse effect on us.
We are also subject to numerous federal, state and local laws relating to such matters as safe working
conditions, manufacturing practices, environmental protection, fire hazard control and hazardous substance
disposal.
Foreign Regulation
We will be subject to a variety of regulations governing clinical trials and sales of our products outside the
United States and are currently subject to requirements of law in South Africa. We must obtain approval of
our products by the comparable non-U.S. regulatory authorities prior to the commencement of product
marketing in the country whether or not we have obtained FDA approval. The approval process varies from
country to country and the time needed to secure approval may be longer or shorter than that required for
FDA approval. These applications require the completion of extensive preclinical and clinical studies and
manufacturing and controls information.
Reimbursement
Biopure's ability to successfully commercialize its human product will depend in significant part on the
extent to which reimbursement of the cost of such product and related treatment will be available from
government health administration authorities, private health insurers and other organizations. Third-party
payors are increasingly challenging the price of medical products and services. Significant uncertainty exists as
to the reimbursement status of newly approved health care products, and there can be no assurance that
adequate third-party coverage will be available to enable Biopure to maintain price levels sufficient for
realization of an appropriate return on its investment in product development. The public and the federal
government have recently focused significant attention on reforming the health care system in the United
States. A number of health care reform measures have been suggested, including price controls on
therapeutics. Public discussion of such measures is likely to continue, and concerns about the potential effects
of different possible proposals have been reflected in the volatility of the stock prices of companies in the
health care and related industries.
Item 2. Properties
Biopure has manufacturing facilities in Pennsylvania for the collection and separation of blood and in
Cambridge, Massachusetts, where processing is completed. In connection with Biopure's application for
marketing approval for Oxyglobin, and again following the Company's 2002 plant expansion, the FDA
inspected these facilities for compliance with good manufacturing practices. The Medicines Control Agency,
on behalf of the European Medicines Evaluation Agency, also inspected Biopure's facilities prior to granting
marketing approval for Oxyglobin.
Biopure manufactures separation materials in a 10,000 square foot plant in New Hampshire. The current
annual lease payment for this facility is $56,000. The lease expires on March 31, 2005. Biopure has an option
to extend this lease for an additional five years.
Biopure leases two facilities for office and research space in Massachusetts. One lease covers 24,000
square feet, and its current annual lease payment is $262,000. This lease expires on December 31, 2007.
Biopure has an option to extend this lease for ten five-year periods, or an additional 50 years. The other lease,
of office space, covers 14,000 square feet. This lease expires on February 29, 2008, and annual lease payments
are $329,000.
Biopure leases 33,000 square feet of manufacturing space under four leases in Massachusetts. The current
annual lease payments for these facilities is $283,000. The leases expire on November 30, 2005. Biopure has
an option to extend these leases for four five-year periods, or an additional 20 years, with an exclusive right to
negotiate for an additional 25 years. Biopure owns 18,000 square feet of manufacturing space in Pennsylvania.
It also leases warehouse space in New Hampshire.
Biopure's current process is designed to be scalable, such that additional capacity can be obtained by
adding duplicate equipment and additional raw material including power and water. In fiscal 2002, Biopure
completed construction of a 1,700 square foot building abutting the existing research and manufacturing
building and added utilities to maximize production in Cambridge. The Cambridge facilities as enlarged
currently have the design capacity to produce approximately 75,000 units of Hemopure or 262,500 units of
Oxyglobin per year, operating continuously. This plant is designed to attain capacity to produce approximately
100,000 units of Hemopure or 350,000 units of Oxyglobin per year, operating continuously, following
additional validation of new product-fill equipment that was installed during the plant expansion. This capacity
can be used for any combination of Oxyglobin and Hemopure units.
Biopure has purchased land and completed engineering work sufficient to support the start of construction
of a new plant with a designed annual capacity of 500,000 units of Hemopure. In December 2002 Biopure
signed a lease for this facility, which will be effective once financing has been completed. The site will
accommodate the additional construction of a plant to supply another 500,000 units of Hemopure. Biopure
believes that the engineering from this plant will be applicable to any future new plants.
Item 3. Legal Proceedings
Neither the Company nor any of its subsidiaries is a party to, and none of their properties are the subject
of, any pending legal proceedings.
Biopure and its former Chairman and Chief Executive Officer were named as defendants in a purported
class action (resulting from the consolidation of five actions, the first of which was filed on February 5, 2002)
in the U.S. District Court for the District of Massachusetts (the "Court") by alleged purchasers of Biopure's
common stock and subsequently amended (the "complaints"). The complaints claimed that Biopure violated
the federal securities laws by publicly disseminating materially false and misleading statements regarding the
anticipated time of a biologic license application Biopure expected to make to the FDA and that Biopure
failed to disclose materially adverse information regarding the data Biopure gathered in the Phase III clinical
trials in support of its FDA application, resulting in the artificial inflation of Biopure's common stock price
during the purported class period of May 8, 2001 through March 21, 2002. By Memorandum And Order dated
September 4, 2002, the Court granted defendants' motion to dismiss in its entirety, dismissing all of plaintiffs'
claims with prejudice. The plaintiffs appealed the decision but withdrew their appeal and dismissed with
prejudice in return for a mutual general release, including any claim of Biopure for the recovery of Biopure's
attorneys' fees.
Item 4. Submission of Matters to a Vote of Security Holders
No matters were submitted to a vote of security holders during the fourth quarter of the fiscal year
covered by this report.
Executive Officers of the Company
The executive officers of Biopure are as follows:
| Name |
|
Age |
|
Position |
|
|
|
| Thomas A. Moore |
53 |
President and Chief Executive Officer |
| Carl W. Rausch |
54 |
Vice Chairman and Chief Technical Officer |
| Maria S. Gawryl, Ph.D. |
49 |
Senior Vice President, Research and Development |
| Jane Kober |
59 |
Senior Vice President, General Counsel and Secretary |
| Francis H. Murphy |
64 |
Chief Financial Officer |
| William A. Eudailey |
58 |
Vice President, Marketing |
| Geoffrey J. Filbey |
59 |
Vice President, Engineering |
| Carolyn R. Fuchs |
50 |
Vice President, Human Resources |
| Douglas M. Hansell, M.D. |
43 |
Vice President, Medical Affairs |
| Alain Massot |
56 |
Vice President, International Marketing |
| Howard P. Richman, D.P.M. |
51 |
Vice President, Regulatory Affairs and Compliance |
| Barry L. Scott |
53 |
Vice President, International Business Development |
Thomas A. Moore has been President of Biopure since July 2002. From 1996 to 2002 he was President
and Chief Executive Officer of Nelson Communications, Inc., a leading medical communications company.
From 1973 to 1996, he held various positions with The Procter & Gamble Company, the last of which was
Group Vice President of The Procter & Gamble Company and President of Health Care Products Worldwide.
He holds a B.A. degree from Princeton University. Mr. Moore is chairman of the Institute for Cancer
Prevention and serves as a director of Interleukin Genetics Inc., which develops gene-based diagnostics, and of
Alteon, Inc., a developer of drugs to reverse certain effects of aging.
Carl W. Rausch is a co-founder of Biopure and has served as Vice Chairman and Chief Technical Officer
of Biopure since July 2002. From 1997 until 1999, Mr. Rausch was President of Biopure, and from 1984 until
2002 was Chairman and Chief Executive Officer. He holds an M.S. degree in chemical engineering from the
Massachusetts Institute of Technology and holds an M.S. degree in medical engineering and a B.S. degree in
chemical engineering from Tufts University.
Maria S. Gawryl, Ph.D. has been Senior Vice President, Research and Development of Biopure since
1999. From September 1990 to April 1999, she was Vice President, Research and Development. Dr. Gawryl
holds a Ph.D. in immunology from the University of Connecticut. She did post-doctoral work at the University
of Connecticut Health Center and Rush Presbyterian, St. Luke's Medical Center. She holds a B.S. degree in
math and chemistry from Antioch College.
Jane Kober has been Senior Vice President, General Counsel and Secretary of Biopure since 1998. From
June 1989 to April 1998, she was a partner in LeBoeuf, Lamb, Greene & MacRae, L.L.P. Ms. Kober holds a
J.D. degree from Case Western Reserve University, an M.A. degree from the University of Chicago and a
B.A. in English from the Pennsylvania State University. She serves as a director of HTV Industries, Inc.
Francis H. Murphy has been Chief Financial Officer of Biopure since 1999. Previously, Mr. Murphy had
been International Vice President and business manager for Japan, Latin America and Asia Pacific for the
Corning Science Product Division of Corning Incorporated. He holds an M.B.A. degree from Boston
University and a B.S. degree in industrial engineering and a B.A. degree from Rutgers University.
William A. Eudailey became Vice President, Marketing, in February 2000. From 1996 through 1999,
Mr. Eudailey was Vice President of Separations Business of Corning Incorporated, and from 1995 to 1996 he
was Vice President Worldwide Marketing for the Science Products Division of Corning Incorporated. He
holds a Pharm.D. degree and a B.S. in pharmacy from the University of Tennessee College of Pharmacy.
Geoffrey J. Filbey joined Biopure in 1985 and has served as Vice President, Engineering since 1995.
Mr. Filbey holds a B.Sc. degree in engineering from the City University in London, England.
Carolyn R. Fuchs has served as Vice President, Human Resources since 1998. From October 1996 to
June 1998, she was an independent consultant. From May 1991 to October 1996, she worked at National
Medical Care. Ms. Fuchs holds a M.Ed. degree in counseling and a B.S. degree in psychology from the
University of Massachusetts at Amherst.
Douglas M. Hansell joined Biopure as Vice President, Medical Affairs, in January 2003. From February
2001 until joining Biopure he was a visiting physician and assistant anesthetist at Massachusetts General
Hospital, Harvard University, where he was engaged in fellow, resident and medical student education and
evaluation. From 1999 to 2000 he was Chief Medical Officer and Vice President for Medical Affairs of the
Emerson Health System, a hospital and affiliated entities in Concord, Massachusetts. From 1992 to 1999 he
was a visiting physician and assistant anesthetist at Massachusetts General Hospital, Harvard University. He
holds the B.S. and M.D. degrees from the University of Illinois and a Master of Public Health degree from
Harvard University.
Alain Massot joined Biopure as Vice President, International Marketing in 2000. From 1995 to 2000,
Mr. Massot was a consultant in international market development to biotechnology and high technology
companies. From 1993 to 1996, Mr. Massot was Senior Vice President, International PerSeptive Biosystems,
Inc. Mr. Massot holds an M.S. in chemical engineering from the Sorbonne University and holds degrees in
computer programming.
Howard P. Richman joined Biopure as Vice President, Regulatory Affairs and Compliance in 2001. From
1998 to 2001, Dr. Richman worked for MacroChem, where he was Senior Director of Regulatory Affairs,
Quality Assurance, and Chemistry Manufacturing and Controls. From January 1998 to June 1998,
Dr. Richman was Senior Director of Clinical and Regulatory Affairs at Synsorb Biotech. From 1993 to 1998,
he was Director of Regulatory Affairs, Regulatory Compliance, and Business Development at Covance
Clinical and Periapproval Services, Inc. From 1991 to 1993, Dr. Richman served as a pharmaceutical
consultant to the FDA. He holds a D.P.M. degree from New York College of Podiatric Medicine and a B.S.
degree in chemistry and biology from St. John's University.
Barry L. Scott has been Vice President, International Business Development since June, 2002. From 1998
until 2002 Mr. Scott worked for Bristol-Myers Squibb Company, most recently as Vice President,
International Business Development, Europe. From 1996 until 1998 he was the general manager of Bristol-Myers
Squibb, Ltd., South Africa. Mr. Scott holds the Diploma in Education from the University of Rhodesia
and the Diploma in Marketing Management from the Institute of Marketing Management, South Africa.
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