Biopure is one of the leading companies in the development and manufacture of oxygen carrying solutions. Biopure’s first-in-class product for human use is Hemopure, which is a Hemoglobin-based oxygen carrying solution (HBOC). It is also known as Hemoglobin Glutamer-250 (bovine) or HBOC 201.

Manufacturing

Hemopure is made of chemically stabilized, cross-linked bovine (cow) hemoglobin situated in a salt solution. Hemoglobin by itself is toxic to the kidneys because it contains stroma lipids, which are contaminated with endotoxins. If the stroma lipids are removed, however, then the Hemoglobin has too high an affinity for oxygen, which means less oxygen off-loading to the tissues. In order to assure that the Hemoglobin is not toxic, but still therapeutically useful, it must be stabilized. Stabilization can be achieved through a number of methods, but Hemopure stabilizes the hemoglobin by cross-linking it. This is done by cross-linking the two alpha, and the two beta subunits. This then stabilizes the alpha-beta dimers, which in turn makes the hemoglobin molecule more stable, and also reduces its affinity for oxygen, making it easier to deliver oxygen to the tissues. A picture of the structure of hemoglobin is presented below, including the positions of the alpha and beta subunits.

Safety Measures

Since the Hemoglobin used in Hemopure is derived from cows, Biopure goes through extensive lengths to make sure that Hemopure is: free of pathogens, infectious agents (BSE), and chemically pure, including:

• Using only very tightly monitored herds, where the country of origin, food supply and health are closely supervised.
• The use of external experts who closely regulate the strict manufacturing process of Hemopure to determine the capability to remove potential pathogens.
• Strict observance of the global industry and regulatory standards.
• Extensive clinical trials.

Advantages of Hemopure vs. RBC’s

Hemopure is smaller in size (up to 1,000 times smaller than a typical red blood cell) and has less viscosity than human red blood cells (which contain hemoglobin). This means that it can carry more oxygen at a lower blood pressure than red blood cells. Also, because of its smaller size, it can carry oxygen through partially obstructed or restricted blood vessels, where RBC’s cannot reach, as seen in the diagrams below.

Inadequate tissue oxygenation resulting from occluded arteries can result in heart attack, angina, or transient ischemic attack, which is a precursor to stroke. Traditionally, these conditions have been treated by blood transfusions, but RBC’s are often too big to pass through the occlusion, which is why Hemopure can potentially be very helpful. Some of the trials done to demonstrate the benefits of Hemopure are below:

Trials

• At the American Society of Anesthesiologists in 1999, medical researchers presented data from a preclinical canine study showing that Hemopure helped maintain normal heart function during a 90% constriction of a coronary artery.

• US Phase III Orthopedic Surgery Trial. 1998 This is non-emergency surgery involving bones and joints. The point of this trial was to avoid RBC transfusions for six weeks following the operation. It was a randomized, RBC controlled, multi-center study that used 688 patients from the U.S. South Africa, Europe and Canada. 350 patients received Hemopure, and the remainder received RBC transfusions. Up to 300 g of Hb (10 units of Hemopure) could be injected, before, during or after the surgery. The primary goal was achieved, and the avoidance of RBC transfusion in at least 35% of the patients using Hemopure was achieved.
• Non-U.S. Phase III Non Cardiac Surgery Trial.1998. This was done in Europe and South Africa, and the goal again was to avoid RBC transfusions, but only for 28 days after the surgery. This study used 160 patients, 83 of which were treated with Hemopure, and 77 of which were treated with normal RBC transfusions. Up to 210 grams of Hb (7 units of Hemopure) were allowed during a six-day treatment time. This trial obtained its goal, as 43% of the patients treated with Hemopure were able to avoid RBC transfusions.
• U.S. Phase II Post-Cardiopulmonary Bypass surgery Trial. 1997. This was a double blind, randomized, RBC controlled, multi-center study in post-cardiopulmonary patients. This surgery included the use of a heart-lung machine which traditionally has been associated with RBC transfusions. The object of this trial was to avoid RBC transfusions 28 in patients for 28 days after the procedure. There were 98 patients in the study, 50 of which used Hemopure, and 48 who used RBC transfusions. Up to 120 g (4 units of Hemopure) could be used up to 3 days after the surgery. 34% of the patients who used Hemopure were able to avoid RBC transfusions, which again met the trial’s goal.

Where is Hemopure Now?

Hemopure is currently approved in South Africa for the use of surgical patients who are anemic, thereby reducing or eliminating the need of blood transfusions for these patients. It is currently in Phase III Clinical Trials in South Africa and Europe. In the U.S. Hemopure, is currently under review by the F.D.A. and is conducting animal studies. In March, 2003, the U.S. Naval Medical Research Center (NMRC) signed a collaborative research and development agreement with Biopure to help fund and conduct a trial on the effects of Hemopure in out-of-hospital resuscitation of patients with severe hemorrhagic shock. This trial, named “Restore Effective Survival in Shock” (RESUS) and over $14 million in Congressional, Navy, Army, and Air Force funding has been given so far to support the trauma development program for Hemopure. Hemopure has also been approved for compassionate use.