http://www.boston.com/business/technology/biotechnology/articles/2003/11/03/building_blood/
Building Blood
Companies face high hurdles in the quest for a safe substitute
By Ross Kerber, Globe Staff, 11/3/2003
Bleeding trauma patients being rushed to Massachusetts General Hospital or Boston Medical Center in ambulances might be in line for a lifesaving boost: an infusion of artificial blood. Currently patients can't receive blood transfusions until they reach an emergency room. But trauma specialists at both hospitals are in talks with Northfield Laboratories Inc. about joining a clinical trial of the company's brew of refined human hemoglobin, one of several experimental products meant to replace lost blood cells or to improve the oxygen capacity of a patient's remaining blood.
Known as "blood substitutes," these products are intended for surgery and emergency care, with longer shelf lives than donated human blood and no danger of a potentially fatal mismatching. As concerns about HIV and mad cow disease reduce the pool
of donors, companies seeking to bring a blood product to market believe they are pursuing a major medical advance. They find support from at least one adviser to the US Food and Drug Administration.
"This is an area that has real potential to create type-less red blood cells, which are immediately available and free of any risk of viral transmission," said Dr. James R. Allen, a hematologist and president of the American Social Health Association in Durham, N.C. "It has tremendous appeal."
Yet every company in the field has struggled, despite decades of research and total investment approaching $1 billion -- a common situation in biotechnology. While the challenges facing each treatment are unique, in sum they suggest that the companies aren't racing one another to market so much as stumbling toward an elusive goal.
In March, Hemosol Inc. of Toronto halted its clinical trial of an oxygen-carrying therapeutic; since January the pharmaceutical giant Baxter International Inc. ended two ventures in the artificial-blood sector and wrote off investments of several hundred million dollars.
Only last week, Biopure Corp. of Cambridge said it will not be able to submit safety data on its Hemopure product to the FDA until June, and in the meantime, will lay off 72 people, about a third of its work force.
Northfield, based in Evanston, Ill., faced bankruptcy before raising an extra $10.6 million from investors in July. It had hoped to have marketing approvals already for its PolyHeme product, but instead the FDA wanted more information.
Now Northfield is trying to sign up trauma centers and ambulance crews to test its product on patients who are losing so much blood they might die before reaching the hospital. These patients currently receive only plasma, since human blood transfusions involve too many compatibility issues to be conducted on ambulances. (Under federal rules, crews won't need a waiver to administer the experimental treatment to patients who might die without it.)
Northfield chief executive Steven A. Gould said artificial-blood products represent a unique challenge for the FDA because all of the proposed products are so different. "What's unusual about blood is that you have so many companies trying to do a first-in-class product at the same time," he said.
"It's been a very tough market," said Sapna Srivastava, analyst at ThinkEquity Partners in New York, which has done investment banking work for Biopure. "And it's also something the FDA doesn't have the best handle on, so the parameters aren't really set as far as what they need for efficacy and safety standards."
Blood is made up of a fluid known as plasma, mostly water but also containing proteins, dissolved nutrients, and waste products. A typical adult has 10 units of blood; a unit is 450 milliliters, or just under a pint. Within plasma float three types of cells -- red blood cells, mainly consisting of the protein hemoglobin, which carries oxygen from the lungs to the tissues and removes carbon dioxide; white blood cells, or leukocytes, which fight infections; and platelets, which clot to stop bleeding.
Successful transfusion procedures began a century ago. Then chemicals were introduced that allowed blood to be stored as a liquid and plasma was isolated as a simple emergency blood-replacement. American patients receive 14 million units of blood a year.
Logistical problems remain, chiefly blood's 42-day shelf life. Military officers also want blood-replacement products that can be used in the field without complicated blood-type matching. In all the Pentagon has spent $15 million to come up with substitutes, officials estimate, and Northfield and Biopure both receive military funds. Also, Sangart president Robert M. Winslow has run a military blood-research program in San Francisco.
The main avenue of artificial blood research involves altering hemoglobin, either from human or animal sources. But the products supplied by Biopure, Northfield, Hemosol, and Baxter must overcome weaknesses. One common problem is that modified hemoglobin can quickly dissipate in the bloodstream. Another issue is the potential of small hemoglobin particles to block kidney function, essential to removing waste from the system.
A different approach has been taken by Alliance Pharmaceutical Corp. of San Diego, which has developed a chemical to carry oxygen to the tissues -- a hydrocarbon whose hydrogen atoms have been replaced by fluorine. But Alliance hasn't gotten beyond preliminary trials and its partner, Baxter, pulled out in January.
"Milestones were not being hit," said a Baxter spokeswoman. "As we looked at our R&D portfolio, we saw there were more promising areas." Alliance executives did not return e-mail and phone messages.
Northfield, Biopure, Hemosol, and Sangart say they expect to work through their difficulties. For instance, Biopure's chief executive, Thomas A. Moore, dismissed the pounding the company took in the market last Friday, when the stock lost 39 percent of its value on bad news. He said the prospects are "still encouraging," since the company could tap a $2 billion market if it wins FDA approvals. The company has raised $475 million since its founding in 1984 and had only $31.9 million on hand as of Sept. 15.
A spokeswoman for Toby Silverman, FDA medical supervisor for hematology reviews, said she wasn't permitted to be interviewed on commercial subjects. But in an e-mail, Silverman outlined several basic concerns about blood-substitute research as a whole.
"There are . . . no good criteria for dosing of individual oxygen therapeutics at this time," she wrote. In addition, she wrote, the FDA wants all of the products to be studied for their use in both elective surgery and trauma. "Reduction in mortality in a setting where blood is not available does not mean that an oxygen therapeutic is as safe as blood in a situation where one might make a choice."
In other words, the FDA fears that any blood product approved for limited use might be deployed more widely as a blood substitute, said a US Army hematologist, Thomas J. Reid. The danger is that long-term health risks that a trauma patient might be willing to accept might not be appropriate for an elective-surgery procedure. "They're afraid they'll let the horse out of the barn," said Reid, of the Walter Reed Army Institute of Research in Silver Spring, Md.
Another reason the FDA will be extra cautious, Reid said, is that blood transfusion therapies were adopted before any FDA reviews were required. "When your current standard of care has never been rigorously evaluated and never will be, you have a hard time comparing a research subject," Reid said.
Some say the constraints are worth it because any therapies that reach the market will command a high price. Hospitals now pay more than $200 a unit, nearly double the price of several years ago because of shortages and new processing to reduce risk of infection. Northfield's Gould said he hopes to charge more than $1,000 per unit for the company's PolyHeme product.
"We're thinking of this not necessarily to replace blood, but to use when blood is not available," he said. "We anticipate a premium to blood, based on the additional benefit."
Ross Kerber can be reached at [email protected].