When a U.S. soldier is wounded in combat, his lost blood is often replaced with Hextend®, a plasma expander developed by BioTime (www.biotimeinc.com). The high molecular weight plasma expander also is being used in high blood loss surgery at hospitals in the U.S., including the M.D. Anderson Cancer Clinic, Massachusetts General, The Cleveland Clinic, and Kaiser Permanente.
BioTime’s primary goal is to develop and license a variety of blood plasma expanders to replace traditional blood-based products and older synthetic products.
Plasma volume expanders like BioTime’s flagship product, Hextend, are used to treat blood loss in surgical or trauma patients until blood loss becomes so severe that a transfusion of packed red blood cells or other blood products is required. Hextend, approved for use in major surgery, is distributed in the U.S. and Canada by Hospira (www.hospira.com) and in South Korea by CJ Corporation.
Hextend’s formulation incorporates normal physiological levels of electrolytes and glucose, “thus helping to maintain blood biochemistry,” says Hal Sternberg, Ph.D., vp of research. It is the only blood plasma volume expander that contains lactate, multiple electrolytes, glucose, and a medically approved form of starch called hetastarch, explains Dr. Sternberg. “Hextend is based on a high molecular weight starch,” explains Judith Segall, vp of operations, “and that is part of our marketing challenge.” The older 6% hetastarch in saline solutions is required by the FDA to be labeled with a warning that those products are not recommended for use as a cardiac bypass prime solution, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been disconnected. “We have not been required to add that warning to our labeling of Hextend,” she continues. Nonetheless, Segall says the two products are often confused.
She points out that Hextend is competing against albumin in the U.S. for plasma volume extension. In 1999, the University of California at San Francisco switched from albumin to Hextend as the first line colloid. The 9,000 units of albumin it used were reduced to about 2,700 units, with the difference largely replaced by Hextend. “In one year, we estimate that this switch to Hextend saved UCSF about $500,000,” says Segall.
Like any new product, Hextend also must overcome inertia in the medical community. “The challenge is to educate physicians to understand that our new products may offer benefits not found in the products that they have become accustomed to using,” explains Segall.
She also points out that although U.S. blood banks often experience supply shortage, the domestic blood supply is generally considered safe, posing another marketing challenge. In Canada, however, “there was a scandal regarding AIDS a few years ago,” points out Segall. Canada hence reduced reliance on blood products as much as possible and increased its reliance on synthetic plasma volume expanders, she adds.
“In Europe, the situation is similar to that of Canada, with AIDS and mad cow disease” posing a perceived threat to the blood supply, according to Segall. Another BioTime product PentaLyte® may benefit as it is based on the same pentastarch as the product of choice in Canada. Similar to Hextend, PentaLyte may be preferred when shorter acting volume expansion is needed.
BioTime is working to enter other markets abroad. Last April, BioTime signed agreements with Summit Pharmaceuticals International (www.summitpharma.co.jp)to develop Hextend and PentaLyte in Japan, Taiwan, and the People’s Republic of China. Summit has brought in Maruishi Pharmaceutical to participate in product development and marketing.
Additional licensing agreements are in place with Hospira for Australia, Mexico, and Central and South America. Obtaining regulatory approval in those regions is in the early stages. According to the 2005 annual report, future revenues depend significantly upon licensing revenues.
If Hospira obtains the license to PentaLyte, now in Phase II trials at Duke University Medical Center, BioTime would be reimbursed for its product development costs, which now exceed $3 million. Opportunities here seem favorable, as pentastarch-based plasma expanders already are accepted by the medical establishments in Canada, Japan, and several E.U. countries, says Segall. The PentaLyte Phase II study began during April 2005 and although the company is hesitant to project a completion date, management says it is proceeding according to plan.
In addition to developing Hextend and PentaLyte, BioTime is working in a new field of therapeutic hypothermic surgery, in which the body is chilled to near freezing temperatures and the blood is totally replaced to buy more time for surgeons engaged in complicated procedures requiring the suspension of circulation. The company received a $300,000 research grant from the National Heart, Lung, and Blood Institute to develop HetaCool® as a blood plasma volume expander for profound therapeutic hypothermia.
Dr. Sternberg points out that HetaCool and Hextend are two different products. HetaCool is a version of Hextend used for complete blood volume replacement at very low temperatures. Hextend is used for partial replacement.
“The use of HetaCool calls for the addition of sodium bicarbonate before it is applied to the subject, which enables better buffering capacity and raises the pH to be more suitable for low temperatures and for use without blood,” he explains.
In BioTime’s therapeutic hypothermic experiments at the Texas Heart Institute at the University of Texas Medical School in Houston, animal subjects are cooled to just above freezing. HetaCool is used to completely replace their blood and thus increase the available time in which to perform critical surgeries requiring cardiac and circulatory arrest. The NIH grants called for lowering the body temperature to below 6°C for two hours to prove feasibility. HetaCool could, potentially, be used in high fluid volume procedures in cardiovascular surgery, trauma treatment, and organ transplantation.
It’s too early, however, to speculate on either the time-frame or cost for bringing this product to market. “To the best of my knowledge, we are the only group in the world that has taken primates to just above the ice point for more than one hour and revived them with good neurological outcome,” says Segall.
In the early 1990s, investigators at Barrow Neurological Institute in Phoenix chilled four baboons to as low as 2.5°C deep esophageal temperature and maintained three of them below 10°C using BioTime’s blood substitute from 51 to 137 minutes. During that time, “they were clinically dead,” with no brain activity and no pulse, Dr. Sternberg says.
All animals survived complete blood replacement and profound hypothermia and appeared normal upon gross observation. The baboons were scored according to a 160-point system evaluating motor function, coordination, behavior, and cognitive skills.
All animals that were kept below 10°C received scores of 160/160. However, one baboon who spent only 1 minute below 10°C received a score of 130/160 because the animal did not exhibit the level of aggressive behavior normally seen in baboons.
Complete blood replacement and profound hypothermia appear to be key to achieving neurologic recovery as these baboon studies and subsequent pig studies demonstrate, according to Dr. Sternberg, who admits that many of BioTime’s options are limited by its operating revenues. Grants provide another possible funding option.
In a round of belt-tightening, BioTime employees voluntarily cut their 2005 salaries by nearly $87,000, while the company decreased its general and consulting fees and its investor and public relations expenses by a total of just over $102,000 and cut printing costs by nearly $36,000. Previously, to avoid hiring a CEO upon the death of Paul Segall, the company created the Office of the President, a triumvirate CEO position, filled by Segall, Dr. Sternberg, and Harold D. Waitz, Ph.D., vp of regulatory affairs.
BioTime has made notable inroads but still has a long, uphill battle before it becomes profitable, according to Segall. BioTime was delisted from the American Stock Exchange in 2005. The reason, notes Segall, is that “BioTime did not have the $6 million of shareholders’ equity or the total market capitalization needed to meet the exchange’s continued listing standard, and the exchange no longer has the flexibility to waive its quantitative listing requirements.”
The company’s stock is now traded OTC. According to Segall, an American Stock Exchange spokesperson says the exchange is considering creating a microcap tier, which may benefit BioTime.