CD&D

In light of recent news that blood substitutes have led to a 30% increase in the risk of death and a nearly threefold chance of having a heart attack, Synthetic Blood International (SBI; Costa Mesa, California) has attempted to distance itself from the "blood substitute" sector.

In particular it is differentiating its flagship product, Oxycyte, saying it is not hemoglobin-based and not — as the company's name clearly proclaims as its focus — a synthetic blood product.

To widen that distance, the company this month said it would ask shareholders at a June 17 meeting to change the name from Synthetic Blood to Oxygen Biotherapeutics.

"We have several biotherapeutic solutions in the making, yet none of them is synthetic blood," Chris Stern, CEO and chairman of the company, told Cardiovascular Devices & Drugs. "We are currently focusing on traumatic brain injury, sickle cell pain crisis, wound treatment [such as an over-the-counter and clinical device], organ transport, heart attack, stroke, and, as a long shot, spinal cord injury. Adopting a new name will better reflect the broader scope of our development activities."

Oxycyte is the company's therapeutic oxygen carrier — a perfluorocarbon-based blood substitute — with application first as a treatment for traumatic brain injury and, if found to be successful, several other indications down the road, as Stern noted.

"Initially when the company was founded, the focus was on developing a blood substitute," Dick Kiral, president of SBI, told CD&D. "But a few years back, we really changed the strategic direction to focus on oxygen delivery."

SBI's attempt to clarify its difference from the other blood substitute products under development were prompted by an analysis of a number of hemoglobin-based oxygen carrier (HBOC) trials in a recent issue of the Journal of the American Medical Association, which said there is a "clinically important increase in risk of mortality and risk of myocardial infarction across HBOC trials" and that "more troubling, trials continue to be planned and conducted in the presence of accumulating knowledge as demonstrated by the cumulative meta-analyses."

The FDA and National Institutes of Health also held a workshop in late April on HBOCs. During that meeting, the JAMA report was center stage.

Authors of that study suggest that no further Phase III studies be conducted with HBOCs, given the known toxicities.

"Until the mechanisms and potential toxicities of HBOC products are better understood, patients cannot be placed at unacceptable risk," wrote lead study author Charles Natanson, MD, of the critical care medicine department in the NIH Clinical Center.

"I just came back from the HBOCs meeting in Bethesda," Kiral said. "There seems to be some safety issues and cardiovascular events reported. The FDA will publish a paper looking at the whole thing overall. But the tone of the meeting was 'don't treat all HBOCs alike,' in response to the fact that JAMA grouped findings about various products."

Although Oxycyte could be used as a blood substitute, Kiral said that the synthetic perfluorocarbon foundation of the product enables it to carry five times more oxygen than hemoglobin, making it an effective means of transporting oxygen to tissues and carbon dioxide to the lungs for disposal. He said this translates to an absence of the safety issues identified in the JAMA article.

"We're using Oxycyte in a therapeutic way, focusing on traumatic brain injury," Kiral said. "We're not trying to replace blood. This allows us to enter a lot more markets, rather than just as a general blood substitute, which have a bad name overall because you're not really replacing all the functionality of the lost blood. You replace volume and oxygen, but none of the clotting factors are replaced."

Last May, SBI reported results from a Phase IIa pilot trial of Oxycyte in human isolated closed-head injuries, which was conducted at the Reanimation Engineering Shock Center at the Virginia Commonwealth University (Richmond, Virginia). Nine patients received a single dose of Oxycyte within four to 12 hours after entering the hospital.

The company said that data collected from these patients mirrored what was found in earlier animal experiments, and patient outcomes were dramatically better than expected, as compared to historical controls.

Current treatments for these kinds of head injuries involve supportive care, surgical drainage of blood from inside the skull, and the administration of added oxygen through the lungs. But nothing is available to improve oxygen delivery to the brain tissues that are starving for oxygen and dying. SBI says it is trying to fill that niche.

Kiral said SBI filed an application with the FDA for a Phase IIb/III trial comparing Oxycyte with currently available therapy in up to 200 patients. It's intended to be a randomized, double blind, and placebo-controlled trial at six major neurosurgery centers throughout the world.

Discussions, briefings and a Department of Defense (DoD) grant have been submitted for further investigations.

"We've been going back and forth with FDA, answering questions and dealing with the usual stumbling blocks," he said. "We're hoping, if everything goes well, we'll start that trial in early summer."

The U.S. Office of Naval Research has funded research related to the use of PFCs for the treatment and prevention of decompression sickness (DCS) over the last six years. DCS causes tissue damage when bubbles in the blood vessels block delivery of oxygen to the tissues.

Oxycyte, SBI says, not only delivers the oxygen, but it helps to remove the bubbles. The program to develop Oxycyte as a treatment for DCS is a major component of the Navy's Disabled Submarine Initiative.

Kiral said the Navy will seek FDA approval for the use of PFCs in the treatment of DCS. About $6.5 million in DoD grants have been submitted and are under review.

Although SBI has adequate funding for the near term, with help provided via grants to the U.S. Navy and Army researchers, the company will be looking for additional funding in about a year and half to continue the development of Oxycyte.

Thus far, the regulatory road for all of the blood substitute products have been never-ending, except for opportunistic investors and constant restructuring and reshaping

In theory, a blood-substitution product shouldn't be that hard to develop — it doesn't need to stop the growth of renegade cancer cells, it doesn't need to abate amyloid plaques in the brain. It simply needs to carry oxygen to tissues with no toxicity.

One of the companies pursuing this product is Biopure (Cambridge, Massachusetts), founded in 1984. By 1986 it had filed an investigational new animal drug application for Oxyglobin, to treat canine anemia. The product is a sterile, intravenously administered solution consisting of chemically stabilized hemoglobin in a balanced salt solution. Two years after that, it filed an investigational new drug application for Hemopure, a chemically stabilized bovine hemoglobin product, again in a balanced salt solution.

Clinical work for both products went on through the 1990s, with Biopure beginning a pivotal trial for Oxyglobin in 1993. In 1995, the company moved across the Charles River to Cambridge and began submitting a new animal drug application for Oxyglobin.

By 1997, Biopure was ready for a Phase III general non-cardiac surgery trial of Hemopure in South Africa and Europe. A year later, Biopure not only filed for approval of Oxyglobin in Europe, but also received U.S. clearance to sell the animal product.

Through the 1990s, the company raised net funding of $242 million, and in May 1999, it filed for its initial public offering, seeking $86 million. It ended up netting $37.7 million in its IPO, and then raised $83.7 million in a follow-on offering the next year.

Things went well in 2001, with the company launching Oxyglobin in Europe and receiving approval to sell Hemopure in South Africa. Primary endpoints were met in a Phase III orthopedic surgery Hemopure trial in the States.

The biologics license application for Hemopure for acute anemia in orthopedic surgery patients and to eliminate or reduce allogeneic red-blood-cell transfusions in those patients was placed in the FDA's hands in mid-2002.

Back and forth with the FDA continued through 2003, and after a January 2004 meeting the FDA wanted three animal studies done, estimated to take six months. This was followed by class-action lawsuits were filed against Biopure, alleging the failure to disclose safety concerns to the investing public, the resignation of company president/CEO and board member Thomas Moore resigned. The SEC issued Wells Notices to four Biopure officers in May 2004, indicating the SEC might recommend a civil suit against the officers for violating securities laws.

Biopure is now in clinical work on Hemopure for cardiovascular indications such as ischemia or acute anemia.

The company is currently seeking regulatory approval in the UK and has been meeting with the UK's Medicines and Healthcare Products Regulatory Agency to clarify issues concerning Hemopure. It said it has scheduled a meeting for May 29 with the MHRA to clairy a variety of issues concerning Hemopure.

It said that a letter from the commission expressed reassurance concerning a number of questions raised in an earlier comment letter but that other "major" issues still must be resolved.

Other comopanies and their difficulties in this sector:

• Baxter International (Deerfield, Illinois) halted its blood substitute program for HemAssist in 1998, after spending an estimated $500 million on the effort.

• Alliance Pharmaceutical (San Diego) once had its product, Oxygent, in a Phase III cardiac surgery study and faced questions about adverse events. Like Biopure, Alliance has cut staff now down to 35.

• Northfield Laboratories (Evanstown, Illinois) filed for approval of PolyHeme in 2001 as an alternative to blood transfusions for patients with acute blood loss. The FDA turned down that application, citing concerns over an earlier trial that used historical models to compare effectiveness. Northfield has a Phase III trial under way, aimed at trauma in both civilian and military settings when blood is not available.

• Hemosol (Tornoto), developing Hemolink, put the product on the shelf to focus on commercializing blood proteins.