Therapeutic focus - blood substitutes struggling to make headway

The FDA is likely to refuse to allow Northfield Laboratories to start marketing its haemoglobin-based oxygen carrier (HBOC) PolyHeme later this month, a move that will represent the latest set back to a field that has seen decades of research, but as yet yielded no safe alternative to human blood.

The need for such a product is clear, in both medical and military settings. But side effects have stymied efforts, with heart attack, high blood pressure and organ toxicity regularly encountered, leading overall to a much higher risk of death, clearly the worst outcome of all. For this reason there are currently few products in active development, and the market is unlikely to see a launch in the near future (see table below).

Northfield's product is the most advanced according to EvaluatePharma, and unfavourable efficacy in a phase III trial, plus a higher risk of heart attack, means commentators hold out little hope for the drug’s approval by the April 30 PDUFA action date (Event - Northfield PDUFA decision is matter of life or death, April 7, 2009).

Encouraging results

Sangart is the also pretty well advanced with its product, Hemospan, having recently completed two phase III trials. Rather than go down the trauma route like Northfield, Sangart pursued an operative setting. It pitted Hemospan against Voluven, a widely-used blood plasma substitute used to increase blood volume, to prevent perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anaesthesia.

Because the company is private, it did not have to publish the full results of the trials, conducted in 850 patients. However it has said that while the primary endpoints of the two trials were met, with Hemospan demonstrating superiority in treating hypotensive episodes, the product failed to demonstrate a mortality benefit. The company blamed this on the fact that the studies were underpowered for this secondary endpoint, because the patients were at a low risk of death. As such, the group scrapped plans to file the product for approval in this indication, and will conduct further trials in a different area, as yet to be decided.

Whether poor trial design was the real reason for the disappointing results is hard to determine. Importantly, though, no “major clinically important safety concerns” were reported, and there was no statistically significant imbalance in the incidence of serious adverse events.

Sangart believes its product, which it describes as “fourth generation”, has a real chance of overcoming the hypertensive side effects of other HBOCs, and does look to be promising. The fact that last month a further $50m was raised from existing investors to continue development is certainly a vote of confidence.

Other HBOCs are thin on the ground; Therapure also has a pre-clinical candidate which is a combination of haemoglobin and a plasma expander.

No substitute

The other main area of research into blood substitutes is perfluorocarbons, although many people working in the field do not use the term “blood substitute”, because the products do not contain haemoglobin. Because oxygen has a much greater solubility in perfluorocarbons than plasma, the theory behind these products is that their administration can cause the oxygen content of plasma to increase, thus avoiding the need for HBOCs and their associated side effects.

Unfortunately, this area of research has also not yet yielded any marketed products.

Oxygent is probably the most advanced, and has been researched by a handful of companies, and abandoned by several, over the last few years. Its owner Alliance Pharmaceutical Corp is currently hovering on the verge of bankruptcy, although a Chinese partner and Leo Pharma have certain rights to carry on research. Still, with limited news available, what will happen with this product in the future remains unclear.

Oxygen Biotherapeutics is preparing for a phase II trial of its perfluorocarbon product, Oxycyte, which should commence in the second quarter of this year, in Israel and Switzerland, in traumatic brain injury patients. When used as an intravenous emulsion, Oxycyte can carry as much as five times more oxygen than haemoglobin, and the company has so far reported no adverse events, although clinical trials have been limited.

As such, it appears doctors have a wait on their hands before viable and lifesaving blood substitutes, whether HBOC or perfluorocarbon, appear.

Blood substitute products in development
Product Pharmacological Class Company
Filed PolyHeme Haemoglobin-based oxygen carrier Northfield Laboratories
 Phase III Hemospan Haemoglobin-based oxygen carrier Sangart
Phase II Oxygent Perfluorocarbon-based oxygen carrier Alliance Pharmaceutical/Leo Pharma
Phase I Oxycyte perfluorocarbon therapeutic oxygen carrier Oxygen Biotherapeutics
 Pre-clinical HRC 101 Haemoglobin-based oxygen carrier Therapure BioPharma
Suspended - Phase III Oxygent Perfluorocarbon-based oxygen carrier Baxter International
Abandoned - Phase III HemAssist Haemoglobin-based oxygen carrier Baxter International
PolyHeme Haemoglobin-based oxygen carrier Pfizer
Oxygent Perfluorocarbon-based oxygen carrier Nycomed
Abandoned - Phase II Optro Haemoglobin-based oxygen carrier Eli Lilly
Oxygent Perfluorocarbon-based oxygen carrier Johnson & Johnson
Abandoned - Phase I Cord Blood Cells Stem cell therapy Celgene
Recombinant Hemoglobin Haemoglobin-based oxygen carrier Baxter International
Abandoned - Pre-clinical Fluorocarbon Gas Emulsion Perfluorocarbon-based oxygen carrier Sonus Pharmaceuticals
Fluorocarbon Gas Emulsion Perfluorocarbon-based oxygen carrier ImaRx Therapeutics

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