αα–Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?

Abstract

In 1998, Baxter Healthcare announced that it was abandoning its product, diaspirin–crosslinked hemoglobin (DCLHb), the first ‘blood substitute’ to complete all phases of human trials. The company announced that the phase III (pivotal) trials in humans had resulted in an unexpectedly high survival in a group of patients serving as controls for those who received their product in a trauma setting. It is not possible to quantitate the time, efforts and money that were expended in the course of developing this product, from 1985 to 1998. It is rumored that the giant healthcare company had expended more than a half billion dollars on this product, not to mention the investment in the same product by the US Army, the National Institutes of Health and many independent university–based scientists. The disappointment was profound and far–reaching. Although the threat of HIV transmission by banked blood has all but disappeared in the developed world, still the bulk of the world’s population faces blood shortages, which this product and its future generations might have helped alleviate. Only Baxter and the Food and Drug Administration may forever know key elements of the history of development of this product. However, because the US Army decided to make its version of the product widely available to scientists, there is a substantial published record, contributed to by both Baxter and independent scientists. Examination of this record leads to the conclusion that there is no single reason for failure. However, it shows that the characteristic hemodynamic response caused by ααHb increased vascular resistance, and probably eliminates its potential as a red cell substitute. Newer solutions that overcome this limitation should fare better in clinical development when this problem is overcome.

Hb‐based oxygen carriers: are we there yet?

“…The unfavorable outcomes for the treatment groups in the HemAssist trials 19,73 has not precipitated a halt to the development of HBOCs. Rather, this experience has led all participants to redouble their efforts for a better understanding 46,74 of the chemistry, physiology, and pharmacology of those products in clinical trials as well as those under development and design. Furthermore, the HemAssist trials have resulted in a reassessment of clinical trial design for those patients with expected high mortality rates 75 .…”

The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers

“…Most notably, the vasoactivity of bis(3,5-dibromosalicyl)fumarate (diaspirin)-cross-linked Hb (DCLHb), also known as αα-crosslinked Hb (ααHb, HemAssist TM ) (40, 41) has drawn much scientific and public attention because of the ill-fated clinical trial with this HBOC. It was the first blood substitute that reached Phase III clinical trials in trauma patients, sponsored by Baxter Healthcare Corporation (Illinois, USA) (42). However, the study had to be abandoned prematurely as soon as it was recognized that treatment with HemeAssist TM significantly increased the risk of myocardial infarction and death relative to control patients receiving traditional treatments (43).…”

Pharmacodynamic Study of Polymerized Porcine Hemoglobin (pPolyHb) in a Rat Model of Exchange Transfusion

“…So far, the principle raw material for HBOCs ' manufacture comes from human and bovine hemoglobin [6,7]. However, due to the limited supply of human Hb and the possible threat of human blood transmitted diseases such as hepatitis and HIV and cross-species transmission of prion [8], porcine Hb has been developed as a new source of HBOCs [9]. Among different types of HBOCs, those based on the use of the glutaraldehyde polymerization method for hemoglobin and enzymes [10] are the most promising products in commercial development and some of them have been tested clinically in patients [11][12][13].…”