> (1) There are 12 millions blood transfusions in USA per year.
Yes, but how many open heart surgeries are there per year? If FDA approval does unfold, that is the only use rHb1.1 will be approved for.
> (2) In my estimation, the number of patients in whom there is need
> for transfusions and have endotoxin related severe septicemia may
> not amount to more than 5000 per year.
When bleeding is involved, so is infection. The enhanced effect of cell-free hemoglobin + endotoxin is not desired and weighs against the benefit/risk criteria that FDA uses for the approval process, a very big issue.
> (3) Cell free Hb has half life of appr.24 hrs, so people with
> chronic transfusion need may not benefit from cell free Hb, till
> long half life products are put in use. Let us estimate that cell
> free Hb will be suitable for 5 million blood units substituions.
> So, even if 5000 were excluded from 5 million, that still leaves
> 99.9% of market, where this scenerio does not apply.
Cross-linked hemoglobin has a half life of approx. 4 hours, not 24. Even in liposome-encapsulated hemoglobin, the half-life doesn't approach 24 hours. To extrapolate market size for blood substitutes is at best wishful thinking as it is unclear how FDA will view these products in terms of benefit/risk. The fact is that zero companies are seeking FDA approval in terms of being an overall blood substitute, though they always state the overall number of transfused units as their market size. For Somatogen's case, it would be more accurate to state the number of units used in open heart surgery as their market size.
> (4)...DO YOU THINK FDA WILL ALLOW SUCH TRIALS TO GO ON?
The FDA will step in right away on toxicity issues but not on efficacy(therapeutic value) issues.
> with Presbyterian mutation that delivers Oxygen better than natural
> Hb.
This is very debatable, even with a four unit transfusion the majority of the oxygen is still carried by the red blood cell. Studies using the swine model have shown that a cell-free low affinity cross-linked hemoglobin does no better than an albumin solution or even Ringer's acetate in terms of oxygen delivery.
> Lilly may have felt that they were bearing most of the expenses
> and risks under the agreement but were excluded from the most
> lucrative US markets.
The US is not the most lucrative market for blood substitutes as the blood banking procedures here provide a very safe product. However, that is not the case for third world countries and Eastern Europe. Lilly knew exactly what they had signed.
Of note, even assuming a 24 hour half life, if two units are transfused, after 24 hours you have one unit of "junk" your system has to deal with. For this reason, most clinical trials with blood substitutes have involved "heavy bleeding" models like open heart surgery because a lot of the product simply goes away through bleeding. In addition, the breakdown products of hemoglobin (free heme in particular) are known to be toxic. Surely a hematologist can inform us about iron-related toxicities.
The science and technology behind Optro is truly novel, however one must evaluate a drug in terms of benefit/risk. One must weigh risk (published reports on endotoxin effects, hypertension, neural damage, free iron effects, white cell activation, etc.) versus potential benefit(does it have therapeutic value in the open heart surgery?).
The red cell has more functions than simply carrying the hemoglobin around, perhaps one of those reasons is to keep the hemoglobin away from everything else. Replacing a cell with a protein is not as simple as it appears.
Mark. |
