Action of ATIII -- My increasing conviction that ATIII in DIC will prove significantly effective.
I'll add my voice to Jesse et al's on the Wiedermann paper. Agreed it is dense and requires some physiologic saavy, but impressive in the animal and human data it brings in support of ATIII's effect in DIC.
While there is much more going on, what it tries to make clear is that:
1) ATIII has beneficial anti-clotting properties by binding and inactivating thrombin -- and so descreases the production of microthrombi that diffusely clot capillaries and lead to multi-organ dysfunction,
And by a completely SEPARATE mechanism,
2)ATIII has beneficial antiflammatory properties. The heparin-binding sites on ATIII also bind the HSPG's (think of them as molecular fingers sticking out from a number of cells, including white blood cells and cells lining the blood vessels) and in doing so, DECREASE the release of inflammatory mediators. It is THIS function that appears to be completely disabled by even very small amounts of therapeutically-administered heparin, as the 'therapeutic' heparin administered in the blood appears to prevent ATIII's binding to the HSPG's on cells in the body.
On a separate, but related front:
Despite my prior posts raising some cautions on placing too much stock in the Kyber-Sept post hoc analysis, and with the obvious caveat that the author of this review does have a dog in the hunt (as the author of paper #4), Wiedermann in this paper presents as lucid and convincing a case as can be made that ATIII will bear fruit as he describes:
1) there were new data prompting a specific re-evaluation of the heparin-less subset,
2) that heparin-less subset had been defined by the Kypersept investigators prior to the testing, (heparin was apriori defined as a concern -- which decreases the risk of a statistical 'fishing expedition' falsely raising hopes)
3) on re-eval, that those in the heparin-less group with DIC had significant improvement, while those without did not (lending support to a clear (and expected) mechanism),
4) and when in those most likely to be helped by ATIII (with pre-test mortality of >30% but <60% -- that is those who were truly sick, but not inevitably going to die), the ATIII had significant good effect in those both with and without heparin, and that this beneficial effect was even more pronounced in the subset who didn't get heparin.
The 4 points above might be subtle (or appear insignicant) to some, but from a methodologic/statistical POV -- just think of it as the midset of the FDA reviewers who will be reviewing these data -- they make much more compelling the Kypersept 'subset' analysis as having some basis in reality - and increase the expectation of reproducibility -- which could mean an easy $10/share value for DIC alone for GTCB if so.
As I've written multiple times before, Big Pharma may not be nice, but they are not stupid, nor without greed.
GTCB is an increasingly compelling story -- and some very smart Big Pharma will make this OBVIOUS to the sheep (not goats) of Wall St. shortly. Glad we're on board now, and looking forward to the ride.
Best,
MTB
AI
