Hi Dew, Jesse, Vinny,
Will add mine to the voices calling this paper another chunk of data suggesting GTCB's Atryn in DIC study will work. Having a viable mechanism makes me a lot happier than 'ATIII has anti-inflammatory properties (insert hand waving here).'
In brief, in addition to the suggestion for a mechanism, I was struck but the simple declarative nature of the first sentence: "Antithrombin (AT) improves the outcome of septic patients with intravascular coagulation." -- A statement I very much hope to have accepted as a simple declaration in the future, but that certainly isn't at present.
Since the investigators are Japanese, and ATIII is reportedly being used in sepsis there already (I've been told), I went to the full paper for 'new' sources of this seeming confidence. There were none -- largely just the KS subset data (cite #4 below from their opening paragraph).
2) I was struck by the wide range in effect by dosing. I've not run the numbers, but trust the dose ranging of the Phase II trial will more than suffice to have good effect (i.e. do we just need to replete low levels, or are super-physiologic levels needed for good effect).
I keep wondering how many more windings of the GTCB spring are needed before it violently releases into the $3-5/share range.
Best,
MTB
"Introduction
Antithrombin (AT), a physiological inhibitor of serine proteases such as thrombin [1], has been
shown to reduce the mortality of baboons challenged with E. coli not only by inhibiting coagulation,
but also by attenuating inflammatory responses [2]. However, the clinical efficacy of AT is
controversial [3]. In a recent randomised, placebo-controlled, double-blinded, prospective phase III
study, AT administration had no effect on the mortality of patients with severe sepsis. Moreover, its
use was associated with an increased risk of bleeding [4]. However, post hoc subgroup analysis
from the same trial suggested that the 90-day mortality was reduced in a subgroup of severe
sepsis patients receiving AT when compared to those receiving placebo [5]. Of these, only a
subgroup of these patients that satisfied the criteria for disseminated intravascular coagulation and
that did not receive concurrent heparin treatment, had a greater survival benefit when receiving AT."
as compared to the patients that received placebo [5]. Despite this, the mechanism(s) by which AT
reduces the mortality of patients with severe sepsis is not fully understood.
References
1. Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiologic role
of this natural anticoagulant mechanism. Am J Med 1989; 87: 2S-9S.
2. Taylor FB, Jr., Emerson TE, Jr., Jordan R, Chang AK, Blick KE. Antithrombin-III prevents
the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988; 26: 227-35.
3. Loubele S, ten Cate H. Local administration of recombinant human antithrombin in a mouse
model of peritoneal sepsis. J Thromb Haemost 2006; 4: 2340-3.
4. Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R,
Keinecke, HO, Warren BL, Opal SM, for the KyberStep investigators. High-dose antithrombin III in
the treatment of sever sepsis in patients with a high risk of death: efficacy and safety. Clin Care
Med 2006; 34:285-92.
5. Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, Keinecke HO,
Warren BL, Opal SM. Treatment effects of high-dose antithrombin without concomitant heparin
in patients with severe sepsis
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