Replies to post #3714 on GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Scientific Rationale for ATryn in DIC/sepsis
(This is the summary version.)

The only approved drug for sepsis is LLY’s Xigris, which has been a commercial flop for the simple reason that it’s not a great drug (#msg-12483101).

Xigris does not address DIC, specifically, but rather sepsis in general. ATryn, on the other hand, is being targeted at DIC within the context of sepsis. I think it’s fair to say that these are two distinct markets. Moreover, a key differentiator of ATryn vs other drugs that have been considered as possible treatments for sepsis is that ATryn is both an anti-inflammatory agent and an anticoagulant (#msg-16968800).

The overall understanding of DIC in sepsis has advanced greatly in the past few years as the 2001 Kybersept data have been thoroughly analyzed for clues as to what went wrong (#msg-19225961). This, in turn, has led to renewed testing of antithrombin in animal models of DIC/sepsis, and the results of this testing have been encouraging (#msg-20150658).

With a firm scientific grounding from the new preclinical data and an enhanced understanding of the ramifications of Kybersept, it would seem that GTC’s DIC program has a good chance to bear fruit.

[DewDiligence]

AT in SIRS / Sepsis:

This paper says a low level of antithrombin is
the best known predictor of organ failure in SIRS.
(SIRS is a superset of sepsis in which the cause of
trauma is something other than a discernable infection.)

http://tinyurl.com/yrthon

>>
Predicting the Severity of Systemic Inflammatory Response Syndrome (SIRS)-Associated Coagulopathy With Hemostatic Molecular Markers and Vascular Endothelial Injury Markers

J Trauma. 2007 Nov;63(5):1093-1098.
.
Iba T, Gando S, Murata A, Kushimoto S, Saitoh D, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, Mayumi T, Ikeda T, Ishhikura H, Ueyama M, Ogura Y, Endo S, Shimazaki S; the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Study Group.

Division Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine (S.G.), Hokkaido University Graduate School of Medicine; Department of Trauma & Critical Care Medicine (A.M.), Kyorin University School of Medicine; Department of Emergency & Critical Care Medicine (S.K.), Nippon Medical School; Department of Traumatology and Critical Care Medicine (D.S.), National Defense Medical College; Critical and Intensive Care Medicine (Y.E.), Shiga University of Medical Science; Department of Critical Care and Traumatology (Y.O.), National Disaster Medical Center; Department of Surgery 1 (K.O.), School of Medicine, University of Occupational and Environmental Health; Emergency and Critical Care Medicine (K.K.), Kawaguchi Municipal Medical Center; Department of Emergency Medicine and Intensive Care (T.M.), Nagoya University School of Medicine; Department of Critical Care and Emergency Medicine (T.I.), Tokyo Medical University Hachioji Medical Center; Department of Emergency and Critical Care Medicine (H.I.), National Hospital Organization, Kyoto Medical Center; Shakaihoken Cyukyo Hospital (M.U.); Department of Traumatology and Acute Critical Care Medicine (H.O.), Osaka University Medical School; Department of Critical Care Medicine (S.E.), School of Medicine, Iwate Medical University; and Department of Trauma & Critical Care Medicine (S.S.), Kyorin University School of Medicine.

INTRODUCTION: The changes in biomarkers of coagulation or fibrinolysis, anticoagulation, inflammation, and endothelial damage occur in patients with systemic inflammatory response syndrome (SIRS). The purpose of this study is to assess the prognostic value of these markers in patients with SIRS-associated hypercoagulopathy.

METHODS: Sixty-six SIRS patients with a platelet count less than 15.0 x 10/mm in three university hospital intensive care units were enrolled in this prospective, comparative study. Blood samples were obtained on day 0 and day 2. Twelve hemostatic, inflammatory, and vascular endothelial indices were measured and the data were compared between the severe group (patients with a total maximum Sequential Organ Failure Assessment score of 10 or more and nonsurvivors; n = 25) and the less-severe group (Sequential Organ Failure Assessment score <10; n = 41).

RESULTS: Significant changes between the groups were observed in platelet count, fibrin or fibrinogen degradation products, interleukin-6, soluble thrombomodulin, antithrombin (AT) activity, and protein C activity, both on day 0 and on day 2. In contrast, the d-dimer, soluble fibrin, plasmin-alpha2-antiplasmin complex, and E-selectin levels were higher in the severe group only on day 2. No significant difference was seen regarding the thrombin-AT complex and total plasminogen activator inhibitor on both days. A comparison of the areas under the receiver operating characteristic curve revealed the AT activity to be the best predictor of a progression of organ dysfunction.

CONCLUSION: The changes in some hemostatic molecular markers and vascular endothelial markers were conspicuous in patients with organ dysfunction. The AT activity is considered to be the most useful predictor of organ dysfunction.
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[DewDiligence]

Scientific Rationale for ATryn in DIC/sepsis (summary version)

[This is a repost of Msg #3715
with fixes for the bad hyperlinks.]


The only approved drug for sepsis is LLY’s Xigris, which has been a commercial flop for the simple reason that it’s not a great drug (#msg-12483101).

Xigris does not address DIC, specifically, but rather sepsis in general. ATryn, on the other hand, is being targeted at DIC within the context of sepsis. I think it’s fair to say that these are two distinct markets. Moreover, a key differentiator of ATryn vs other drugs that have been considered as possible treatments for sepsis is that ATryn is both an anti-inflammatory agent and an anticoagulant (#msg-23010821).

The overall understanding of DIC in sepsis has advanced greatly in the past few years as the 2001 Kybersept data have been thoroughly analyzed for clues as to what went wrong (#msg-20150658). This, in turn, has led to renewed testing of antithrombin in animal models of DIC/sepsis, and the results of this testing have been encouraging.

With a firm scientific grounding from the new preclinical data and an enhanced understanding of the ramifications of Kybersept, it would seem that GTC’s DIC program has a good chance to bear fruit.

[DewDiligence]

Detailed Scientific Rationale for Atryn in DIC/Sepsis
(See bottom for original Kybersept study.)

[Added link to Wiedermann abstract.]


“Treatment Effects of High-Dose
Antithrombin Without Concomitant
Heparin in Patients With Severe
Sepsis With/Without Disseminated
Intravascular Coagulation”
Kienast, J et al
J Thromb Haemost. 2006 Jan;4(1):90-7
Abstract: #msg-9313165.
Paper: http://ihub.bedida.net/Key_DIC_sepsis_article.pdf

“Benefit/Risk Profile of High-Dose
Antithrombin in Patients with Severe
Sepsis Treated With and Without
Concomitant Heparin”
Hoffmann, J et al
Thromb Haemost. 2006 May;95(5):850-6.
Abstract: #msg-10993909.

“Antithrombin for Severe Sepsis?
Try Again But Without the Heparin!”
Jilma, B
Thromb Haemost. 2006 May;95(5):755.
Editorial: #msg-20139747.

“High-Dose Antithrombin in the Treatment
of Severe Sepsis in Patients with a High
Risk of Death: Efficacy and Safety”
Wiedermann, CJ
Crit Care. 2006 Feb 34(2):285-92.
Abstract: #msg-9363231

“Recombinant Human Antithrombin Inhibits
Thrombin Formation and Interleukin-6
Release in Human Endotoxemia”
Leitner, JM et al
Clin Pharmacol Ther. 2006 Jan;79(1):23-34.
Abstract: #msg-9313029.

“Endogenous Anticoagulant Therapy
for Sepsis: Success and Failure”
Wiedermann, CJ
Internist (Berl). 2007 Mar 28;
Abstract: #msg-18336592

“New Aspects in Management of
Disseminated Intravascular Coagulation:
DIC and Antithrombin”
Uchiba, M
Japanese J of Intensive Care Med, 25:11 843-848 (2001);
#msg-19983732.


Preclinical support

“Efficacy of Antithrombin in the Prevention of
Microvascular Thrombosis During Endotoxemia”
Sorg, H et al
Thromb Res. 2007 May 17;
Abstract: #msg-19868753.

“Treatment Effects of Antithrombin on Coagulation
Abnormalities in Rats With Endotoxaemia”
Qiao, YJ et al
Abstract: #msg-18166129


The original Kybersept study

“High-Dose Antithrombin in Severe
Sepsis: A Randomized Controlled Trial”
Warren, B et al
JAMA 2001 286:1869
http://scalpel.stanford.edu/articles/AT3.pdf