Replies to post #5032 on GTC Biotherapeutics (fka GTCB)

[DewDiligence]

ATryn vs Factor Xa Inhibitors

[Reposted to fix bad links in msg #3406.]


Apixaban and other Factor Xa inhibitors in development (rivaroxaban from Bayer/JNJ and LY517717 from LLY) are not direct competitors of ATryn. Nor are low-molecular-weight heparins such as Lovenox, which act on FXa.

The diagram in #msg-23010615 depicts a simplified version of the clotting cascade. Thrombin (also called Factor II) catalyzes the conversion of FV->FVa and FVIII->FVIIIa; this creates a feedback loop though FXa that accelerates the production of more thrombin. (The feedback loop is omitted from the diagram in for simplicity.) Thus, inhibiting FXa inhibits the feedback loop and causes less thrombin to be produced. However, without a normal amount of circulating antithrombin, such inhibition is not effective, and an excessive—and clinically dangerous—amount of thrombin can be produced.

The above discussion applies to essentially any thrombotic condition. For disseminated intravascular coagulation (DIC) secondary to sepsis, the need for a sufficient amount of circulating antithrombin is even stronger. As shown in the diagram in #msg-23010821, both anti-inflammatory and anti-thrombin activity are vital to avert the cascade responsible for DIC in sepsis. ATryn has both anti-thrombin and anti-inflammatory properties.

Finally, it’s important to bear in mind that ATryn is intended to be a treatment for acute indications; its cost and administration by infusion makes it impractical for chronic use. On the other hand, the FXa inhibitors being developed by Big Pharma are pills whose economic justification comes mostly from their potential in chronic-use settings.

[DewDiligence]

[Semi-OT] This graphic shows the MoA of MNTA’s
M118; note the prominent role played by antithrombin:

#msg-24393520