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Alnylam Releases Positive Preclinical Data from Hemophilia Program


Alnylam Pharmaceuticals this week released preclinical data showing that ALN-AT3, its investigational treatment for hemophilia and other bleeding disorders, can normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate hemophilia inhibitor model.

The findings were presented at the XXIV Congress of the International Society on Thrombosis and Haemostasis in Amsterdam.

According to the company, a single subcutaneous dose of ALN-AT3 that resulted in plasma antithrombin reduction of 90 percent led to normalization of thrombin generation in hemophilia B mice. I a microvessel laser injury model, both hemophilia A and hemophilia B mice treated with a single subcutaneous dose of ALN-AT3 demonstrated “marked improvements” in hemostatic plug formation compared to untreated animals.

Meanwhile, in wild-type non-human primates, repeat dosing with ALN-AT3 resulted in “potent, titratable, and reversible silencing of plasma antithrombin, the company said.

Weekly subcutaneous doses of 0.50 mg/kg resulted in 90 percent antithrombin knockdown, and an ED50 knockdown was achieved at a dose as low as 0.125 mg/kg, Alnylam added.

“Dosing was continued for over five months with consistent pharmacologic effects, including no evidence of tachyphylaxis or any neutralizing immune response associated with prolonged exposure to ALN-AT3.”

In a hemophila inhibitor model, in which a hemophilia A phenotype is induced via administration of a polyclonal anti-factor VIII antibody, six weekly doses of ALN-AT3 at 0.25 or 0.50 mg/kg resulted in an “expected” level of antithrombin knockdown, as well as a statistically significant dose-dependent increase in thrombin generation, restoring this hemostatic parameter back to normal.

“These results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key proof of concept for the program,” Alnylam said.

ALN-AT3 is slated to move into phase I testing later this year.