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Alnylam Presents Preclinical Data from Hemophilia, Hemoglobinopathy Programs


Alnylam Pharmaceuticals this week presented preclinical data from its hemophilia and bleeding disorder program, showing that its subcutaneously administered drug candidate ALN-AT3 could trigger potent, dose-dependent, durable target knockdown in non-human primates.

The company also reported data indicating that its hemoglobinopathy treatment ALN-TMP had disease-modifying effects in an animal model of B-thalassemia.

The data were presented at the 54th American Society of Hematology annual meeting this week.

ALN-AT3 is comprised of siRNAs targeting the anticoagulant antithrombin, or AT, and formulated with Alnylam's GalNAc-conjugate technology. It is expected to be ready for human testing by mid-2013.

Alnylam said that a single subcutaneous dose of ALN-AT3 resulted in potent knockdown of serum AT, with an ED50 of 1 mg/kg in non-human primates.

“AT suppression was durable, with effects lasting greater than six weeks after a single dose,” the company said. In addition, weekly subcutaneous doses of ALN-AT3 led to sustained AT knockdown of approximately 80 percent and greater than 90 percent at 0.5 mg/kg and 1.5 mg/kg, respectively.

“These data enable an estimation of an ED50 dose for weekly subcutaneous administration at 0.15 [to] 0.3 mg/kg at a volume of injection for human administration expected to be less than 0.5 mL/injection,” Alnylam said. “Moreover, increased thrombin generation was closely correlated with AT reduction, with an up to four-fold increase in peak thrombin at 90 percent AT reduction.”

ALN-TMP is designed to inhibit transmembrane protease, serine 6, or Tmprss6. The company's data indicate that systemic administration of the drug could reduce the severity of anemia as evidenced by an approximately 1 g/dL increase in total hemoglobin in a mouse model.

Treatment was also found to significantly attenuate extra-medullary hematopoiesis, including a two- to three-fold reduction in spleen size, and decrease ineffective erythropoiesis, with a three- to four-fold decrease in reticulocyte count, an approximate 30 percent increase in red blood cell count (RBC), and a normalization of RBC morphology and lifespan.

“Finally, ALN-TMP administration was found to restore the ratio of alpha globin to beta globin, thereby correcting the genetic defect associated with B-thalassemia with possible implications for the treatment of other hemoglobinopathies such as sickle cell anemia,” Alnylam said.

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