Pre-Clinical Data from “Alnylam 5×15” Programs Presented at ASH 2013

Pre-Clinical Data from “Alnylam 5×15” Programs Presented at ASH 2013

We presented pre-clinical data from three programs within our “Alnylam 5×15” RNAi therapeutic pipeline: ALN-AT3 for the treatment of hemophilia and rare bleeding disorders (RBD), ALN-CC5 for the treatment of complement-mediated diseases, and ALN-TMP for the treatment of β-thalassemia and iron overload disorders. These data were presented at the 55th Annual Meeting of the American Society of Hematology (ASH) held December 7 – 10 in New Orleans.



ALN-AT3


In these studies, repeat administration of ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than levels required to achieve 50% AT knockdown. Further, the new studies demonstrate that ALN-AT3 administration achieves complete correction of the activated Partial Thromboplastin Time (aPTT) – an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia – in HA mice.

ALN-CC5


Our pre-clinical results demonstrated that subcutaneous administration of ALN-CC5 in non-human primates (NHPs) led to an up to 98% knockdown of serum C5, which was associated with an up to 94% inhibition of hemolytic activity. Knockdown of C5 was durable, with greater than 90% knockdown sustained for up to three weeks after the final dose of the multi-dose study. In addition, multi-dose administration of ALN-CC5 resulted in robust and durable inhibition of hemolytic activity and was shown to be highly correlated with serum levels of C5.

ALN-TMP



Results presented at ASH showed that weekly subcutaneous administration of ALN-TMP resulted in robust knockdown of TMPRSS6 mRNA in mice, with about 90% knockdown achieved at a dose of 1.0 mg/kg.  This level of knockdown was associated with a two-fold increase in serum hepcidin levels and a greater than 50% decrease in transferrin saturation. In addition, results from studies in a mouse model of β-thalassemia intermedia showed that administration of ALN-TMP – but not the iron chelator deferiprone – ameliorated anemia and extramedullary hematopoiesis, including increases in hemoglobin, decreases in serum erythropoietin, and reduction in splenomegaly. On the other hand, ALN-TMP and deferiprone were found to act alone or in an additive manner toward reducing serum and liver iron levels.



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