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.


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.


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.


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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