New Pre-clinical Data with our Hemophilia Program

New Pre-clinical Data with our Hemophilia Program

At the World Federation of Hemophilia World Congress in July 2012, scientists presented pre-clinical data with ALN-AT3, our development candidate targeting antithrombin (AT) for the treatment of hemophilia.  The new data demonstrate potent and durable AT knockdown with subcutaneous administration of ALN-AT3.  ALN-AT3 was shown to improve thrombin generation in hemophilia animal models.




Results presented included studies performed to identify the optimal endogenous anticoagulant target and delivery modality for further RNAi therapeutic development in hemophilia.  siRNA targeting both PC and AT were designed, synthesized, and evaluated in vivo, showing robust, dose-dependent silencing of the target mRNA.  An RNAi therapeutic targeting AT was selected for further development.  First, using a validated in silico model of human thrombin generation, knockdown of AT was found to generate significantly higher levels of thrombin in the absence of factor VIII as compared with knockdown of PC.  In addition, exogenous supplementation of human plasma depleted of both factor IX and AT showed that an approximately 50% decrease in endogenous AT can significantly correct thrombin generation in a hemophilia setting.  A GalNAc-siRNA conjugate was selected as the delivery modality for further development.  Specifically, a large series of GalNAc-siRNA were designed and synthesized, leading to the selection of ALN-AT3 as the program’s development candidate.  As a GalNAc-siRNA conjugate, ALN-AT3 achieves target gene knockdown with subcutaneous dose administration, a highly preferred mode of administration in the setting of hemophilia.  Based on these results, Alnylam will be advancing ALN-AT3 for its hemophilia program in our “Alnylam 5×15” product strategy.

Additional data presented demonstrate that subcutaneous administration of ALN-AT3 results in potent, dose-dependent, and durable silencing of AT in preclinical models and that AT reduction can normalize thrombin generation, establishing proof-of-concept for this program.  ALN-AT3 demonstrated potent activity in both mice and non-human primates, with an ED50 for AT plasma protein knockdown of approximately 1 mg/kg after a single subcutaneous dose.  Studies showed a very durable response, where a single subcutaneous dose of ALN-AT3 achieved nadir knockdown of AT at about day 10, with effects lasting over 25 days.  These data support a once-a-week or twice-a-month subcutaneous dosing paradigm with ALN-AT3 for the treatment of hemophilia.  In studies performed in mouse models of hemophilia, ALN-AT3 was found to achieve dose-dependent knockdown of endogenous AT and to significantly increase thrombin generation.  Specifically, in a mouse model of hemophilia, animals treated with ALN-AT3 showed a complete normalization of thrombin generation to levels found in wild-type mice.  These results confirm the findings from human genetics where co-inheritance of prothrombotic traits in hemophilia patients is associated with improved hemostasis.  Further, these new data with ALN-AT3 establish clear pre-clinical proof of concept for this novel therapeutic strategy



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