Alnylam (ALNY) Offers New Pre-Clinical Data on RNAi Therapeutic Program in Hemophilia

July 11, 2012 8:04 AM EDT
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with its RNAi therapeutic for the treatment of hemophilia at the World Federation of Hemophilia World Congress being held July 8-12, 2012 in Paris. Alnylam scientists presented data comparing robust RNAi-mediated silencing of protein C (PC) and antithrombin (AT), two natural anticoagulant proteins. Studies showed that AT, an endogenous inhibitor of thrombin generation, is the optimal anticoagulant target and Alnylam has now designated ALN-AT3, an RNAi therapeutic targeting AT, as the development candidate for its hemophilia program. ALN-AT3 utilizes Alnylam’s proprietary GalNAc-siRNA conjugate delivery approach enabling subcutaneous administration with the potential for a once-weekly or twice-monthly dosing regimen. In pre-clinical animal models of hemophilia, administration of ALN-AT3 resulted in increased thrombin generation demonstrating proof of concept for this novel strategy. Alnylam expects to file an investigational new drug (IND) application for ALN-AT3 in 2013.

These new results 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 its “Alnylam 5x15” product strategy. Further efforts on ALN-APC, an RNAi therapeutic targeting PC, will therefore be stopped.

Additional data presented demonstrate that subcutaneous administration of ALN-AT3 results in potent, dose-dependent, and durable silencing of AT in pre-clinical models and that AT reduction can normalize thrombin generation in the setting of hemophilia, 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. 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, we believe these new data with ALN-AT3 establish clear pre-clinical proof of concept for this novel therapeutic strategy.

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