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Alnylam Provides Key 2012 Goals for RNAi Therapeutics Pipeline

Alnylam Scientists Present New Data on RNAi Therapeutics at 53rd ASH Annual Meeting

ALN-APC: Hemophilia

ALN-APC is a systemically delivered RNAi therapeutic targeting protein C, a genetically defined target. Protein C is expressed exclusively in the liver, circulates in plasma, and defines a key natural anticoagulant pathway. Activated protein C (APC) inactivates factors Va and VIIIa, both proteins in the blood coagulation pathway, resulting in reduced thrombin generation. ALN-APC provides a pharmacologic strategy to reproduce the human genetics observed with co-inheritance of prothrombotic factors in hemophilia. RNAi silencing of protein C is expected to increase thrombin generation in hemophilia patients thereby reducing the frequency of bleeding.

Pre-clinical data presented at the 53rd American Society of Hematology (ASH) data demonstrate dose-dependent silencing of protein C mRNA with silencing of greater than 90% and an ED50 of approximately 0.02 mg/kg. When administered as a single dose of 0.3 mg/kg, the lipid nanoparticle (LNP)-formulated siRNA achieved greater than 75% silencing of protein C mRNA with effects lasting for over two weeks.

ALN-APC is the fourth development program to be designated as part of our Alnylam 5x15 strategic initiative. Alnylam is exploring both systemically delivered LNP and subcutaneously delivered GalNAc-conjugate approaches for ALN-APC with the goal of selecting the clinical candidate in the first half of 2012. Alnylam plans to advance its ALN-APC program toward the clinic with a goal of initiating a Phase I clinical trial in the first half of 2013 with data expected in the second half of 2013.

ALN-APC Clinical timeline

Disease Info

Hemophilia is a hereditary disorder caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in factor VIII, and there are greater than 40,000 registered patients in the U.S. and the E.U. Hemophilia B, defined by loss-of-function mutations in factor IX, affects approximately 9,500 patients in the U.S. and E.U. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of hemophilia A patients will develop an antibody to their replacement factor - a very serious complication; these 'inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have inherited a prothrombotic mutation in factor V (known as factor VLeiden) which results in resistance to protein C, a natural anticoagulant protein. Other hemophilia patients have been described that have co-inherited deficiencies in protein C itself. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for factor VIII or factor IX treatment as part of their disease management.