in vivo non-human primate data showing durable silencing of PCSK9 for more than 30 days following a single dose administration, with reduction in LDL cholesterol levels of approximately 50%; unlike results reported with monoclonal antibody strategies targeting extracellular PCSK9 (Chan et al., Proc. Natl. Acad. Sci. USA, 106(24): 9820-5, 2009), RNAi-mediated silencing of both intracellular and extracellular PCSK9 resulting in no lowering of HDL (or healthy) cholesterol; in vivo rodent data demonstrating the ability to utilize a novel dual-targeting approach to silence PCSK9 and a second undisclosed gene involved in lipid metabolism with a single RNAi therapeutic, resulting in a reduction in total cholesterol of greater than 40%; and, in vivo rodent data showing that injection of multiple siRNAs packaged in a single LNP formulation results in silencing of as many as 10 distinct target genes simultaneously.

These new data continue to support the development of an RNAi therapeutic strategy of targeting PCSK9 for disease intervention in hypercholesterolemia, said Jay Horton, M.D., Professor of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center. Based on its novel mechanism and promising pre-clinical data observed to date, an RNAi therapeutic targeting PCSK9 has the potential to lower LDL cholesterol while preserving HDL cholesterol, and possibly function synergistically with statins for the treatment of hypercholesterolemia.

Alnylam is developing ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-PCS is a systemically delivered RNAi therapeutic comprised of an optimized siRNA encapsulated in a second generation LNP formulation. Alnylam expects to advance its ALN-PCS program toward the clinic with a goal of initiating a Phase I clinical trial in 2011.