Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication in The Lancet of complete study results from a Phase I trial with ALN-PCS, a systemically administered RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. The paper, titled “ Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial,” (Fitzgerald, et al., The Lancet, doi:10.1016/S0140-6736(13)61914-5) reports the results of a study evaluating single intravenous dose administration of ALN-PCS, in the absence of concomitant lipid-lowering agents such as statins. Specifically, ALN-PCS administration resulted in a rapid, dose-dependent reduction in plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of low-density lipoprotein cholesterol (LDL-C) – a clinically validated endpoint – of up to 57% relative to baseline and placebo. The knockdown of PCSK9 and lowering of LDL-C were also found to be durable, with effects lasting for weeks after a single dose. This new paper documents the first human proof of concept for an RNAi therapeutic impacting a clinically validated endpoint.
“Our data with ALN-PCS demonstrate that inhibition of PCSK9 synthesis by an RNAi therapeutic may be a potentially safe and novel approach to reduce LDL-C. The study also documents the first human proof of concept for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C,” said Kevin Fitzgerald, Ph.D., Senior Director of Research at Alnylam and lead author on the paper. “We believe that the unique mechanism of action for ALN-PCS, which inhibits the synthesis of PCSK9 inside liver cells – thereby reducing both its intracellular and extracellular functions – provides a differentiated strategy for PCSK9 antagonism. This mechanism of action results in consistent clinical activity across a wide range of baseline PCSK9 plasma levels, including in individuals with very high PCSK9 levels. Together with The Medicines Company, we are now advancing ALN-PCSsc, a GalNAc-siRNA targeting PCSK9, which we believe will enable subcutaneous dose administration with a wide therapeutic index, and expect to designate our development candidate by the end of this year.”