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Treatment of Hypercholesterolemia as New Development Program

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Alnylam Pharmaceuticals has announced that it will advance a systemically delivered RNAi therapeutic for the treatment of hypercholesterolemia as its next clinical development program.

This program, in collaboration with University of Texas Southwestern Center at Dallas, is focused on evaluating new approaches for reducing LDL cholesterol levels using RNAi therapeutics directed to the disease target called proprotein convertase subtilisn/kexin type 9, or PCSK9.

Alnylam expects to submit an investigational new drug (IND) application for this program in 2007.

PCSK9 is a gene involved in the metabolism of LDL cholesterol, or so-called "bad cholesterol." The normal role of the PCSK9 protein is to break down the cell surface receptor for LDL; when there is less PCSK9 protein, there is more receptor on the cell surface to remove LDL from the bloodstream.

In human studies, researchers at UT Southwestern Medical Center have discovered that mutant forms of PCSK9 that have increased activity are linked with a familial form of hypercholesterolemia.

Conversely, recent research published in the New England Journal of Medicine has demonstrated that other mutations in humans, those that lower PCSK9 function, are associated with decreased cholesterol levels and an 88 percent risk reduction in cardiovascular disease.

"PCSK9 is a compelling target for a potential breakthrough treatment of hypercholesterolemia and complications of acute coronary syndromes," said John Maraganore, Ph.D., President and Chief Executive Officer of Alnylam.

"Although PCSK9 is well validated based on human genetics, it has been a difficult protein to target using traditional drug discovery approaches. As a result we believe it is an ideal target for a systemic RNAi approach, particularly in light of our recent progress with systemic delivery of RNAi therapeutics."

"There is a clear unmet medical need for novel agents that can lower LDL cholesterol and PCSK9 appears to be an excellent target for disease intervention in hypercholesterolemia," said Jay Horton, M.D., Associate Professor of Internal Medicine and Molecular Genetics, UT Southwestern Medical Center.

"Based on its novel mechanism of action and pre-clinical data to date, we believe an RNAi therapeutic targeting PCSK9 has the potential to lower LDL cholesterol, while functioning synergistically with statins in the treatment of hypercholesterolemia."

Data recently presented by Alnylam scientists at the Oligonucleotide Therapeutics Society meeting have shown that small interfering RNAs (siRNAs), the molecules that mediate RNAi, can silence the PCSK9 gene in mice as measured by reductions in messenger RNA (mRNA) levels.

Further, gene silencing of PCSK9 mRNA resulted in reductions in cholesterol levels, yielding in vivo evidence that pharmacologic targeting of PCSK9 may result in potential therapeutic benefit.

The in vivo efficacy data for PCSK9 were obtained using systemic RNAi delivery technologies such as those described by Alnylam earlier this year in primate studies where systemic RNAi targeting apolipoprotein B (apoB), another protein involved in cholesterol metabolism, resulted in reduced levels of apoB mRNA and protein, and significant lowering of LDL cholesterol.