Healthcare Industry News:  PCSK9 


 News Release - December 5, 2006

Alnylam Advances a Systemically Delivered RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia as New Development Program

Company Expects to File IND for PCSK9 Program in 2007

CAMBRIDGE, Mass.--(HSMN NewsFeed)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY ), a leading RNAi therapeutics company, announced today 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 (UT) Southwestern Medical 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 an important 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 (N. Engl. J. Med. 354, 1264-1272, 2006) 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 meaningful 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 (Nature 441: 111-114, 2006) 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.

Alnylam will be presenting updates on its research and development programs, including its hypercholesterolemia program, at its R&D Day to be held this morning beginning at 8:30 a.m. ET at the Sofitel New York in New York City. A replay of the presentation will be posted on the Alnylam website approximately three hours after the event, and will be archived for 30 days.

About Hypercholesterolemia

Hypercholesterolemia, or high levels of cholesterol in the blood, contributes to many diseases, most notably cardiovascular disease. Some forms of hypercholesterolemia can be treated through dietary restrictions and medicines such as statins, however, large populations are not being met by statin therapy including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, and other patient populations that are statin in-tolerant.

About RNA Interference (RNAi)

RNA interference, or RNAi, is a naturally occurring mechanism within cells for selectively silencing and regulating specific genes. Since many diseases are caused by the inappropriate activity of specific genes, the ability to silence genes selectively through RNAi could provide a new way to treat a wide range of human diseases. RNAi is induced by small, double-stranded RNA molecules. One method to activate RNAi is with chemically synthesized small interfering RNAs, or siRNAs, which are double-stranded RNAs that are targeted to a specific disease-associated gene. The siRNA molecules are used by the natural RNAi machinery in cells to cause highly targeted gene silencing.

About Alnylam

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is building a pipeline of RNAi therapeutics; its lead program is in Phase I human clinical trials for the treatment of respiratory syncytial virus (RSV) infection, which is the leading cause of hospitalization in infants in the U.S. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, and Biogen Idec. The company, founded in 2002, maintains global headquarters in Cambridge, Massachusetts, and has an additional operating unit in Kulmbach, Germany. Alnylam is honored to be the "emerging/mid-cap" company recipient of the 2006 James D. Watson Helix Award, the biotechnology industry's award for outstanding achievement. For more information, visit

Alnylam Forward-Looking Statements

Various statements in this release concerning our future expectations, plans, and prospects, including the timing for the filing of an investigational new drug application for, and statements regarding the development of, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including risks related to: our approach to discover and develop novel drugs, which is unproven and may never lead to marketable products; our ability to fund and the results of further pre-clinical and clinical trials; obtaining, maintaining and protecting intellectual property utilized by our products; our ability to enforce our patents against infringers and to defend our patent portfolio against challenges from third parties; our ability to obtain additional funding to support our business activities; our dependence on third parties for development, manufacture, marketing, sales, and distribution of products; the successful development of our product candidates, all of which are in early stages of development; obtaining regulatory approval for products; competition from others using technology similar to ours and others developing products for similar uses; our dependence on collaborators; and our short operating history; as well as those risks more fully discussed in the "Risk Factors" section of our most recent report on Form 10-Q on file with the Securities and Exchange Commission. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Alnylam does not assume any obligation to update any forward-looking statements.

Source: Alnylam Pharmaceuticals

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