Alnylam Announces Progress in Pre-Clinical Hypercholesterolemia RNAi Therapeutic and microRNA Programs.

- Data Demonstrate In Vivo Activity with Systemic RNAi Therapeutics Targeting PCSK9 for Hypercholesterolemia 

- Advancements with Antagomirs, Potential RNAi Therapeutics that Target microRNAs

CAMBRIDGE, Mass. -- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it presented pre-clinical data at the 2nd Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) held October 19-21, 2006 in New York City. Alnylam scientists presented pre-clinical in vivo efficacy data from its hypercholesterolemia program evaluating new approaches for reducing LDL-cholesterol levels using RNAi therapeutics directed to a disease target called proprotein convertase subtilisn/kexin type 9, or PCSK9. Alnylam is conducting this program in collaboration with researchers at University of Texas Southwestern Medical Center at Dallas with a focus on developing RNAi therapeutics for PCSK9, a key gene involved in the regulation of LDL cholesterol. An update on Alnylam's microRNA (miRNA) effort was also presented at the meeting.

Data presented at the OTS meeting showed for the first time 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 the PCSK9 mRNA resulted in meaningful reductions in cholesterol levels, yielding the first in vivo evidence that pharmacologic targeting of PCSK9 can result in potential therapeutic benefit. The in vivo efficacy data for PCSK9 was 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.

"We are very encouraged that within months of the initiation of our program, we have obtained data demonstrating that systemic RNAi targeting PCSK9 showed in vivo efficacy in animal models," said Victor Kotelianski, M.D., Ph.D., Vice President, Research at Alnylam. "PCSK9 is a compelling target for the novel treatment of hypercholesterolemia where there is substantial clinical validation from human genetics, and where a systemically delivered RNAi therapeutic represents an exciting approach for disease intervention."

In addition, Dr. Markus Stoffel, Professor at The Rockefeller University and Alnylam collaborator and Scientific Advisory Board member, presented an update on antagomirs, an RNAi therapeutic strategy to silence microRNAs (miRNAs.) miRNAs are a recently discovered category of genes that encode small RNAs that in turn regulate a larger number of genes in the human genome through the RNAi pathway. Abnormal expression or mutation of miRNAs has been implicated in disease processes including cancer, viral infection, and metabolic disease. Antagomirs are a potential new class of chemically modified RNA-based drugs that specifically silence miRNAs following therapeutically relevant administration in animals, and their discovery was first reported by scientists at Alnylam and The Rockefeller University in the journal Nature (Nature 438: 685-689, 2005). The company believes that this research creates the opportunity to design antagomirs that target miRNAs in the context of human diseases.

The data presented from the miRNA program builds on previous studies showing that intravenous administration of antagomirs resulted in profound reduction of corresponding miRNA expression in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries, and adrenals. New findings demonstrated that direct administration of antagomirs to the central nervous system resulted in silencing of miRNAs expressed in the brain. In addition, the key structural features of antagomirs and their mechanism of action was further explored, showing that antagomirs as short as 19 nucleotides in length maintain a high degree of selectivity, and that antagomirs can mediate enzymatic degradation of the targeted miRNA.

"Antagomirs have the potential to be a new RNAi therapeutic approach to regulate miRNAs in vivo, possibly representing a novel strategy for silencing miRNAs involved in the cause or pathway of human disease," said Muthiah Manoharan, Ph.D., Vice President, Drug Discovery at Alnylam. "We continue to make important advances with our antagomir platform, which we view as an important component of our leading capabilities for discovery and development of innovative medicines that harness the RNAi pathway."

Alnylam and The Rockefeller University have a collaboration agreement for research in the field of RNAi. Alnylam has taken an exclusive license to all of The Rockefeller University's interest in antagomir technology.

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 microRNA (miRNA)

RNAi can also be induced by microRNAs, or miRNAs, that occur naturally within all mammalian cells. The miRNA molecules are encoded by the cell's own genes, giving rise to small RNA molecules that are similar in structure to siRNAs. There are believed to be over 250 confirmed miRNA genes in the human genome and there are many other predicted miRNAs. miRNAs are thought to work through RNAi to regulate the activity of an estimated one-third of genes in the genome. The inappropriate absence or presence of specific miRNA molecules in various cells has been shown to be associated with specific human diseases, including cancer and viral infections. Alnylam scientists and collaborators have discovered antagomirs, a class of chemically modified RNA-based drugs that are designed to specifically silence miRNAs in human disease.

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 www.alnylam.com.

Alnylam Forward-Looking Statements

Various statements in this release concerning our future expectations, plans, and prospects, including with respect to the potential for RNAi therapeutics, the development of RNAi therapeutics targeting PCSK9, and the development of antagomirs for the treatment of disease, 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.