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Alnylam and Collaborators Publish New Preclinical Research on RNAi-Mediated Silencing of PCSK9

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Aug 12, 2008 - Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today announced that new pre-clinical data from its hypercholesterolemia program was published in Proceedings of the National Academy of Sciences (Frank-Kamenetsky, M., et al (August 11, 2008) Proc. Natl Acad. Sci. USA, 10.1073/pnas.0805434105). The published, peer-reviewed data demonstrate for the first time that a chemically synthesized small interfering RNA (or siRNA, the molecules that mediate RNAi) targeting the gene proprotein convertase subtilisin/kexin type 9 (PCSK9) achieves acute and durable lowering of total cholesterol levels in both mice and rats, and LDL cholesterol levels in non-human primates. Human genetic studies have correlated increased levels of PCSK9 with an increased risk of cardiovascular disease (Abifadel et al., Nature Genetics, 34 (2): 154-6; 2003). Conversely, human genetic studies have confirmed a nearly 88 percent reduced risk of cardiac events in subjects with decreased levels of PCSK9 (Cohen et al., New England Journal of Medicine, 354: 1264-72; 2006).

The new research, conducted by Alnylam scientists in collaboration with scientists at UT Southwestern Medical Center in Dallas, Alnylam Europe (now Roche Kulmbach), and the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, demonstrated in vivo efficacy for an RNAi therapeutic targeting PCSK9 in mice, rats, and non-human primates. Specifically, the data showed:

-- potent silencing of PCSK9 mRNA in mouse, rat, non-human primate, and in a transgenic model expressing human PCSK9;

-- highly selective silencing of the PCSK9 messenger RNA (mRNA) by PCSK9 specific siRNAs as compared with unrelated siRNA controls and lack of induction of INF(alpha) and TNF(alpha) by chemically modified siRNA compounds;

-- proof of an RNAi mechanism of action as determined by 5'-RACE measurements;

-- acute onset of action and long durability of biologic effect with reductions in total cholesterol levels in rodents and LDL cholesterol in primates observed by 48 to 72 hours that lasted 2 to 3 weeks after a single administration;

-- mechanistic rationale for cholesterol lowering as demonstrated by reduction in PCSK9 plasma protein levels and a concomitant increase in LDL-receptor levels in liver;

-- therapeutic efficacy as measured by significant reductions in LDL-cholesterol levels by up to 60 percent of pre-dose levels in nonhuman primates; and,

-- tolerability as analyzed by numerous measurements including liver triglyceride levels with no statistical differences observed between treatment versus control groups.

Partial results of this study were previously presented at the XVI International Symposium on Drugs Affecting Lipid Metabolism in October 2007.

"We are very encouraged by the significance of these findings, including data in non-human primates, which continue to validate PCSK9 as an attractive target for a systemic RNAi therapeutic approach given its ability to achieve acute and durable reductions in LDL cholesterol," said Victor Kotelianski, M.D., Ph.D., Vice President of Research at Alnylam. "PCSK9 is well validated based on human genetics, but it has been a difficult protein to target using traditional drug discovery modalities, such as small molecules and monoclonal antibodies. Thus, RNAi affords perhaps the only viable approach for new medicines targeting this key mechanism for control of LDL metabolism."

"There is a clear unmet medical need for novel agents that can lower LDL cholesterol, and PCSK9 appears to be an excellent, genetically validated target for disease intervention," said Jay Horton, M.D., Professor of Internal Medicine and Molecular Genetics, UT Southwestern Medical Center. "Based on its novel mechanism of action and pre-clinical data to date, an RNAi therapeutic targeting PCSK9 has the potential to rapidly lower LDL cholesterol, while possibly functioning synergistically with statins in 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 liposomal nanoparticle formulation.

About PCSK9

PCSK9 is an important gene involved in the metabolism of LDL 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 cholesterol from the bloodstream. In human studies, 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 (Cohen et al., New England Journal of Medicine, 354: 1264-72; 2006) has demonstrated that other mutations in humans, including those that lower PCSK9 function, are associated with decreased LDL cholesterol levels and an 88 percent risk reduction in cardiovascular disease.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. RNAi therapeutics target the cause of diseases by potently silencing specific messenger RNAs (mRNAs), thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

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 leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, hypercholesterolemia, and Huntington's disease. 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 Medtronic, Novartis, Biogen Idec, Roche, Takeda, and Kyowa Hakko Kogyo. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam has established "RNAi 2010" which includes the company's plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, visit

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, 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: Alnylam's approach to discover and develop novel drugs, including ALN-PCS, which is unproven and may never lead to marketable products; obtaining, maintaining and protecting intellectual property; Alnylam's ability to enforce its patents against infringers and to defend its patent portfolio against challenges from third parties; Alnylam's ability to obtain additional funding to support its business activities; Alnylam's ability to realize future milestones and royalties as well as co-development and co-commercialization opportunities; Alnylam's dependence on third parties for development, manufacture, marketing, sales and distribution of products; obtaining regulatory approval for products; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's dependence on collaborators; and Alnylam's short operating history; as well as those risks more fully discussed in the "Risk Factors" section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam does not assume any obligation to update any forward-looking statements.


Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207 (Investors)
Yates Public Relations
Kathryn Morris, 845-635-9828 (Media)


Posted: August 2008