Alnylam Scientists Contribute to Discovery of a New Disease Gene in Cardiovascular Disease

– New Findings Published in Nature Highlight Applications of RNAi Technology in Genome-Wide Association Studies –

CAMBRIDGE, Mass.--(EON: Enhanced Online News)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of new research findings in the journal Nature describing the discovery and validation of the role of the gene Sort1 in the development of cardiovascular disease, including myocardial infarction (MI). This work was done with collaborators at University of Pennsylvania (UPenn) School of Medicine, Massachusetts General Hospital (MGH), and the Broad Institute. The collaborative effort combined genome-wide association studies (GWAS) and RNAi technology to identify and validate novel genes as targets for new therapies for heart disease.

“a major scientific breakthrough that happens once every decade or so”

“We are excited by the important advances we are making in the discovery and validation of novel genes in cardiovascular disease and metabolic syndrome,” said Kevin Fitzgerald, Ph.D., Senior Director, Research at Alnylam. “This work illustrates the power of our RNAi platform to significantly enhance the value of genome-wide association studies, and to functionally link phenotypes at complex genetic loci to specific pathways, mechanisms and ultimately individual gene targets. We look forward to continuing our efforts in the discovery of novel pathways and targets that may allow for therapeutic intervention in the reduction of cholesterol and prevention of heart attacks.”

“Worldwide, heart disease is the leading cause of mortality, and it is our goal with this effort to identify new gene targets for potential disease intervention in this area of profound medical need,” said Sekar Kathiresan, M.D. of the Center for Human Genetic Research and Cardiovascular Research Center and Director, Preventive Cardiology at MGH. “I am encouraged by the results of our disease association studies to date and am pleased with the combined efforts of my team at MGH, and collaborators at UPenn, the Broad Institute, and Alnylam to extend the association data to mechanism and function.”

Coronary heart disease (CHD) is the leading cause of mortality in both men and women worldwide and its incidence is highly correlated with levels of cholesterol and triglycerides in the blood. Plasma concentrations of low-density lipoprotein cholesterol (LDL-C, or “bad” cholesterol) and high-density lipoprotein cholesterol (HDL-C, or “good” cholesterol), as well as triglycerides, have a strong inherited basis and recent genetic association studies have linked previously unsuspected genes to these complex traits. Despite aggressive use of LDL-C-lowering medications such as statins, many individuals do not achieve LDL-C levels recommended by clinical guidelines. There remains a need for new medicines for reducing LDL-C.

The work described in Nature (Musunuru et al., Nature 466: 714-721, 2010) is part of a collaborative effort focused on validating novel genes as targets for new therapies for lipid disorders and heart disease, and provides early proof of concept on how GWAS combined with RNAi technology can yield important new insights into disease biology. Recent GWAS – including a report published in the same issue of Nature – have identified a locus on chromosome 1p13 as strongly associated with both high LDL-C levels and incidence of MI and CHD. The findings published in Nature today show through a series of studies in patient cohorts and human-derived hepatocytes that a common non-coding polymorphism at the 1p13 locus creates a novel transcription factor binding site which in turn increases the expression of several liver genes. Using a combination of over-expression and RNAi silencing techniques, the gene Sort1 was identified as a candidate gene responsible for the associated CHD effects. Knockdown in mouse liver using RNAi demonstrated that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Specifically, results showed the following for animals treated with an siRNA targeting Sort1:

• a 70%-80% reduction in Sort1 mRNA expression in liver, confirmed to be due to RNAi-mediated cleavage;
• a greater than 90% knockdown of Sort1 protein expression;
• in Apobec1–/–; APOB Tg mice, a 46% increase in total cholesterol compared to control mice at two weeks, with a more than two-fold increase in LDL-C; and,
• a significant increase in plasma VLDL levels.

“Our expertise in translational medicine as applied to human lipid disorders and their association with human disease, combined with our collaborators’ expertise in development of RNAi therapeutics, represents a powerful and rare opportunity to advance new innovative medicines in this area,” said Daniel Rader, M.D., the Cooper-McClure Professor of Medicine at the UPenn School of Medicine.

The work is being conducted under a two-year, $2.4 million research grant awarded to UPenn under the “American Recovery and Reinvestment Act of 2009.” The grant – Award Number RC2HL101864 from the National Heart, Lung, and Blood Institute – is funding studies in laboratories at UPenn School of Medicine, MGH, and Alnylam. The goal is to mechanistically evaluate the metabolic and molecular effects of novel genes implicated by human genetic studies in prevention of cardiovascular disease and to discover and develop RNAi therapeutics towards these gene candidates. Through an agreement with UPenn and MGH, Alnylam will retain the rights to develop and commercialize RNAi therapeutics from the research effort.

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. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific 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 for the treatment of a wide range of disease areas, including respiratory syncytial virus (RSV), liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington’s disease. In addition, Alnylam formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in manufacturing processes for biotherapeutic products, including recombinant proteins and monoclonal antibodies. 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, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Alnylam Forward-Looking Statement

Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s views with respect to the potential for the development of RNAi therapeutics to treat cardiovascular disease and metabolic syndrome, 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 Alnylam’s ability to discover and develop novel drug candidates, including drug candidates to treat cardiovascular disease and metabolic syndrome, 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.