Alnylam Presents New Pre-Clinical Data on RNAi Therapeutics at Oligonucleotides Therapeutics Society (OTS) Meeting

– Research Findings Include Rational Design of Mimetic Lipoprotein Particles (MLPs), a Novel Delivery Technology, New Data Regarding Potency of RNAi-Mediated Gene Silencing, and an Update on RNA Activation Research Efforts –

CAMBRIDGE, MA, USA | November 5, 2009 | Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it presented new data related to its overall delivery research efforts including the rational design of Mimetic Lipoprotein Particles, or MLPs, a novel technology for the systemic delivery of small interfering RNAs, or siRNAs, the molecules that mediate RNAi. In addition, Alnylam scientists and collaborators presented additional new data on systemic delivery and provided an update on RNA activation (RNAa) technology. These new data were presented at the 5th Oligonucleotide Therapeutics Society/19th Antisense Joint Symposium held November 3-6, 2009 in Fukuoka, Japan.

“Delivery of siRNAs remains one of the most important objectives in our efforts to advance RNAi therapeutics to patients,” said Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished Alnylam Fellow. “Accordingly, we are very excited by our new efforts in the rational design of MLPs, a whole new strategy for systemic delivery. Indeed, MLPs are designed to harness natural physiologic pathways in their delivery of siRNAs and they represent an important convergence of Alnylam’s research on conjugate- and lipid nanoparticle-based delivery strategies. In addition to our continued efforts on a wide range of other delivery technologies, this new line of research continues to demonstrate Alnylam’s scientific leadership in RNAi.”

In a poster titled “Lipophilic siRNA Delivery by Reconstituted Lipoprotein Particles In Vivo” Tomoko Nakayama, Ph.D., Associate Director, Research at Alnylam, presented for the first time the rational design and characterization of MLPs as an RNAi delivery platform. MLPs were designed to mimic the physiologic properties of endogenous lipoprotein particles and were engineered using recombinant human apolipoprotein A1 (rh-apoA1) or recombinant human apolipoprotein E (rh-apoE), phosphatidylcholine, and a cholesterol-conjugated siRNA (chol-siRNA). The resulting MLPs had biophysical properties comparable to normal high-density lipoprotein (HDL, or “good” cholesterol) particles including a mean diameter size of approximately 10 nm. The stoichiometry for siRNA:particle loading ratio was observed to be 1:1. The reported in vivo studies were performed in mice using MLPs with chol-siRNAs targeting apolipoprotein B (apoB), the major apolipoprotein involved in the metabolism of low-density lipoprotein (LDL, or “bad”) cholesterol. Administration of the MLP resulted in silencing of the apoB mRNA by up to 80% with an associated 50 to 80% reduction in levels of plasma apoB protein and cholesterol in mice. These data also demonstrated significant improvements in the potency of apoB silencing when using MLP-delivery of siRNAs as compared with use of chol-siRNAs alone. The study further demonstrated that apoE-MLP was more effective in delivering siRNAs than apoA-MLPs, at least as measured for the silencing of the liver-expressed target gene.

In addition, Dr. Muthiah Manoharan, Alnylam’s Vice President, Drug Discovery, gave a talk titled “Chemical Strategies for Delivering RNAi” in which he presented new research on lipid nanoparticle and conjugate-based delivery of siRNA. The new data showed continued improvement in the in vivo potency of siRNA delivered by lipid nanoparticles (LNPs), where the median effective dose (ED50) for gene silencing was achieved at microgram/kilogram dose levels. Further, quantitation of siRNA revealed the ability to achieve ED50 target gene silencing at tissue levels of approximately one nanogram/gram tissue.

“The resulting research efforts of our scientists and collaborators continue to represent what we believe is remarkable progress on delivery of RNAi therapeutics,” said Dr. Manoharan. “Importantly, with the novel LNP formulations we have discovered, we are now on a research trajectory for in vivo gene silencing potency of siRNA at single-digit microgram/kilogram dose levels. Further, we have now documented for the first time that the siRNA tissue levels required for gene silencing are approximately one nanogram/gram tissue, highlighting the power of harnessing a natural, catalytic mechanism.”

Further, Alnylam scientists and collaborator Dr. Masayuki Matsui from the laboratory of Dr. David R. Corey, Professor in the Departments of Pharmacology & Biochemistry, University of Texas Southwestern Medical Center (UTSW) at Dallas, presented new data on their RNAa research efforts in a poster titled “Activation of LDL Receptor Gene Expression by Promoter-Targeted Duplex RNAs.” In these studies, double-stranded “anti-gene” RNAs (agRNAs) targeting the promoter region of the LDL receptor (LDLR) were discovered that increase LDLR expression up to four-fold. The action of agRNAs was dose-dependent and durable for about one week. In functional studies, LDLR activation by agRNAs was found to result in increased binding of fluorescently labeled LDL particles to hepatocyte-derived cells in a culture system and to have additive effects together with the action of lovastatin in upregulation of LDLR protein levels. RNAa with agRNAs targeting the LDLR promoter could define a novel approach for the treatment of hypercholesterolemia.

Other presentations from Alnylam scientists at the OTS meeting include the following.

* A presentation titled “Development of an RNAi Therapeutic Targeting KSP and VEGF for the Treatment of Liver Cancers” by Dinah Sah, Ph.D., Vice President, Research, CNS and Oncology, which provided an overview of the progress Alnylam has made to date with its ALN-VSP program which is in a Phase I clinical trial in patients with advanced solid tumors with liver involvement, including hepatocellular carcinoma (HCC).
* A presentation by Alnylam Scientific Advisory Board member and collaborator, Judy Lieberman, M.D., Ph.D., Senior Investigator of the Immune Disease Institute and Professor of Pediatrics, Harvard Medical School. The presentation, titled “Silencing sexual transmission of HSV-2 and HIV,” detailed the progress to date to develop an RNAi topical microbicide to provide protection from the transmission of the herpes simplex virus-2 (HSV-2) and for human immunodeficiency virus (HIV).
* A poster presented by Alnylam scientists titled “Conjugation strategies for RNAs using click chemistry,” which describes approaches to improve cellular uptake of siRNAs by conjugating lipophilic molecules, carbohydrates, and polyamines to appropriate sites of RNA molecules.

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; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection and is partnered with Cubist and Kyowa Hakko. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, hypercholesterolemia, Huntington’s disease, and TTR amyloidosis. 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, and Cubist. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam established “RNAi 2010” in January 2008 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, 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, please visit

SOURCE: Alnylam Pharmaceuticals, Inc.

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