Alnylam and Collaborators Publish Research on a New Class of Chemically Modified RNAi Therapeutics that Target Two Distinct Cellular Mechanisms

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today announced the publication of a new study in Nature Medicine by scientists from the University of Bonn in collaboration with Alnylam. The new pioneering research documents the design and evaluation of "3p-siRNAs,” a new class of RNAi therapeutics comprised of small interfering RNAs (or siRNA, the molecules that mediate RNAi) which are designed and chemically modified to activate RIG-I (retinoic acid-induced gene I, a cytoplasmic immunoreceptor which strongly induces type I interferon and NK cell responses). The study showed that a 3p-siRNA specific for the anti-apoptotic factor bcl-2 may be a highly effective anti-cancer agent in several animal models. 3p-siRNAs that are designed toward other gene targets may also have applications in infectious disease and as vaccine adjuvants.

"In our first collaborative paper with the Hartmann lab in 2005, also published in Nature Medicine, we defined certain structural features of siRNAs that were found to stimulate immune responses, ensuring we can reliably avoid these responses in designing our RNAi therapeutics,” said Rachel Meyers, Ph.D., Senior Director of RNAi Lead Development at Alnylam. "In this new research, 3p-siRNAs were designed to intentionally promote a potent immune stimulatory mechanism in concert with gene silencing. We believe this approach could represent a potentially new and effective strategy for cancer therapy, as it has been shown that many cancers are better treated through a combination therapy approach.”

The new research (Poeck et al., Nature Medicine, advance online publication 2 November 2008; doi:10.1038/nm.1887) describes the design of 3p-siRNAs, through the combination of sequence-based complementarity to a target gene and chemical modification of the 5’-ends of the sense and antisense strands of the same siRNA with a triphosphate moiety. With a bcl-2-specific sequence, 3p-siRNAs led to a robust in vivo apoptotic effect, provoking massive programmed cell death of tumor cells and resulting in a greater than 80 percent reduction in total lung metastases in melanoma and adenocarcinoma mouse models. Furthermore, the beneficial effect of 3p-siRNA dual targeting was confirmed by the observation that more modest anti-tumor effects were observed when either bcl-2 targeting (with non-3p-containing bcl-2-specific siRNAs) or RIG-I activation (with non-specific 3p-siRNAs) alone was employed. RNAi-mediated effects in vivo were confirmed using a method called 5’ Rapid Amplification of cDNA Ends (5’RACE) and specific RIG-I activation was confirmed by measurements of interferon responses, including confirmatory studies in interferon receptor and toll-like receptor knockout mice. The molecular proof of a dual mechanism for RNAi silencing and RIG-I activation confirms that both cellular pathways are engaged by 3p-siRNAs in the same cellular compartment, the cytoplasm.

"We are excited by these results which demonstrate that 3p-siRNAs represent a novel single molecule-based combinatorial approach in which RIG-I activation can trigger the immune system and an oncogene can be silenced to promote apoptosis, together powerfully targeting key molecular events that govern tumor cell survival,” said Gunther Hartmann, M.D., Director of the Department of Clinical Chemistry and Clinical Pharmacology with the Central Laboratory of the University Hospital in Bonn, Germany. "We look forward to continuing our collaborative efforts with Alnylam as we pursue this promising RNAi therapeutic approach.”

"This new research with the Hartmann lab is illustrative of Alnylam’s success in working with leading labs across the world in the broad discovery and advancement of RNAi therapeutic strategies. It is also continued demonstration of our commitment to scientific excellence through publication of our research in peer-reviewed journals, this being the ninth such publication this year,” said Jack Schmidt, M.D., Chief Scientific Officer of Alnylam. "We’re excited about the potential opportunities for 3p-siRNAs in oncology, infectious disease, and potentially vaccine strategies and we look forward to continued efforts in advancing this new area of research.”

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, and Roche. 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 http://www.alnylam.com.

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 ability to achieve technical success and to successfully develop 3p-siRNAs; Alnylam’s approach to discover and develop novel drugs, 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 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 annual 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.