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Alnylam and Collaborators Publish Scientific Paper Documenting Discovery of Second Generation MC3 Lipid Nanoparticles (LNPs)

– Seminal Paper by Scientists from Alnylam, AlCana, and the University of British Columbia Shows Rational Design, Synthesis, and Evaluation of More Than 50 Novel Lipids and Delineation of Critical Parameters for Potent In Vivo Efficacy –

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jul. 13, 2012-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and collaborators announced today the publication of a scientific paper documenting the discovery of novel lipids used in second generation lipid nanoparticles (LNPs) for systemic delivery of RNAi therapeutics. These results were published in a paper titled “Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo” (DOI: 10.1002/anie.201203263) in the journal Angewandte Chemie International Edition. The findings describe the rational design, synthesis, and evaluation of novel lipids, including MC3, that have led to the discovery of Alnylam’s proprietary second generation LNP platform for systemic delivery of RNAi therapeutics. This research was conducted in collaboration with scientists from AlCana Technologies, Inc. and the University of British Columbia (UBC).

“This new paper documents the work performed by Alnylam, AlCana, and UBC scientists leading to the discovery of novel lipids, including MC3, that demonstrate remarkably improved in vivo potency for systemic delivery of RNAi therapeutics. In addition, our results have led to the identification of a key structural feature of novel ionizable lipids, specifically the pKa of the amino group of the lipid, required for optimal in vivo efficacy,” said Muthiah Manoharan, Ph.D., Senior Vice President, Drug Discovery. “The MC3 lipid and resulting second generation LNPs have now advanced into clinical stages of evaluation. These novel LNPs exhibit significant improvements in potency and broadened therapeutic index for RNAi therapeutics, as evidenced by our recent human data with ALN-PCS, and also define Alnylam’s LNP platform for advancement of ALN-TTR02 and potentially other ‘Alnylam 5x15’ programs.”

The results published in this new paper reveal key insights for optimizing systemic delivery of RNAi therapeutics with LNPs. The findings describe a comprehensive structure-activity relationship (SAR) study resulting in the design, synthesis, and evaluation of over 50 novel lipids. In an earlier study a particular lipid, DLin-KC2-DMA, was identified as a highly potent cationic lipid when incorporated into LNP encapsulating siRNA targeting the factor VII (FVII) mRNA (Semple, et al., Rational design of cationic lipids for siRNA delivery, Nat. Biotechnol. 28, 172-176; 2010); the researchers used this lipid as the starting point for their SAR study. The resulting data demonstrated a close relationship between the apparent acid dissociation constant, or pKa, of the ionizable amino lipid head groups present in the LNPs and their ability to elicit potent hepatic gene silencing in vivo. This effect of the pKa is likely due to enhanced endosomal release of the siRNA in the cytoplasm where it can harness the RNAi pathway. In this new paper, an LNP formulation based on DLin-MC3-DMA – or simply MC3 – was identified as one of the most potent lipids.

Earlier this year, the United States Patent and Trademark Office (USPTO) issued a Notice of Allowance of claims for a patent application which covers the MC3 lipid; the patent has now been issued (U.S. Patent No. 8,158,601). This patent includes 30 claims covering composition of matter and formulations of MC3, as well as methods of using these compositions and formulations, and recognizes the novelty of the MC3 lipid for systemic delivery of RNAi therapeutics.

Alnylam’s proprietary MC3 LNP delivery platform is being utilized in development programs as part of the company’s “Alnylam 5x15™” product strategy including: ALN-TTR02, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia; and potentially other programs.

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 leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its “Alnylam 5x15TM” strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programs in advanced stages, on its own or with a partner by the end of 2015. Alnylam has additional partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington’s disease. The company’s leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, and Ascletis. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for applications in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam’s VaxiRNA™ platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including without limitation, statements regarding the potential of novel lipids, including MC3, to demonstrate significant improvements in potency and broadened therapeutic index for RNAi therapeutics, Alnylam’s views with respect to the potential for RNAi therapeutics utilizing such novel lipids, including ALN-TTR02 and ALN-PCS, and Alnylam’s expectations regarding its “Alnylam 5x15” product strategy, 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, without limitation, Alnylam’s ability to discover and develop novel drug candidates, successfully demonstrate the efficacy and safety of its drug candidates utilizing its novel LNPs, including ALN-TTR02 and ALN-PCS, the pre-clinical and clinical results for these product candidates, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, obtaining, maintaining and protecting intellectual property, including its patents covering MC3, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, and Alnylam’s ability to establish and maintain strategic business alliances and new business initiatives, 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.

Source: Alnylam Pharmaceuticals

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
or
Spectrum (Media)
Amanda Sellers, 202-955-6222 x2597

"Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release regarding Alnylam Pharmaceuticals's business which are not historical facts are "forward-looking statements" that involve risks and uncertainties. For a discussion of such risks and uncertainties, which could cause actual results to differ from those contained in the forward-looking statements, see "Risk Factors" in the Company's Annual Report or Form 10-K for the most recently ended fiscal year.