Alnylam and Collaborators Publish Novel Method for Detection of Tissue-Specific, RNAi-Mediated Gene Silencing – New Results Published in the Journal “RNA” Demonstrate Utility of Circulating Extracellular RNA Detection (cERD) Method in Quantifying Circulating Messenger RNA and Micro-RNA in Serum and Cerebrospinal Fluid to Monitor Tissue-Specific RNA Knockdown and to Confirm RNAi Proof of Mechanism – Business Wire CAMBRIDGE, Mass. -- December 20, 2013 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of a new paper describing a novel technique called circulating Extracellular RNA Detection (cERD). The paper, titled “Tissue-specific gene silencing monitored in circulating RNA” (Sehgal et al., RNA, doi:10.1261/rna.042507.113) appears online as an Advance Article in the journal RNA. The cERD method enables the quantification of circulating messenger RNA (mRNA) and micro-RNA (miRNA) as a way of monitoring tissue-specific RNA silencing. It also enables confirmation of an RNAi-mediated mechanism of action using a PCR-based technique. The cERD method could have broad applicability in clinical studies since it allows for monitoring of tissue-specific mRNA levels using a non-invasive technique. “Detection of target gene knockdown is typically made possible by measurement and quantification of mRNA levels in tissue samples and, if the target protein is secreted, corresponding protein levels in serum or plasma. Further, establishing proof of mechanism for RNAi therapeutics involves analysis of RNAi-mediated target mRNA cleavage with a PCR-based technique in tissue samples. However, the utility of these techniques is limited, since many proteins do not enter circulation, and the need to collect biopsies creates a significant challenge to the routine monitoring of mRNA expression levels or the RNAi mechanism of action in tissues,” said Rachel Meyers, Ph.D., Vice President of Research and RNAi Lead Development at Alnylam. “These new published data establish the applicability of the cERD method in multiple species, including rats and non-human primates, and thus the general utility of measuring circulating serum mRNA to confirm RNAi-mediated tissue gene silencing. Specifically, we have shown that changes in circulating RNA levels correspond closely to changes in tissue RNA levels, suggesting that RNA levels from biological fluids provide an accurate ‘real-time’ representation of tissue RNA status. These findings are important to the development of RNAi therapeutics, as the cERD method could be extended to the clinical setting to allow the routine, accurate, and frequent measurement of organ-specific target gene knockdown and/or RNAi mechanism without the need for tissue biopsies.” The new research published in RNA shows that mRNAs encoding tissue-specific gene transcripts can be detected in biological fluids. Specifically, RNAi-mediated target mRNA silencing in the liver by systemic siRNA administration resulted in quantitative reductions in serum mRNA levels that were shown to closely correlate with the degree and kinetics of mRNA silencing in liver tissue. Further, by identifying the predicted RNAi cleavage products via analysis of circulating RNA in serum, the authors demonstrated the use of cERD to verify the RNAi mechanism for target gene knockdown. For example, Alnylam recently published results in which the RNAi mechanism was confirmed using the cERD method in serum collected from humans participating in a Phase I clinical trial (Coelho et al., N Engl J Med 2013;369:819-29). In addition, administration of an anti-miR directed against a liver-specific miRNA led to decreased levels of the miRNA in serum, showing that cERD can also be applied to monitoring pharmacodynamics for microRNA therapeutics. Moreover, the authors quantified expression of an adenoviral transgene in the liver by measuring levels of circulating mRNA, suggesting that measurement of mRNA levels in serum can be applied to the analysis of exogenously delivered genes and thus can be a useful tool for gene therapy applications. Finally, using the cERD method, the authors monitored and quantified the degree of silencing of a brain-expressed mRNA in cerebrospinal fluid following intraparenchymal siRNA infusion to the central nervous system. 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 RNA (siRNA), 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 toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-ANG, an RNAi therapeutic for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst other programs. As part of its “Alnylam 5x15” 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 and ALN-VSP for the treatment of liver cancers. 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, Ascletis, Monsanto, Genzyme, and The Medicines Company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. 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, Cell, the New England Journal of Medicine, and The Lancet. 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 press release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s expectations regarding its “Alnylam 5x15” product strategy, Alnylam’s views with respect to the potential for RNAi therapeutics, and Alnylam’s views with respect to the use of the cERD method in clinical studies 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 and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam’s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, Alnylam’s ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam’s dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. 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 explicitly disclaims any obligation to update any forward-looking statements. Contact: Alnylam Pharmaceuticals, Inc. Cynthia Clayton, 617-551-8207 Vice President, Investor Relations and Corporate Communications or Spectrum Amanda Sellers (Media), 202-955-6222 x2597
Alnylam and Collaborators Publish Novel Method for Detection of Tissue-Specific, RNAi-Mediated Gene Silencing
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