Alnylam and Collaborators Publish New Pre-clinical Data on Delivery of RNAi Therapeutics to Key Cell Types Regulating Immune and

Alnylam and Collaborators Publish New Pre-clinical Data on Delivery of RNAi Therapeutics to Key Cell Types Regulating Immune and Inflammatory Diseases
-- Publications in Nature Biotechnology and Molecular Therapy with Collaborators from Massachusetts General Hospital, Massachusetts Institute of Technology, and University of British Columbia Demonstrate Robust Silencing of Target Genes in Inflammatory Disease Cells, Including Macrophages and Dendritic Cells --

CAMBRIDGE, Mass., Oct 11, 2011 (BUSINESS WIRE) -- Alnylam Pharmaceuticals, Inc. /quotes/zigman/92224/quotes/nls/alny ALNY -0.34% , a leading RNAi therapeutics company, announced today the publication of two peer-reviewed papers documenting systemic delivery of RNAi therapeutics to certain immune and inflammatory cells. These studies provide a foundation for the potential development of RNAi therapeutics to silence disease genes in these cell types for the treatment of inflammatory, autoimmune, and cardiovascular diseases, as well as certain cancers.

"We have made demonstrable progress with our RNAi therapeutics efforts for silencing of disease genes expressed in liver, including our programs on transthyretin amyloidosis, severe hypercholesterolemia, and liver cancers currently in clinical trials. In addition, our scientists and their extensive network of collaborators continue to make progress on systemic delivery of siRNA to a broader range of cell types and tissues. This includes the promising results in these two new papers on the delivery of RNAi therapeutics to antigen-presenting immune cells, such as macrophages and dendritic cells," said Tatiana Novobrantseva, Ph.D., Associate Director of Research at Alnylam. "These new advances highlight the potential for RNAi therapeutics to silence disease genes involved in the cause and pathway of immune and inflammatory diseases."

In a study titled "Therapeutic siRNA silencing in inflammatory monocytes in mice," (Leuschner et al., Nat. Biotechnol., 2011, 10.1038/nbt.1989) Alnylam scientists and collaborators at Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT) demonstrated silencing of a target gene in cells involved in inflammatory disease. This study utilized siRNA designed to target the gene CCR2, a chemokine receptor that mediates trafficking of monocytes to injured tissues. When formulated in a novel and proprietary lipid nanoparticle (LNP) formulation and administered systemically in an animal model, this siRNA showed rapid blood clearance, accumulated in spleen, bone marrow and liver, and was found to localize to monocytes. Administration of the LNP-formulated CCR2-specific siRNA resulted in target gene silencing in monocytes; this was shown to be mediated by RNAi, as evidenced by a molecular biology technique known as 5'-RACE. As a result of CCR2 silencing in monocytes, a number of therapeutic effects were observed in a broad range of distinct pre-clinical animal models. Specifically, siRNA treatment attenuated the recruitment of inflammatory monocytes in atherosclerotic plaques, reduced the infarct size after coronary artery occlusion, prolonged normal glycemic levels in diabetic mice after pancreatic islet transplantation, and, resulted in reduced tumor volumes in two independent cancer models.

"With these new findings, we have demonstrated broad-based efficacy of targeting monocyte CCR2 as an anti-inflammatory strategy in cardiovascular disease, cancer and transplant rejection," said Matthias Nahrendorf, M.D., Ph.D., Assistant Professor at Harvard Medical School and Principle Investigator at the Center for Systems Biology, MGH. "We believe that this study describes an exciting convergence of in vivo RNAi technologies with recent insights into monocyte biology, thereby opening a new translational avenue to approach the many diseases driven by these cells."

The second study was titled "Influence of Cationic Lipid Composition on Gene Silencing Properties of Lipid Nanoparticle Formulations of siRNA in Antigen-Presenting Cells (APCs)" (Basha et al., Molecular Therapy, 2011, doi:10.1038/mt.2011.190). In this study, Alnylam scientists and collaborators at The University of British Columbia (UBC) evaluated a range of novel lipids and LNP formulations that enable effective in vivo siRNA silencing of target genes expressed in antigen-presenting cells, namely macrophages and dendritic cells. Specifically, the study examined the uptake, intracellular trafficking, and gene silencing potency in primary macrophages and dendritic cells. Among other findings, data from this study showed that novel compositions and also increased LNP size result in optimized delivery of siRNA to APCs as compared to liver. These and other novel insights on composition, size, and other physicochemical properties of LNPs for delivery of RNAi therapeutics to immune cells form the basis for intellectual property on new therapeutic applications.

"Lipid nanoparticles are promising in vivo delivery systems for silencing target genes with siRNA. While the greatest progress has been realized for silencing target genes in the liver, steadfast progress has been made for applications in other cell types and tissues," said Pieter Cullis, Ph.D., Professor Biochemistry and Molecular Biology at UBC. "There exist many potential applications for an RNAi approach targeting certain classes of immune cells such as dendritic cells and macrophages, including new therapies for the treatment of autoimmune disease and cancer immunotherapy."

About 'Alnylam 5x15'

The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in Phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. This strategy leverages Alnylam's clinical progress on siRNA delivery, including definitive human proof-of-concept data for systemic delivery. By the end of 2015, the company expects to have five such RNAi therapeutic programs in advanced clinical development. These include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, ALN-APC for the treatment of hemophilia, and one additional program from the company's ongoing discovery efforts that will be designated and advanced into development later in 2011. Alnylam intends to commercialize the products arising under the "Alnylam 5x15" strategy itself in the United States and potentially certain other countries; the company will seek development and commercial partners in other global territories.

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-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-APC for the treatment of hemophilia. As part of its "Alnylam 5x15(TM)" strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in advanced stages of clinical development by the end of 2015. Alnylam has additional partner-based 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, and Cubist. 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 application in biologics manufacturing, including recombinant proteins and monoclonal antibodies. 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 Alnylam's views with respect to the potential for systemic delivery of RNAi therapeutics to certain immune and inflammatory cells, as well as Alnylam's expectations with respect to 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 delivery approaches, including systemic delivery of RNAi therapeutics to certain immune and inflammatory cells, and novel drug candidates, successfully demonstrate the efficacy and safety of its drug candidates in preclinical and human clinical trials, and 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, Inc.



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