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Alnylam Files Clinical Trial Application for ALN-TTR02, an RNAi Therapeutic Targeting Transthyretin for the Treatment of Transthyretin-Mediated Amyloidosis

– Company Expects to Initiate Trial in First Half of 2012 with Data in Third Quarter of 2012 –

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jan. 6, 2012-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-TTR02, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). ALN-TTR02 is a systemically delivered RNAi therapeutic, targeting the TTR gene, that comprises an siRNA formulated in a second-generation lipid nanoparticle (LNP). Following clearance of the CTA, Alnylam expects to initiate the ALN-TTR02 Phase I study in the first half of 2012 with data expected to be reported in the third quarter of 2012.

“We are very committed to the continued advancement of our ALN-TTR program, which we believe has the potential to emerge as the leading innovative medicine for the treatment of ATTR. Indeed, our preliminary ALN-TTR01 trial results showed rapid and durable lowering of TTR serum levels in ATTR patients with just a single dose; we can confidently expect even more robust results with ALN-TTR02 which utilizes our second-generation lipid nanoparticle delivery platform,” said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. “To put this new program into context, pre-clinical studies have shown that administration of ALN-TTR02 results in a greater than 10-fold improvement in TTR silencing as compared with ALN-TTR01. Moreover, our recent preliminary clinical results with ALN-PCS, utilizing the same second-generation LNP formulation as ALN-TTR02, demonstrated initial safety and robust potency with greater than 65% silencing of the protein target, PCSK9, at the current dose level. Accordingly, we very much look forward to the continued advancement of ALN-TTR02, including the start of this Phase I clinical trial in healthy volunteers in the first half of this year and data in the third quarter. We also expect to initiate a Phase II study with ALN-TTR02 in familial amyloidotic polyneuropathy, or FAP, patients in the second half of this year with the start of pivotal trials with ALN-TTR02 in 2013.”

ATTR is an autosomal dominant inherited disease caused by mutations in the TTR gene, which is expressed predominantly in the liver and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, gastrointestinal tract, and heart. Alnylam recently presented preliminary results from its Phase I study of ALN-TTR01, which utilizes the identical siRNA as in ALN-TTR02 but formulated in a first-generation LNP. Preliminary data from this study showed that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels in ATTR patients with a mean reduction of 41% relative to placebo (p=0.02). Lowering of TTR was demonstrated to be dose dependent, rapid, and durable after just a single dose. ALN-TTR01 was found to be generally safe and well tolerated. Pre-clinical studies have shown that administration of ALN-TTR02 results in a greater than 10-fold improvement in TTR lowering compared with ALN-TTR01. Moreover, recent preliminary clinical results with ALN-PCS, which utilizes the identical second-generation LNP delivery platform as ALN-TTR02, demonstrated initial safety and the expected improvements in potency.

“RNAi therapeutics represent a novel and compelling approach for the treatment of ATTR. Based on our understanding of the pathogenesis of this disease, TTR lowering defines an encouraging therapeutic strategy,” said Philip Hawkins, FMedSci., Professor of Medicine, University College London Medical School. “The recent preliminary clinical data for ALN-TTR01 in patients are very promising and I am excited about the translation of this second-generation agent in clinical trials, as there are currently few options for patients suffering from this disease.”

As per the filed CTA, the Phase I trial of ALN-TTR02 is planned to be conducted in the U.K. as a randomized, single-blind, single-ascending dose study, enrolling up to 32 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-TTR02. Secondary objectives include characterization of pharmacokinetics of ALN-TTR02 and assessment of clinical activity of the drug as measured by serum TTR levels.

About Transthyretin (TTR)-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is a hereditary, systemic disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for thyroid hormones and retinol binding proteins. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. In its severest form, ATTR represents a major unmet medical need with significant morbidity and mortality as an orphan disease; FAP (familial amyloidotic polyneuropathy) affects approximately 10,000 people worldwide and FAC (familial amyloidotic cardiomyopathy) affects approximately 40,000 people worldwide. ATTR patients with FAP have a mean life expectancy of five to 15 years from symptom onset and the only treatment option is liver transplantation; as a result there is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

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 at or around the end of 2011. Alnylam intends to focus on developing and commercializing certain 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 for other core products both in the United States and 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 5x15TM” 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’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 Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-TTR01, ALN-TTR02, and ALN-PCS, the therapeutic potential for its second-generation lipid nanoparticle delivery technology, the filing of a CTA with the MHRA to initiate a Phase I clinical trial with ALN-TTR02 and the expected timing of regulatory clearance and clinical trial initiation for ALN-TTR02, its expectations with respect to the timing and success of its clinical and pre-clinical trials, including for ALN-TTR01, ALN-TTR02 and ALN-PCS, the expected timing for initiation of a Phase II study in FAP with ALN-TTR02 and the potential start of pivotal trials with ALN-TTR02 in 2013, its expectations regarding the reporting of data from its ALN-TTR02 clinical trial, 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, including those formulated in its second-generation lipid nanoparticle delivery technology, including ALN-TTR02, and ALN-PCS, 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, 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
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.