Alnylam Presents Key Pre-Clinical Proof-of-Concept Data for ALN-AS1, an RNAi Therapeutic Targeting Aminolevulinate Synthase-1 (ALAS-1) for the Treatment of Porphyria

RNAi Therapeutics Targeting ALAS-1 Completely Block Production of Toxic Heme Biosynthesis Intermediates that Cause Symptoms and Disease Pathology

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented key pre-clinical proof-of-concept data from its RNAi therapeutic program targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP). The new research findings were presented at the International Congress of Porphyrins and Porphyrias being held May 16 – 18, 2013 in Lucerne, Switzerland. Specifically, Alnylam scientists and collaborators at the Icahn School of Medicine at Mount Sinai in New York City presented data from pre-clinical models of the human disease showing that RNAi therapeutics targeting ALAS-1 can completely block the abnormal production of toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of AIP. Alnylam's AIP drug candidate, ALN-AS1, is part of the company's "Alnylam 5x15" product development and commercialization strategy, in which the company aims to advance five genetic disease target programs into clinical development, including programs in late stages, by the end of 2015.

"Our pre-clinical data clearly show that RNAi therapeutics targeting ALAS-1 can achieve potent, rapid, and durable suppression of the toxic heme biosynthesis intermediates that cause the symptoms and disease pathology of AIP. As such, these findings provide key, pre-clinical, proof-of-concept data for our ALN-AS1 program, which we believe could become a transformative therapy for patients with AIP, an ultra-rare genetic disease with enormous unmet medical need," said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. "We are now extending these pre-clinical results to a GalNAc-siRNA conjugate development candidate that enables subcutaneous dose administration, and our current data with prototype molecules provide clear validation of this strategy. With our ongoing efforts, we expect to finalize selection of a GalNAc-siRNA development candidate for our ALN-AS1 program in late 2013, leading to an investigational new drug filing for this program in 2014."

"AIP is an ultra-rare genetic disorder caused by an inherited deficiency in porphobilinogen deaminase that can result in accumulation of toxic intermediates in the heme biosynthesis pathway. Patients with AIP present with acute and/or recurrent attacks including severe, life-threatening abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations," said Robert J. Desnick, M.D., Ph.D., Dean for Genetics and Genomic Medicine and Professor and Chair Emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. "There is clear need for new therapies to treat acute attacks and prevent recurrent attacks, and we are very encouraged by the potential of an RNAi approach for the treatment of this debilitating, life-threatening disease."

"Our pre-clinical work with Alnylam has shown that RNAi-mediated silencing of ALAS-1 results in essentially complete abrogation of the toxic heme biosynthesis intermediates that cause the symptoms and disease pathophysiology of AIP. In preliminary studies, we have also shown that RNAi-mediated silencing of ALAS-1 is more effective than heme administration in the treatment of an acute attack," said Makiko Yasuda, M.D., Ph.D., Assistant Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. "RNAi has the potential to serve as a novel treatment for AIP, and we look forward to continuing our close collaborative efforts with Alnylam on the advancement of this program to the clinic."

There are approximately 5,000 patients in the U.S. and Europe that suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks. Treatment options for AIP patients suffering from an acute attack are limited, and include the use of heme preparations that show limited efficacy and are associated with a number of complications. Currently, there are no drugs available to prevent attacks from occurring. Alnylam's approach is to knockdown ALAS-1, an enzyme upstream of porphobilinogen deaminase (PBGD), in hepatocytes. RNAi-mediated silencing of hepatocyte ALAS-1 could reduce the abnormal production of the toxic heme intermediates, specifically aminolevulinic acid (ALA) and porphobilinogen (PBG), which mediate the symptoms and disease pathology in these patients. A subcutaneously administered RNAi therapeutic targeting ALAS-1 could be used as a prophylactic approach to prevent attacks and as a therapy for acute attacks.

The new research results support the advancement of RNAi therapeutics as a promising strategy for the prevention and/or treatment of acute attacks in patients with AIP. In the new studies, Alnylam scientists and collaborators at Icahn School of Medicine at Mount Sinai presented findings from a mouse model of AIP. Prophylactic administration of an ALAS-1 specific siRNA completely protected the mice from phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and the resulting accumulation of the neurotoxic ALA and PBG heme biosynthesis precursors. This protective effect was dose responsive and durable, with a single dose administration resulting in a protective effect that lasted for at least two weeks. Further, in a treatment model, a single dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and PBG that were elevated during a phenobarbital-induced acute attack. Further, preliminary comparative studies show that ALAS-1 siRNA administration was more effective than heme administration in the treatment of an acute attack. Finally, the company presented results from its ongoing GalNAc-siRNA conjugate efforts enabling subcutaneous dose administration. In particular, a prototype GalNAc-siRNA targeting ALAS-1 was shown to be effective in blocking ALA and PBG production in both prophylactic and treatment models of AIP. The company is on track to designate a GalNAc-siRNA development candidate, ALN-AS1, in late 2013 resulting in an investigational new drug (IND) filing in 2014.

About ALN-AS1

Alnylam is developing ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP). AIP is an ultra-rare autosomal dominant disease caused by loss of function mutations in porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis pathway that can result in accumulation of toxic heme precursors. Patients with AIP suffer from acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations. ALN-AS1 is a GalNAc conjugate targeting ALAS-1, a liver-expressed, rate-limiting enzyme upstream of PBGD in the heme biosynthesis pathway. Inhibition of ALAS-1 is known to reduce the accumulation of heme precursors that cause the clinical manifestations of AIP. ALN-AS1 has the potential to be a therapy for the treatment of acute porphyria attacks, as well as a prophylactic approach for the prevention of recurrent attacks. The company is on track to identify a final development candidate by late 2013 and advance ALN-AS1 into the clinic in 2014. Alnylam intends to directly commercialize ALN-AS1 in North and South America, Europe, and other parts of the world, and intends to seek a partner for this program in Japan and other Asian territories.

About Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is an ultra-rare autosomal dominant disease caused by loss-of-function mutations in porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis pathway. Exposure of AIP patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinate synthase-1 (ALAS-1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of heme intermediates upstream of PBGD that precipitate attack symptoms. Patients with AIP can suffer acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations, and possible death if left untreated. Approximately 5,000 patients in the U.S. and Europe suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks. Treatment options for AIP patients suffering from an acute attack are limited; patients are treated with intravenous heme analogues that have a slow onset and can result in severe thrombophlebitis and iron overload. Currently there is no approved prophylactic treatment available to prevent recurrent attacks, which often occur monthly in women associated with menses. There exists a significant need for therapies for AIP patients.

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: 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 acute intermittent porphyria (AIP); 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; and ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease, amongst other programs. 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 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, andCell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About "Alnylam 5x15™"

The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics toward genetically defined targets for the treatment of 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. By the end of 2015, the company expects to have five such RNAi therapeutic programs in clinical development, including programs in advanced stages, on its own or with a partner. The "Alnylam 5x15" programs include: 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 acute intermittent porphyria (AIP); 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; and ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease, amongst other programs. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in North and South America, Europe, and other parts of the world; these include ALN-TTR, ALN-AT3, and ALN-AS1; the company will seek global development and commercial alliances for other programs.

Alnylam Forward-Looking Statements

Various statements in this 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, including ALN-AS1, its expectations with respect to the timing and success of its clinical and pre-clinical trials, the expected timing of regulatory filings, including its plan to file an IND application and initiate clinical trials for ALN-AS1, its expectations regarding reporting of data from its pre-clinical studies for ALN-AS1 studies, its plans to seek a partner for its ALN-AS1 program and other "Alnylam 5x15" programs, and its expectations regarding the potential market opportunity for ALN-AS1, 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 current report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 7, 2013 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.

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