Alnylam Presents New Pre-clinical Data on ALN-AAT, an RNAi Therapeutic Targeting Alpha-1-Antitrypsin (AAT) for the Treatment of AAT Deficiency Liver Disease

Nov 02, 2013

— New Results in Mouse Model of AAT Deficiency Demonstrate that a Subcutaneously Administered GalNAc-siRNA Conjugate Targeting AAT Reduces Levels of Mutant AAT by Greater than 90%, Attenuates Fibrosis, and Arrests Development of Liver Tumors —

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) in development for the treatment of liver disease associated with AAT deficiency. These data were presented in a poster entitled "Developing an RNAi Therapeutic for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency" at the 64^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, "The Liver Meeting") held November 1 — 5, 2013 in Washington, D.C. AAT deficiency liver disease is a rare genetic disorder, with the most common mutation being in the "Z-allele," which results in the accumulation of the mutant AAT protein (Z-AAT) in liver tissue with subsequent liver injury, fibrosis, and, in some cases, hepatocellular carcinoma. There are approximately 12,000 people in the U.S. and E.U. with liver pathology associated with AAT deficiency.

Alnylam scientists and collaborators presented new results in a transgenic mouse model of Z-AAT protein over-expression showing that subcutaneous administration of a GalNAc-siRNA targeting AAT led to rapid, potent, dose-dependent, and durable knockdown of AAT of greater than 90%, as well as a significant reduction in fibrosis and the incidence of liver tumors. ALN-AAT is a program in the company's "Alnylam 5x15" product development and commercialization strategy, by which the company aims to advance five RNAi therapeutic programs toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015.

"We are excited about the potential for RNAi therapeutics for the treatment of liver disease associated with AAT deficiency, a rare genetic disorder. AAT deficiency liver disease is caused by the mutant ‘Z allele' of the AAT gene, whose protein misfolds, accumulates in liver cells, and causes cellular damage. Our therapeutic hypothesis is that an RNAi therapeutic that silences the mutant Z-AAT will prevent the development and/or progression of liver disease," said Rachel Meyers, Ph.D., Vice President of Research and RNAi Lead Development at Alnylam. "Our new pre-clinical data with a GalNAc-siRNA conjugate against AAT demonstrate rapid, potent, dose-dependent, and durable knockdown of AAT to greater than 90% resulting in a significant reduction of liver fibrosis and tumor formation. If these results extend in clinical studies, we believe that ALN-AAT could become an important treatment option for the management of disease in people with AAT deficiency."

"People that are homozygous for the mutant Z allele make up approximately 95% of patients with AAT deficiency. These individuals have a lifetime risk of liver disease of 10% to 50%, which manifests as cholestatic disease, cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur in children and adults and is currently managed with supportive care, or in the case of liver failure, with liver transplantation. Clearly, there is a very high unmet need for novel therapies for AAT-deficient patients with liver disease," said Jeffrey Teckman, M.D., Professor in the Department of Pediatrics and Director of Gastroenterology and Hepatology at Saint Louis University School of Medicine. "In collaboration with Alnylam scientists, we have demonstrated in pre-clinical studies that RNAi therapeutics targeting AAT can significantly ameliorate AAT-mediated liver pathology, including reducing levels of liver AAT aggregates and improving hepatocyte morphology. Our new pre-clinical data with GalNAc-siRNA conjugates extend these findings with a clinically viable, subcutaneously administered RNAi therapeutic, where we have also demonstrated reductions in the development of liver fibrosis and hepatocellular carcinoma. I very much look forward to the further advancement of ALN-AAT as a potential treatment for this devastating genetic disease with limited treatment options."

New data presented at The Liver Meeting are based on an AAT-targeted siRNA conjugated to an N-acetylgalactosamine (GalNAc) ligand, which is designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Studies were performed in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous administration of a GalNAc-siRNA conjugate targeting Z-AAT led to dose-dependent knockdown of serum levels of human Z-AAT. A single dose of 3 mg/kg led to greater than 95% knockdown of Z-AAT protein that lasted for greater than two weeks. In a multi-dose experiment, twice-weekly dosing at 0.5 mg/kg led to greater than 90% knockdown. Finally, in aged mice (25-46 weeks old) with advanced, established liver disease, repeat administration of a GalNAc-siRNA conjugate against AAT every other week for 18 weeks resulted in a significant reduction (p < 0.05) in the incidence of liver tumors associated with Z-AAT overexpression (1/6, 16.7%) when compared to those mice treated with PBS (4/6, 66.7%). Animals treated with the AAT-targeted GalNAc-siRNA also exhibited significant (p < 0.05) reductions in levels of Col1a2 (a marker of fibrosis) and PtPrc (a marker of immune cell infiltration) relative to PBS-treated animals.

About Alpha-1 Antitrypsin (AAT) and AAT Deficiency

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). A deficient serum level of the protein can render the lungs susceptible to emphysema. About 95% of patients with alpha-1 antitrypsin deficiency carry two copies of the abnormal Z allele (PiZZ patients). There are approximately 120,000 in the U.S. and major European countries thought to be homozygous for the Z allele (PiZZ), and it is estimated that about 10% have an associated liver pathology caused by the misfolded protein encoded by the pathogenic Z-allele. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, which utilizes purified AAT from the plasma of healthy donors to increase circulating and airway levels of AAT and restore its function in the lungs. The only treatment options presently available for patients with cirrhosis caused by mutant AAT accumulation in the liver are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in AAT-deficient PiZZ patients may represent a promising new way to treat this rare disease.

About GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple "Alnylam 5x15" 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 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 porphyria including 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; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, amongst other programs. As part of its "Alnylam 5x15^TM" 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.

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 porphyria including 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; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, 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, ALN-AS1, and ALN-CC5, amongst other programs.

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, including ALN-AAT, its expectations with respect to the success of clinical trials for ALN-AAT, and its plans with respect to the commercial opportunity for the ALN-AAT program, 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, including ALN-AAT, 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 Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 9, 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.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
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Media Contact
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Source: Alnylam Pharmaceuticals, Inc.

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