Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Alpha-1 Antitrypsin


Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency

- New Research Presented at 63rdAnnual Meeting of the American Association for the Study of Liver Diseases (AASLD, "The Liver Meeting") -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (NAS: ALNY) , a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of liver disease associated with AAT deficiency. These data were presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, "The Liver Meeting") held November 9-13, 2012 in Boston. AAT deficiency is a rare genetic disease that can result in severe lung and liver pathology; approximately 10,000 patients are diagnosed worldwide. In a presentation titled "Developing an RNAi Therapeutic for Liver Disease Associated with Alpha-1 Antitrypsin Deficiency," Alnylam scientists presented results showing robust RNAi-mediated silencing of AAT liver mRNA and serum protein in a transgenic mouse model of mutant AAT ("Z-AAT") protein overexpression. The new RNAi therapeutic program, ALN-AAT, represents a novel approach for the treatment of liver disease associated with AAT deficiency.

"In line with our 'Alnylam 5x15' product strategy, we are excited about the potential for RNAi therapeutics for the treatment of AAT deficiency, a rare, genetic condition that causes lung and liver disease," said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development at Alnylam. "We are very encouraged by these new pre-clinical data with ALN-AAT showing potent knockdown of AAT that results in significant improvements in liver pathology in disease models."

"Approximately 10,000 people worldwide have been diagnosed with severe AAT deficiency, a rare genetic disease that results in severe lung and liver pathology. AAT patients can develop early onset emphysema as well as liver disease, including hepatitis, cirrhosis, and hepatocellular carcinoma. While lung disease associated with AAT deficiency has been addressed with AAT replacement therapy, there are limited treatment options for 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. "We are very encouraged by these data with ALN-AAT and look forward to further advancement of an RNAi therapeutic approach for the treatment of this genetic disease."

ALN-AAT is a new RNAi therapeutic program for the treatment of liver disease associated with AAT deficiency. New data presented at the Liver Meeting are based on an AAT-targeting siRNA formulated in a lipid nanoparticle (LNP). The AAT siRNA was administered at doses ranging from 0.03 to 1.0 mg/kg in mice overexpressing a human Z-AAT transgene, resulting in robust, dose-dependent silencing of the target mRNA and protein. Specifically, a single intravenous dose of the drug resulted in 90% knockdown of liver mRNA and a greater than 80% decrease in serum AAT at 48 hours post-dose. Furthermore, a 90% reduction in soluble protein monomers in the liver was observed at 1.0 mg/kg, with an 80% reduction seen at 0.3 mg/kg. In addition, in long-term dosing studies, in which transgenic mice overexpressing Z-AAT were dosed every other week for 12 weeks at 0.3 mg/kg, ALN-AAT resulted in a 45% reduction of pathogenic protein polymers and a significant decrease in the size and number of AAT globules in hepatocytes. Long-term dosing also significantly decreased hepatocyte proliferation and liver collagen levels, known markers of liver dysfunction and fibrosis, respectively. Further, ALN-AAT administration resulted in marked improvements in hepatocyte cellular morphology as assessed by electron microscopy. Finally, 98% suppression of liver mRNA and serum protein was observed 48 hours after a single dose of the drug in transgenic mice that had fibrotic livers, illustrating key pre-clinical proof of concept for RNAi-mediated treatment in diseased livers. Alnylam has also identified a GalNAc-siRNA targeting AAT that enables subcutaneous dose administration for further development.

In addition, in a poster titled "Liposome mediated delivery of siRNA to hepatic stellate cells," Alnylam scientists presented new data on the systemic delivery of RNAi therapeutics to quiescent and activated hepatic stellate cells (HSCs). HSCs play a key role in the initiation and progression of liver fibrosis, the excessive accumulation of tough, fibrous scar tissue that occurs in most types of chronic liver diseases. These new data show that siRNA formulated in LNPs result in effective silencing of the HSC-specific gene target, collagen 1a1 (col1a1). Specifically, a single intravenous dose of siRNA against col1a1 yielded robust, dose-dependent silencing of target mRNA in activated HSCs at 48 hours, with an approximate ED50 of 0.1 mg/kg. Furthermore, silencing of col1a1 was confirmed to be RNAi-mediated. These data point to a potential strategy for development of RNAi therapeutics for the treatment of liver fibrosis.

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, and afflicts roughly 10,000 patients worldwide. 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). Although about 19 million Americans are carriers (containing one normal form of the gene and one mutant form), about 100,000 are thought to be homozygous for the Z allele (PiZZ), and it is estimated that less than 10% of affected patients are currently diagnosed. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, whereby purified AAT from the plasma of healthy donors is administered to patients 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 represents a promising new way to treat this rare disease.

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 for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. 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, 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, Cubist, Ascletis, Monsanto and Genzyme. 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, Sanofi, AstraZeneca and Biogen Idec. 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, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

About LNP Technology
Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

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 the potential for ALN-AAT as a treatment for liver disease associated with AAT deficiency, 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 successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for these product candidates, including ALN-AAT, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, 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.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
Amanda Sellers (Media), 202-955-6222 x2597

KEYWORDS: United States North America Massachusetts


The article Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency originally appeared on

Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

Copyright © 1995 - 2012 The Motley Fool, LLC. All rights reserved. The Motley Fool has a disclosure policy.