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

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

 – New Research Presented at 63^rd Annual Meeting of the American Association
        for the Study of Liver Diseases (AASLD, “The Liver Meeting”) –

Business Wire

CAMBRIDGE, Mass. -- November 14, 2012

Alnylam Pharmaceuticals, Inc. (Nasdaq: 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
63^rd 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 ED[50] 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
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,
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 www.alnylam.com.

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.

Contact:

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