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Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for Cardiovascular Disease at American Heart Association Meeting



  Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for
  Cardiovascular Disease at American Heart Association Meeting

  – Company Provides Update on ALN-PCSsc, a Subcutaneously Administered RNAi
Therapeutic Targeting PCSK9, Demonstrating up to 95% Knockdown of PCSK9 and up
 to 67% Reduction of Low Density Lipoprotein Cholesterol (LDL-C) in Non-Human
                                  Primates –

 – Alnylam Broadens Pipeline with ALN-ANG, a Subcutaneously Administered RNAi
   Therapeutic Targeting Angiopoietin-Like 3 (ANGPTL3) for the Treatment of
   Genetic Forms of Mixed Hyperlipidemia and Severe Hypertriglyceridemia –

Business Wire

CAMBRIDGE, Mass. -- November 17, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data from two
RNAi therapeutic programs for cardiovascular disease, including: ALN-PCSsc, an
RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia;
and ALN-ANG, an RNAi therapeutic targeting ANGPTL3 for the treatment of
genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. These
data were presented at the American Heart Association (AHA) Scientific
Sessions held November 16 – 20, 2013 in Dallas, Texas. In a presentation
titled “A Subcutaneous Platform for RNAi Therapeutics Targeting Metabolic
Diseases: PCSK9 and ANGPTL3,”  Alnylam scientists and collaborators presented
updated non-human primate (NHP) data showing that subcutaneous administration
of ALN-PCSsc led to an up to 95% knockdown of plasma PCSK9 and an up to 67%
reduction of low density lipoprotein cholesterol (LDL-C) – in the absence of
statin co-administration. In addition, new results were presented for ALN-ANG,
showing a greater than 95% reduction of triglycerides and greater than 85%
reduction of LDL-C in a rodent model of mixed hyperlipidemia. ALN-PCSsc and
ALN-ANG utilize the company’s proprietary GalNAc-siRNA conjugate delivery
platform, which is designed to achieve targeted delivery of RNAi therapeutics
to hepatocytes through uptake by the asialoglycoprotein receptor, enabling
subcutaneous dose administration with a wide therapeutic index. ALN-PCSsc and
ALN-ANG are programs in the company’s “Alnylam 5x15” product development and
commercialization strategy, where the company aims to advance at least five
RNAi therapeutic programs toward genetically validated disease targets into
clinical development, including programs in advanced stages, by the end of
2015.

“Our recent progress with GalNAc-siRNA conjugates enables advancement of
subcutaneously administered RNAi therapeutics for the treatment of
cardiovascular disease, and our new data presented at the AHA meeting feature
our efforts with ALN-PCSsc and ALN-ANG. With ALN-PCSsc, our new study results
in non-human primates show an up to 95% knockdown of plasma PCSK9 and an up to
67% reduction of LDL-C – in the absence of statin co-administration, with a
very durable knockdown of more than 50 days after the last dose. We believe
these results support a highly competitive target product profile, and we look
forward to advancing ALN-PCSsc toward clinical trials in 2014 with our partner
The Medicines Company,” said Rachel Meyers, Ph.D., Vice President of Research
and RNAi Lead Development at Alnylam. “In addition, our scientists presented
new data from our discovery program with ALN-ANG. Specifically, a lead
GalNAc-siRNA conjugate targeting ANGPTL3 showed a greater than 95% reduction
of triglycerides and a greater than 85% reduction of LDL-C in a mouse model of
mixed hyperlipidemia. These pre-clinical results phenocopy the human genetics
for loss of function in ANGPTL3, and are supportive of our efforts to advance
this new RNAi therapeutic program into later stages of pre-clinical
development.”

New ALN-PCSsc data presented at AHA are based on studies performed in NHPs.
Updated results show that ALN-PCSsc led to an up to 95% knockdown of plasma
PCSK9, with mean PCSK9 knockdown at nadir of 87% (p<0.0001 compared with
pre-dose values according to ANOVA models) and an up to 67% lowering of LDL-C,
with mean LDL-C lowering at nadir of 62% (p<0.0001 compared with pre-dose
values). The level of LDL-C reduction was achieved in the absence of statin
co-administration. Knockdown of PCSK9 and lowering of LDL-C was rapid and
durable, with effects lasting greater than 50 days after the final dose,
supportive of the potential for once-monthly dosing and a highly competitive
target product profile. In February 2013, Alnylam formed an exclusive global
alliance with The Medicines Company for the development and commercialization
of the ALN-PCS program, including ALN-PCSsc. Alnylam and The Medicines Company
have recently announced selection of their Development Candidate for
ALN-PCSsc. Alnylam plans to file an Investigational New Drug (IND) application
in 2014 and will lead the program through the completion of Phase I. The
Medicines Company is responsible for leading and funding development from
Phase II forward and commercializing the ALN-PCS program if successful.

In addition to updating data on the company’s PCSK9 program, Alnylam
scientists and collaborators presented new pre-clinical data from the
company’s ALN-ANG discovery program. ANGPTL3 is an inhibitor of cellular
lipases involved in the metabolism of lipoproteins. Human genetic as well as
exome sequencing studies have identified a statistically significant
relationship of loss-of-function mutations in ANGPTL3 with decreased levels of
triglycerides and LDL-C (N. Engl. J. Med (2010) 363:2220-2227). The new
pre-clinical studies were performed in an “ob/ob” mouse model of obesity and
mixed hyperlipidemia. A single dose of a GalNAc-siRNA targeting ANGPTL3 was
found to lead to robust, dose-dependent knockdown of ANGPTL3 protein, with a
single dose ED[50] of approximately 1 mg/kg. In a multi-dose experiment,
subcutaneous doses of 3.0 mg/kg led to a greater than 95% knockdown of ANGPTL3
protein. This ANGPLT3 protein reduction resulted in a greater than 95%
reduction in triglycerides, and a more than 85% reduction in LDL-C. In
addition, total cholesterol was reduced by greater than 60%. These new data
with ALN-ANG support further advancement of this program for the treatment of
genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, which
are associated with increased risk of coronary artery disease and/or recurrent
pancreatitis.

“Cardiovascular disease remains the leading cause of mortality worldwide.
Elevated LDL-C and triglycerides are two well validated and modifiable risk
factors. A substantial number of patients, especially those at high risk for
cardiovascular disease, are unable to achieve reduced levels of LDL and
triglycerides with current drugs, such as statins or fibrates, and it is clear
that new therapeutic options are needed,” said Daniel J. Rader, M.D.,
professor of Medicine and chief, Division of Translational Medicine and Human
Genetics, at the Perelman School of Medicine at the University of
Pennsylvania. Dr. Rader also serves on Alnylam’s Scientific Advisory Board.
“As a key regulator of LDL receptor levels, liver-expressed PCSK9 is an
important and well validated novel target in molecular medicine for the
treatment of hypercholesterolemia. Likewise, loss-of-function ANGPTL3
mutations in humans are associated with reduced levels of LDL-C and
triglyceride and it is encouraging that an RNAi-based therapeutic targeting
ANGPTL3 expression in the liver reproduced these effects in a mouse model. I
look forward to continued advancement of novel therapeutics, including RNAi,
toward these important disease targets.”

About Hypercholesterolemia

Hypercholesterolemia is a condition characterized by very high levels of
cholesterol in the blood which is known to increase the risk of coronary
artery disease, the leading cause of death in the U.S. Some forms of
hypercholesterolemia can be treated through dietary restrictions, lifestyle
modifications (e.g., exercise and smoking cessation) and medicines such as
statins. However, a large proportion of patients with hypercholesterolemia are
not achieving target LDL-C goals with statin therapy, including genetic
familial hypercholesterolemia patients, acute coronary syndrome patients,
high-risk patient populations (e.g., patients with coronary artery disease,
diabetics, symptomatic carotid artery disease, etc.) and other patients that
are statin intolerant. Severe forms of hypercholesterolemia are estimated to
affect more than 500,000 patients worldwide, and as a result, there is a
significant need for novel therapeutics to treat patients with
hypercholesterolemia whose disease is inadequately managed by existing
therapies.

About ALN-PCS

ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene
proprotein convertase subtilisin/kexin type 9 (PCSK9), a target validated by
human genetics that is involved in the metabolism of low-density lipoprotein
cholesterol (LDL-C, or “bad” cholesterol). ALN-PCS therapies are PCSK9
synthesis inhibitors that lower levels of both intracellular and extracellular
PCSK9, thereby phenocopying the human genetics observed in loss of function or
null human PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum.
Genet. (2006) 79: 514-523). PCSK9 synthesis inhibition through an RNAi
mechanism has the potential to lower tissue and circulating plasma PCSK9
protein levels resulting in higher LDL receptor levels in the liver, and
subsequently lower LDL-C levels in the blood stream. Lower LDL-C is associated
with a decreased risk of cardiovascular disease, including myocardial
infarction and stroke.

About Mixed Hyperlipidemia and Severe Hypertriglyceridemia

Mixed hyperlipidemia is a genetically inherited condition characterized by
very high levels of cholesterol and triglycerides in the blood, both of which
are known to increase the risk of coronary artery disease, the leading cause
of death in the U.S. It is estimated that as many as 1 out of every 100
individuals have mixed hyperlipidemia and are at increased risk of developing
cardiovascular disease. Some forms of mixed hyperlipidemia can be treated
through dietary restrictions, lifestyle modifications (e.g., exercise and
smoking cessation), and medicines such as statins or fibrates; however, a
large portion of mixed hyperlipidemia patients are unable to reach either
their LDL-C and/or triglyceride goals with the current standard of care.
Patients with severe, inherited forms of hypertriglyceridemia (e.g., familial
chylomicronemia syndrome, or “FCS”) are at extremely high risk of developing
recurrent pancreatitis. FCS is a rare orphan genetic disease that affects 1 to
2 individuals per million.

About ALN-ANG

ALN-ANG is an RNAi therapeutic targeting the gene angiopoietin-like 3
(ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and
severe hypertriglyceridemia. ANGPTL3 is a liver-expressed, genetically
validated target that acts to inhibit lipoprotein lipase and endothelial
lipase, and has been shown to increase plasma triglycerides, as well as low
density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol.
Exome sequencing studies have identified a statistically significant
relationship of loss-of-function mutations in ANGPTL3 with decreased levels of
triglycerides and LDL-C (N. Engl. J. Med (2010) 363:2220-2227). A
subcutaneously administered RNAi therapeutic that inhibits ANGPTL3 synthesis
and lowers both LDL-C and triglycerides represents a novel approach to the
treatment of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia. ALN-ANG utilizes Alnylam’s proprietary GalNAc conjugate
delivery platform enabling subcutaneous dose administration.

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: patisiran (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-CC5,
an RNAi therapeutic targeting complement component C5 for the treatment of
complement-mediated diseases; 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-ANG, an RNAi therapeutic
targeting ANGPTL3 for the treatment of genetic forms of mixed hyperlipidemia
and severe hypertriglyceridemia, amongst other programs. As part of its
“Alnylam 5x15” 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: patisiran (ALN-TTR02), an intravenously
delivered RNAi therapeutic targeting transthyretin (TTR) in development for
the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial
amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi
therapeutic targeting TTR in development for the treatment of ATTR in patients
with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic
targeting antithrombin (AT) in development for the treatment of hemophilia and
rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting
aminolevulinate synthase-1 (ALAS-1) in development for the treatment of
porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi
therapeutic targeting complement component C5 in development for the treatment
of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9
in development for the treatment of hypercholesterolemia; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 in development for the treatment of
beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic
targeting alpha-1-antitrypsin (AAT) in development for the treatment of AAT
deficiency liver disease; and ALN-ANG, an RNAi therapeutic targeting ANGPTL3
in development for the treatment of genetic forms of mixed hyperlipidemia and
severe hypertriglyceridemia, 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.

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-PCSsc and ALN-ANG, its
expectations with respect to further advancing ALN-ANG in development, the
filing of an IND application for ALN-PCSsc, its expectations with respect to
the timing and success of clinical trials with ALN-PCSsc, and its expectations
regarding the potential market opportunity for ALN-PCSsc, 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 manage operating expenses, 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 most recent Quarterly Report on Form 10-Q filed
with the Securities and Exchange Commission (SEC) 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.

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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