Alnylam Presents New Pre-Clinical Data on Pharmacology of GalNAc-siRNA Conjugates

  Alnylam Presents New Pre-Clinical Data on Pharmacology of GalNAc-siRNA
  Conjugates

– New Results Demonstrate Achievement of Steady State Liver Drug Levels During
           Chronic Dosing with No Evidence for Drug Accumulation –

  – Steady, Long-Term Knockdown Maintained with High Level of Consistency in
                 Absence of Tachyphylaxis or Sensitization –

Business Wire

CAMBRIDGE, Mass. -- December 19, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data on the
pharmacology of GalNAc-siRNA conjugates at the 12^th US-Japan Symposium on
Drug Delivery Systems held December 16 – 20, 2013 in Lahaina, Maui, Hawaii. In
a presentation titled “Advances in Systemic Delivery of RNAi Therapeutics,”
Alnylam scientists presented new data on tissue drug levels and sustained
target knockdown achieved with long-term chronic dosing of GalNAc-siRNA
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. This
targeted delivery platform enables subcutaneous dose administration with a
wide therapeutic index, and has demonstrated potent and durable gene
silencing, as well as a favorable tolerability profile, in clinical and
pre-clinical studies from multiple programs in the company’s “Alnylam 5x15”
product pipeline.

“Our GalNAc-siRNA conjugate delivery platform is being employed in the
majority of the pipeline programs within our “Alnylam 5x15” product
development strategy. At Alnylam, we are at the forefront of optimizing the
delivery of RNAi therapeutics using this proprietary, now clinically validated
delivery approach,” said Muthiah (Mano) Manoharan, Ph.D., Senior Vice
President of Drug Discovery at Alnylam. “These new data show that weekly
subcutaneous dosing of GalNAc conjugates results in mean steady state drug
levels that compare very favorably with other oligonucleotide platforms that
require 100 to 1000 times greater tissue drug levels to achieve clinically
relevant gene silencing. Furthermore, these data show that chronic dosing
results in sustained target gene knockdown with a high level of consistency in
the absence of any evidence for tachyphylaxis or sensitization. We view these
findings as very encouraging, as they will likely have significant
implications for RNAi-mediated silencing with chronic dosing in the clinical
setting.”

The new data demonstrate the pharmacodynamic and pharmacokinetic properties of
GalNAc-siRNA conjugates following repeat dosing. Specifically, in mouse
studies, weekly subcutaneous dosing of ALN-AT3, an RNAi therapeutic targeting
antithrombin (AT), resulted in mean steady state liver drug levels of
approximately 0.4 and 1.1 micrograms per gram at doses of 0.2 and 0.5 mg/kg,
respectively. These drug levels were shown to correspond to roughly 60% and
75% knockdown of serum AT, and compare very favorably with other
oligonucleotide platforms requiring greater than 100 micrograms of drug per
gram of tissue for similar biologic effects; this corresponds to 100- to
1000-fold lower levels of required tissue exposure for GalNAc-siRNA
conjugates, which could underscore the potential for a more favorable
tolerability profile. Further, no evidence of drug accumulation in liver
tissue during chronic dosing was observed after the third weekly dose. In
addition, data from a long-term pharmacology study were presented with a
GalNAc-siRNA conjugate targeting the transthyretin (TTR) mRNA in mice. Weekly
dosing at 1.0 and 2.5 mg/kg led to steady TTR knockdown of 50% and 80%,
respectively, which was sustained for the entire 196-day time period analyzed.
The TTR knockdown effect was found to be highly consistent with very low
levels of inter-animal variation. Finally, the steady level of knockdown was
achieved with no evidence of tachyphylaxis or sensitization.

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
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) for the treatment of AAT deficiency liver
disease; and ALN-ANG, an RNAi therapeutic 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 press release concerning Alnylam’s future
expectations, plans and prospects, including without limitation, Alnylam’s
expectations regarding its “Alnylam 5x15” product strategy, and Alnylam’s
views with respect to the potential for RNAi therapeutics and GalNAc
conjugates, 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 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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