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Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Hemophilia and Other Bleeding Disorders at 54th

  Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the
  Treatment of Hemophilia and Other Bleeding Disorders at 54th American
  Society of Hematology (ASH) Annual Meeting

  – Efficacy for ALN-AT3, an RNAi Therapeutic Targeting Antithrombin for the
     Treatment of Hemophilia, Demonstrated in Non-Human Primate Models –

  – Progress from the Therapeutic Program to be Included in an Upcoming RNAi
                      Roundtable on Conjugate Delivery –

Business Wire

CAMBRIDGE, Mass. -- December 10, 2012

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data from its
RNAi therapeutic program for the treatment of hemophilia and other bleeding
disorders at the 54^th American Society of Hematology Annual Meeting being
held December 8-11, 2012 in Atlanta. Alnylam scientists presented data showing
that ALN-AT3, a subcutaneously administered RNAi therapeutic targeting
antithrombin (AT), yields potent, dose-dependent, and durable knockdown of AT
in non-human primates (NHPs) with an up to four-fold increase in thrombin
generation. Alnylam’s program in hemophilia comprises part of its ‘Alnylam
5x15’ product strategy, by which the company aims to advance five programs in
clinical development, including programs in advanced stages, by the end of

“Our ALN-AT3 program is central to our ‘Alnylam 5x15’ strategy, which is aimed
at bringing innovative medicines to patients, with a focus on RNAi
therapeutics toward genetically defined targets for diseases with very high
unmet medical need. Hemophilia and other bleeding disorders exemplify these
types of diseases, as there remains significant need for new treatment
options,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and
Chief Medical Officer of Alnylam. “The new data with ALN-AT3 demonstrate
potent and sustained knockdown of serum antithrombin and marked increases in
thrombin generation in non-human primates. ALN-AT3 utilizes our GalNAc-siRNA
conjugate delivery approach enabling subcutaneous dose administration, and is
on track for an investigational new drug filing in mid-2013.”

“New therapeutic options are needed for patients with hemophilia, including
those with inhibitors to their replacement factors, to prevent bleeding and
the associated pathology. In addition, there is growing recognition of unmet
need in patients with other rare bleeding disorders where congenital
deficiencies of blood coagulation factors result in impaired thrombin
generation and bleeding diatheses,” said Claude Negrier, M.D., head of the
Hematology Department and director of the Haemophilia Comprehensive Care
Centre at Edouard Herriot University Hospital in Lyon. “Human genetic data on
co-inheritance of thrombophilic traits in patients with hemophilia support the
hypothesis that inhibition of endogenous anticoagulant proteins, such as AT,
can improve hemostasis. In aggregate, I am very encouraged by the emerging
pre-clinical data on ALN-AT3. Indeed, availability of a subcutaneously
administered therapeutic with a long duration of action could represent an
exciting opportunity for hemophilia patients including those with inhibitors
to their replacement factor, and patients with other rare bleeding disorders.”

In a poster titled “An RNAi Therapeutic Targeting Antithrombin Increases
Thrombin Generation in Nonhuman Primates,” (#3370) Alnylam scientists showed
that subcutaneous administration of ALN-AT3 in NHPs results in potent,
dose-dependent, and durable knockdown in serum AT, resulting in significant
increases in thrombin generation. Specifically, a single subcutaneous dose of
ALN-AT3 led to potent knockdown of serum AT, with an ED50 of 1 mg/kg. AT
suppression was durable, with effects lasting greater than six weeks after a
single dose. In addition, weekly subcutaneous doses of ALN-AT3 in NHPs led to
sustained AT knockdown of approximately 80% and greater than 90% at 0.5 mg/kg
and 1.5 mg/kg, respectively. These data enable an estimation of an ED50 dose
for weekly subcutaneous administration at 0.15-0.3 mg/kg at a volume of
injection for human administration expected to be less than 0.5 mL/injection.
Moreover, increased thrombin generation was closely correlated with AT
reduction, with an up to four-fold increase in peak thrombin at 90% AT
reduction. ALN-AT3 utilizes Alnylam’s proprietary GalNAc-siRNA conjugate
delivery approach enabling subcutaneous dose administration with potential for
a once-weekly or twice-monthly dosing regimen. Alnylam expects to file an
investigational new drug (IND) application for ALN-AT3 in mid-2013.

In addition, results from Alnylam’s ALN-AT3 program will be discussed at an
upcoming RNAi Roundtable on conjugate delivery that the company will host on
Friday, December 14 at 11:00 a.m. ET. The discussion will focus on progress
with the company’s proprietary GalNAc-conjugate platform to deliver RNAi
therapeutics with subcutaneous dose administration. The roundtable will also
include a review of the company’s two leading conjugate programs: ALN-TTRsc
for the treatment of transthyretin-mediated amyloidosis (ATTR) and ALN-AT3 for
the treatment of hemophilia and other bleeding disorders. The webinar will be
available live on the Capella section of the company’s website,, and will also be available for replay on the Alnylam
website within 48 hours after the event.

About Hemophilia

Hemophilias are hereditary disorders caused by genetic deficiencies of various
blood clotting factors, resulting in recurrent bleeds into joints, muscles,
and other major internal organs. Hemophilia A is defined by loss-of-function
mutations in factor VIII, and there are greater than 40,000 registered
patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function
mutations in factor IX, affects greater than 9,500 registered patients in the
U.S. and E.U. Other Rare Bleeding Disorders (RBDs) are defined by congenital
deficiencies of other blood coagulation factors. Standard treatment for
hemophilia patients involves replacement of the missing clotting factor either
as prophylaxis or on-demand therapy. However, as many as one third of
hemophilia A patients will develop an antibody to their replacement factor - a
very serious complication; these 'inhibitor' patients become refractory to
standard replacement therapy. There exists a small subset of hemophilia
patients who have co-inherited a prothrombotic mutation, such as factor V
Leiden, protein C deficiency, and prothrombin G20210A. Hemophilia patients
that have co-inherited these prothrombotic mutations are characterized as
having a later onset of disease, lower risk of bleeding, and reduced
requirements for factor VIII or factor IX treatment as part of their disease
management. There exists a significant need for novel therapeutics to treat
hemophilia patients.

About Antithrombin (AT)

Antithrombin (AT, also known as “antithrombin III” and “SERPINC1”) is a liver
expressed plasma protein and member of the “serpin” family of proteins that
acts as an important endogenous anticoagulant by inactivating factor Xa and
thrombin. AT plays a key role in normal hemostasis, which has evolved to
balance the need to control blood loss through clotting with the need to
prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss
of certain procoagulant factors (Factor VIII and Factor IX, in the case of
hemophilia A and B, respectively) results in an imbalance of the hemostatic
system toward a bleeding phenotype. In contrast, in thrombophilia (e.g.,
factor V Leiden, protein C deficiency, antithrombin deficiency, amongst
others), certain mutations result in an imbalance in the hemostatic system
toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations
may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines
a novel strategy for improving hemostasis.

About GalNAc Conjugates

GalNAc-siRNAs are designed to achieve targeted delivery of RNAi therapeutics
to hepatocyte cells of the liver 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. Notably,
GalNAc-siRNAs are being employed in Alnylam’s ALN-TTRsc and ALN-AT3 RNAi
therapeutic programs for the treatment of transthyretin-mediated amyloidosis
(ATTR) and hemophilia and other bleeding disorders, respectively, both of
which the company expects to have in clinical trials in 2013. GalNAc-siRNAs
are a proprietary Alnylam delivery platform.

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

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for
development and commercialization of novel RNAi therapeutics to address
genetically defined 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-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. Alnylam intends to focus on
developing and commercializing certain programs from this product strategy
itself in the United States and potentially certain other countries; the
company will seek development and commercial alliances for other core programs
both in the United States and in other global territories.

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 and its
proprietary GalNAc-siRNA delivery platform, its expectations regarding the
development of ALN-AT3, including the timing of an IND filing for ALN-AT3, its
expectations regarding the initiation of clinical trials for ALN-TTRsc, and
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 discover and
develop novel drug candidates, including drug candidates utilizing
GalNAc-siRNA delivery, the pre-clinical and clinical results for these product
candidates, including ALN-AT3 and ALN-TTRsc, 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, 202-955-6222 x2597
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