Alnylam Presents New Pre-clinical Data on ALN-AT3, an RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of

  Alnylam Presents New Pre-clinical Data on ALN-AT3, an RNAi Therapeutic
  Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare
  Bleeding Disorders (RBD)

 – New Results Demonstrate an Expanded Therapeutic Index for AT Knockdown and
Complete Correction of Activated Partial Thromboplastin Time (aPTT) in Models
                               of Hemophilia –

    – ALN-AT3 on Track for Phase I Start in Early 2014, with Medicines and
   Healthcare Products Regulatory Agency (MHRA) Approval of Recently Filed
                      Clinical Trial Application (CTA) –

Business Wire

CAMBRIDGE, Mass. -- December 9, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data with
ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD), at the
55^th Annual Meeting of the American Society of Hematology (ASH) held December
7 – 10, 2013 in New Orleans. In these new studies, repeat administration of
ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no
adverse findings up to dose levels 200 times greater than levels required to
achieve 50% AT knockdown. Further, the new studies demonstrate that ALN-AT3
administration achieves complete correction of the activated Partial
Thromboplastin Time (aPTT) – an ex vivo measure of blood coagulation that is
significantly prolonged in hemophilia – in HA mice. ALN-AT3 is a key program
in the company’s “Alnylam 5x15” product strategy, which is aimed at advancing
five RNAi therapeutic programs directed toward genetically validated disease
targets into clinical development, including programs in advanced stages, by
the end of 2015.

“Hemophilia and other rare bleeding disorders are characterized by
deficiencies in specific clotting factors that ultimately lead to inadequate
thrombin generation and a bleeding diathesis. ALN-AT3 is aimed at correcting
these bleeding disorders by knockdown of AT – an endogenous anticoagulant –
thus, increasing thrombin generation and improving hemostasis,” said Akshay
Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of
Alnylam. “These new data presented at ASH demonstrate that repeat
administration of ALN-AT3 is well tolerated in animal models of hemophilia,
and suggest that our RNAi therapeutic has the potential for a wide therapeutic
index in subjects with hemophilia. With MHRA approval of our recently filed
CTA, we look forward to the advancement of ALN-AT3 in our Phase I clinical
trial that we expect to start in early 2014, with data from hemophilia
subjects expected by the end of next year.”

“The unmet need for new therapeutic options to treat hemophilia patients
remains very high, particularly in those patients that develop inhibitory
antibodies to their replacement factor. Indeed, availability of a safe and
effective subcutaneously administered therapeutic with a long duration of
action would represent a marked improvement over currently available
approaches for prophylaxis,” 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. “I continue to be encouraged by
Alnylam’s pre-clinical progress to date with ALN-AT3, including these new data
demonstrating a wide therapeutic index and correction of aPTT for ALN-AT3 in
animals with hemophilia. I look forward to the advancement of this innovative
therapeutic candidate in clinical studies in the months to come.”

In a presentation titled “Expanded Therapeutic Index of Antithrombin Silencing
and Correction of APTT in a Hemophilia A Mouse Model,” Alnylam scientists
presented data demonstrating that, in contrast to wild type (WT) mice, repeat
administration of ALN-AT3 was very well tolerated in HA mice. Specifically, HA
mice treated with ALN-AT3 exhibited no adverse events up to 100 mg/kg – a dose
that is 200-fold greater than the mouse ED[50 ]and that essentially ablates AT
protein levels in blood. In fact, 100% of the treated HA mice survived, with
no adverse clinical signs or changes to body weight parameters. In WT mice
(with intact coagulation systems), repeat administration of over 10 mg/kg
ALN-AT3 led to greater than 90% knockdown of plasma AT, and resulted in the
expected procoagulant phenotype and poor tolerability. This result was
expected since AT knockout in mice and homozygous AT deficiency in humans are
known to be embryonic lethal (J. Clin. Invest. (2000) 106:873-878; Blood
(2008) 112:19-27). To evaluate the potential reversal of ALN-AT3 efficacy, WT
mice treated with 100 mg/kg ALN-AT3 were also treated with exogenous human AT
protein. Co-administration of human AT conferred complete protection from
prothrombotic adverse events observed in WT mice receiving ALN-AT3 alone,
demonstrating that human AT protein could serve as a potential reversal agent
for ALN-AT3, if needed. In addition, HA mice treated with ALN-AT3 exhibited
significant reductions in aPTT relative to control HA mice. Specifically, the
aPTT in HA mice, which is significantly prolonged, was corrected back to aPTT
values observed in WT mice. Collectively, these data suggest a substantially
expanded therapeutic index of AT knockdown in the hemophilia disease
condition, and confirm the active effects for ALN-AT3 that are expected to
reset insufficient thrombin generation in people with hemophilia.

Alnylam remains on track to begin a Phase I trial with ALN-AT3 early in 2014.
Alnylam announced today that it has received CTA approval from the MHRA for
the initiation of the Phase I clinical study. The study will be conducted in
the U.K. as a single- and multi-dose, dose-escalation study consisting of two
parts. The first part will be a randomized, single-blind, placebo-controlled,
single-dose, dose-escalation study, enrolling up to 24 healthy volunteer
subjects. Only low doses of ALN-AT3 will be administered in this part of the
study with stopping rules at greater than 40% AT knockdown, which is believed
to be a well tolerated level of AT knockdown based on pre-clinical studies, in
addition to data from people with heterozygous AT deficiency. The primary
objective of the first part of the study is to evaluate the safety and
tolerability of a single dose of subcutaneously administered ALN-AT3.
Secondary objectives include assessment of clinical activity as determined by
knockdown of circulating AT levels. The second part of the study will be an
open-label, multi-dose, dose-escalation study enrolling up to 18 people with
moderate to severe hemophilia A or B. The primary objective of this part of
the study is to evaluate the safety and tolerability of multiple doses of
subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary
objectives include assessment of clinical activity as determined by knockdown
of circulating AT levels and increase in ex vivo thrombin generation.

About Hemophilia and Rare Bleeding Disorders (RBD)
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 (RBD) are defined by congenital
deficiencies of other blood coagulation factors, including Factors II, V, VII,
X, and XI, and there are about 1,000 patients worldwide with a severe bleeding
phenotype. 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, antithrombin deficiency,
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-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 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-AT3, its expectations
regarding the potential for ALN-AT3 to have a wide therapeutic index in the
hemophilia disease condition, its expectations with respect to the timing,
execution, and success of its clinical trials for ALN-AT3, its expectations
regarding the potential use of human AT as a reversal agent for ALN-AT3, and
its expectations regarding the potential market opportunity for ALN-AT3,
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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