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Alnylam Files Clinical Trial Application to Initiate a Phase I Study for ALN-AT3, a Subcutaneously Administered RNAi Therapeutic



  Alnylam Files Clinical Trial Application to Initiate a Phase I Study for
  ALN-AT3, a Subcutaneously Administered RNAi Therapeutic Targeting
  Antithrombin (AT) for the Treatment of Hemophilia A and B

 – Company Expects to Initiate Phase I Study in Early 2014 with Interim Data
                 from Hemophilia Subjects by Year-End 2014 –

Business Wire

CAMBRIDGE, Mass. -- October 29, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has filed a Clinical Trial Application (CTA)
with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to
initiate a Phase I clinical trial with ALN-AT3, a subcutaneously administered
RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia,
including people with “inhibitors.” Hemophilia is a hereditary disorder caused
by genetic deficiencies in various blood clotting factors, resulting in
recurrent bleeds into joints, muscles, and other major internal organs. By
knocking down AT, ALN-AT3 administration is expected to increase thrombin
generation and reduce disease burden, including annualized bleeding rate,
severity of bleeding, and requirement for replacement factor or bypass agent,
and to potentially improve quality of life. ALN-AT3 is a key program in the
company’s “Alnylam 5x15” product development and commercialization strategy,
in which the company aims to advance five RNAi therapeutic programs toward
genetically validated disease targets into clinical development, including
programs in advanced stages, by the end of 2015.

“Hemophilia is characterized by a genetic deficiency in clotting factors that
ultimately leads to inadequate thrombin generation and a bleeding disorder.
ALN-AT3 aims to correct the hemostatic imbalance in hemophilia by knocking
down AT – an endogenous anticoagulant – thus increasing thrombin generation
and improving hemostasis, and reducing disease burden. This innovative
approach is strongly supported by clinical cases in people with hemophilia who
have co-inherited prothrombotic traits, including AT deficiency, and are
characterized by a milder bleeding phenotype,” said Akshay Vaishnaw, M.D.,
Ph.D., Executive Vice President and Chief Medical Officer at Alnylam. “This
CTA for ALN-AT3 marks our second for an RNAi therapeutic that utilizes our
proprietary GalNAc conjugate delivery platform, which we have now shown to be
clinically validated. Our pre-clinical data with ALN-AT3 have demonstrated
normalization of thrombin generation and improvement of hemostasis in
hemophilia models. We have also demonstrated that ALN-AT3 has a wide
therapeutic index in the context of hemophilia. We very much look forward to
the continued advancement of ALN-AT3, including the start of our Phase I
clinical trial in early 2014 with data from hemophilia subjects expected by
the end of that year.”

ALN-AT3 is a subcutaneously administered RNAi therapeutic that comprises an
siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand.
GalNAc-siRNA conjugates are a proprietary, clinically validated delivery
platform and are designed to achieve targeted delivery of RNAi therapeutics to
hepatocytes through uptake by the asialoglycoprotein receptor. Pre-clinical
studies have shown that subcutaneous administration of ALN-AT3 can normalize
thrombin generation and improve hemostasis in hemophilia mice and fully
correct thrombin generation in a non-human primate (NHP) hemophilia
“inhibitor” model. A single subcutaneous dose of ALN-AT3 that resulted in
plasma AT reduction of approximately 90% led to normalization of thrombin
generation and improvement in hemostasis in hemophilia mice. In wild type
NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and
reversible silencing of plasma AT. Weekly subcutaneous doses of 0.50 mg/kg
resulted in 90% AT knockdown, while an ED50 knockdown was achieved at a dose
as low as 0.125 mg/kg. Furthermore, in an NHP “inhibitor” model, in which a
hemophilia A (HA) phenotype was induced via administration of a polyclonal
anti-factor VIII antibody, ALN-AT3-treated animals showed the expected level
of AT knockdown but also showed a statistically significant (p<0.01)
dose-dependent increase in thrombin generation, fully restoring this
hemostatic parameter back to normal levels. We believe these results
demonstrate that ALN-AT3 can normalize thrombin generation in the absence of
functional levels of factor VIII and/or in the presence of anti-factor VIII
antibodies in a large animal model, providing key proof of concept for the
program. In addition, single doses of ALN-AT3 as high as 500 mg/kg – over
100-fold greater than doses that result in essentially complete ablation of AT
– were well tolerated in HA mice: 100% of animals survived, and there were no
toxicologically significant findings in clinical or pathology exams.

As per the filed CTA, the Phase I trial of ALN-AT3 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. 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 people in the U.S.
and E.U. Hemophilia B, defined by loss-of-function mutations in factor IX,
affects greater than 9,500 people 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 people worldwide with a severe bleeding phenotype. Standard
treatment for people with hemophilia involves replacement of the missing
clotting factor either as prophylaxis or on-demand therapy. However, as many
as one third of people with hemophilia A will develop an antibody to their
replacement factor – a very serious complication; these “inhibitor” subjects
become refractory to standard replacement therapy. There exists a small subset
of people with hemophilia who have co-inherited a prothrombotic mutation, such
as factor V Leiden, antithrombin deficiency, protein C deficiency, and
prothrombin G20210A. People with hemophilia 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 and RBD.

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 reduce disease burden in people with 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: 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-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-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases, amongst other programs. 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 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: 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-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-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases, 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; these include ALN-TTR, ALN-AT3, ALN-AS1, and ALN-CC5, amongst other
programs.

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, Alnylam’s views
with respect to the potential for RNAi therapeutics, including ALN-AT3, its
expectations with respect to the timing and success of clinical trials for
ALN-AT3, and its plans with respect to the commercial opportunity for the
ALN-AT3 program, 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, including ALN-AT3, 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 Quarterly Report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on August 9, 2013 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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