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

   – New Results Demonstrate Correction of Thrombin Generation and Improved
     Hemostasis in Murine Hemophilia Models and Normalization of Thrombin
       Generation in a Non-Human Primate Hemophilia “Inhibitor” Model –

 – Additional Findings Include Demonstration of a Wide Therapeutic Index for
                       ALN-AT3 in Hemophilia Setting –

  – Company Remains on Track to File Investigational New Drug Application in
               Mid-2013 and to Initiate Phase I in Late 2013 –

Business Wire

CAMBRIDGE, Mass. -- July 2, 2013

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 rare bleeding
disorders. The data were presented at the XXIV Congress of the International
Society on Thrombosis and Haemostasis (ISTH) being held June 29 – July 4, 2013
in Amsterdam. The new pre-clinical data demonstrate that ALN-AT3, a
subcutaneously administered RNAi therapeutic targeting antithrombin (AT), can
normalize thrombin generation and improve hemostasis in hemophilia mice and
fully correct thrombin generation in a non-human primate (NHP) hemophilia
“inhibitor” model. 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.
ALN-AT3 utilizes the company’s proprietary GalNAc conjugate delivery platform
which enables subcutaneous dose administration.

“Hemophilia and other rare bleeding disorders are characterized by
deficiencies in clotting factors that ultimately lead to inadequate thrombin
generation and a bleeding phenotype. ALN-AT3 is aimed at correcting these
defects by knockdown of AT – an endogenous anticoagulant – thus, increasing
thrombin generation and improving hemostasis. This innovative approach is
strongly supported in human genetics by findings in hemophilia patients who
have co-inherited prothrombotic traits, including AT deficiency, and are
characterized with a mild bleeding phenotype,” said Akshay Vaishnaw, M.D.,
Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “We are
very excited by these new data with ALN-AT3 which demonstrate normalization of
thrombin generation and improvement of hemostasis in hemophilia models. Most
importantly, we have demonstrated that ALN-AT3 can fully correct thrombin
generation in a non-human primate hemophilia ‘inhibitor’ model, providing key
proof of concept for our program. Finally, by administering highly exaggerated
doses of ALN-AT3 to wild type and hemophilia animals, we’ve demonstrated that
our RNAi therapeutic has a very wide therapeutic index in the hemophilia
setting. We remain on track to file an investigational new drug application
for ALN-AT3 in mid-2013 and to initiate our Phase I study in late 2013.”

“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 am very encouraged by
Alnylam’s pre-clinical progress to date with ALN-AT3, especially the results
in a non-human primate hemophilia ‘inhibitor’ model showing full correction of
impaired thrombin generation. These results are particularly important since
clinical studies have demonstrated that thrombin generation correlates
strongly with bleeding phenotype; severe hemophilia patients have low thrombin
generation as compared to moderate and mild patients who have significantly
higher levels. I very much look forward to the advancement of this important
program in the clinical setting in the months to come.”

In a presentation titled “An RNAi Therapeutic Targeting Antithrombin Increases
Thrombin Generation and Improves Hemostasis,” Alnylam scientists and
collaborators presented data demonstrating efficacy of ALN-AT3 in models of
hemophilia. First, a series of studies were performed in murine models of
hemophilia. A single subcutaneous dose of ALN-AT3 that resulted in plasma AT
reduction of 90% led to normalization of thrombin generation in hemophilia B
(HB) mice. In addition, in a microvessel laser injury model, both hemophilia A
(HA) and HB mice treated with a single subcutaneous dose of ALN-AT3
demonstrated marked improvements in hemostatic plug formation compared to
untreated HA or HB mice. Additional studies were performed in NHP models. In
wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and
reversible silencing of plasma AT3. 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. Dosing was continued for over five months with
consistent pharmacologic effects, including no evidence of tachyphylaxis or
any neutralizing immune response associated with prolonged exposure to
ALN-AT3. Studies were then performed in an NHP hemophilia “inhibitor” model,
in which a HA phenotype was induced via administration of a polyclonal
anti-factor VIII antibody. The anti-factor VIII antibody treatment resulted in
a sharp decrease in plasma factor VIII activity levels to less than 1% of
normal, similar to a severe hemophilia state in the presence of anti-factor
VIII inhibitors. Animals received six weekly doses of saline or ALN-AT3 at
0.25 or 0.50 mg/kg. ALN-AT3 treated animals showed the expected level of AT
knockdown but also showed a statistically significant (p<0.01 by ANOVA)
dose-dependent increase in thrombin generation, fully restoring this
hemostatic parameter back to normal levels. 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.


ALN-AT3 Pre-clinical Efficacy in NHP Hemophilia “Inhibitor” Model
                                                AT                Peak             Peak
                                                Knockdown         Thrombin         Thrombin
                         N        (Mean % ±     (nM)         (% of
                                                SD)               (Mean ±          Normal,
                                                                  SD)              Pre-Dose)
Normal        Pre-dose     12^+     -             97 ± 36      -
              Saline       4        -             37 ± 9       38%
HA              0.25         4        60 ± 10       58 ± 6       60%
Inhibitor         mg/kg
              0.50         4        80 ± 6        97 ±         100%
                  mg/kg                                           27**
** p < 0.01, Dunnett’s post hoc test vs. saline
^+ 12 animals x 3 pre-dose measurements per animal


In addition, Alnylam presented results of tolerability studies that
demonstrate a wide therapeutic index for ALN-AT3 in the hemophilia setting.
Highly exaggerated doses of ALN-AT3 resulting in essentially complete ablation
of AT were evaluated in wild-type and hemophilia mice. Specifically, weekly
doses of ALN-AT3 at 10 or 30 mg/kg in wild-type mice were associated with
mortality, consistent with the genetics of homozygous AT deficiency which is
known to be embryonic lethal. In sharp contrast, seven weekly doses of greater
than 100 mg/kg were very well tolerated in HA mice; 100% of animals survived,
and there were no toxicologically significant findings in clinical or anatomic
pathology exams. Furthermore, single doses as high as 500 mg/kg were very well
tolerated in both HA and HB mice. Since ALN-AT3 efficacy toward improved
hemostasis is achieved at weekly doses less than 1 mg/kg, these results
support a greater than 100-fold therapeutic index for ALN-AT3 in the
hemophilia setting.

Alnylam plans to file an investigational new drug (IND) application for
ALN-AT3 in mid-2013. The company then plans to initiate a Phase I clinical
trial in late 2013, with initial clinical data for ALN-AT3 in hemophilia
patients expected to be reported in 2014.

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: 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 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 the C5 component of the complement pathway 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, and Cell. 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 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 the C5 component of the complement pathway 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, and ALN-AS1; the company will seek global
development and commercial alliances for other programs.

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, the
initiation of clinical trials for ALN-AT3, and the reporting of data from its
ALN-AT3 clinical trials, 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, 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 filed with the Securities and Exchange
Commission (SEC) on May 7, 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 does not assume 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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