New Alnylam Pre-clinical Results on ALN-CC5, an RNAi Therapeutic Targeting Complement Component C5 for the Treatment of

  New Alnylam Pre-clinical Results on ALN-CC5, an RNAi Therapeutic Targeting
  Complement Component C5 for the Treatment of Complement-Mediated Diseases,
  Demonstrate up to 98% Serum C5 Knockdown and up to 94% Inhibition of
  Hemolytic Activity in Non-Human Primates

  – New Research Findings Presented at 55^th Annual Meeting of the American
 Society of Hematology (ASH) Confirm Potential of Subcutaneously Administered
                         RNAi Therapeutic Strategy –

– Alnylam Now Expects to Designate its ALN-CC5 Development Candidate in Early
               2014 with an IND Filing Planned for Early 2015 –

ASH 2013

Business Wire

CAMBRIDGE, Mass. -- December 8, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data with
ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement
component C5 for the treatment of complement-mediated diseases. These data
were presented at the 55^th Annual Meeting of the American Society of
Hematology (ASH) held December 7 – 10, 2013 in New Orleans, and demonstrate
that subcutaneous administration of ALN-CC5 in non-human primates (NHPs) led
to an up to 98% knockdown of serum C5 and an up to 94% inhibition of hemolytic
activity. Alnylam believes that ALN-CC5 – part of the company’s “Alnylam 5x15”
product strategy – represents a novel approach for the treatment of
complement-mediated diseases, with a potentially competitive profile compared
with intravenously administered anti-C5 monoclonal antibody therapy. In
addition, Alnylam presented two separate posters with new pre-clinical data on
ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders.

“C5 is both a genetically and clinically validated target that exemplifies the
potential of Alnylam’s ‘5x15’ product strategy for innovative new medicines.
First, C5 is predominantly expressed in liver, where we have established
robust clinical activity and tolerability for RNAi therapeutics. In addition,
our clinical development plan for ALN-CC5 will be facilitated by serum
biomarkers in Phase I trials and what we believe will be a relatively
streamlined and focused path for advanced development,” said Akshay Vaishnaw,
M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam.
“These new non-human primate data demonstrate that ALN-CC5 can achieve up to
98% knockdown of serum C5 and up to 94% inhibition of hemolytic activity, at
the lower limits of quantitation in these assays. We believe that this effect
is likely to yield clinical benefit in the context of a disease like
paroxysmal nocturnal hemoglobinuria (PNH), in which a greater than 80%
inhibition of hemolytic activity is a clinically established target level
based on published data with eculizumab, an intravenously administered
monoclonal antibody that binds to serum C5. In sum, we believe that a
subcutaneously administered RNAi therapeutic that blocks C5 synthesis could
represent an important advance for the treatment of a broad range of
complement-mediated diseases.”

“The complement system plays a central role in immunity as part of host
defense. However, dysregulation of this pathway can lead to life-threatening
complications in a wide range of human diseases including PNH, atypical
hemolytic uremic syndrome (aHUS), neuromyelitis optica, amongst others,” said
Jeff Szer, M.D., Professor and Director of the Department of Clinical
Haematology and Bone Marrow Transplant Service at Royal Melbourne Hospital and
Director at the Western and Central Melbourne Integrated Cancer Service. “I am
very encouraged by these pre-clinical data showing potent, dose-dependent, and
durable knockdown of serum C5 with greater than 90% inhibition of hemolytic
activity using a subcutaneously administered RNAi therapeutic. If these
results can be extended to the clinical setting, I believe that they could
represent a very promising therapeutic strategy and potential new treatment
option for patients with complement-mediated diseases.”

In a presentation titled “Development of RNAi Therapeutics Targeting the
Complement Pathway” Alnylam scientists presented data showing robust,
dose-dependent, and durable knockdown of serum C5 in NHPs. Multiple doses of
ALN-CC5 at 2.5 or 5.0 mg/kg led to rapid and dose-dependent knockdown of serum
C5 of up to 97.8%, with mean knockdown at nadir of 97.5% (p<0.001) at the top
dose. Knockdown of C5 was durable, with greater than 90% knockdown sustained
for up to three weeks after the final dose. Further, subcutaneous
administration resulted in a consistent greater than 80% knockdown of C5
during the treatment period. The results are consistent with published
literature that shows an hepatic origin for the vast majority of circulating
C5, and confirms that the serum component of locally produced C5 is minimal at
best. In addition, multi-dose administration of ALN-CC5 resulted in robust and
durable inhibition of hemolytic activity. At the top dose of 5.0 mg/kg, an up
to 94% inhibition of hemolytic activity was observed, with a mean nadir
reduction of 92% (p<0.01). Inhibition of hemolytic activity was sustained for
at least two weeks after the final dose. Further, inhibition of hemolytic
activity was shown to be highly correlated with serum levels of C5 (r^2=0.93,
p<10^-15). Importantly, a greater than 80% inhibition in hemolytic activity
has been previously validated in studies of eculizumab, an intravenously
administered monoclonal antibody targeting C5, in patients with PNH as being
associated with clinical benefit (N. Engl. J. Med. (2004) 350:552-559; N.
Engl. J. Med. (2006) 355:1233-1243). A summary of key data are provided below:


Serum C5 Knockdown and Inhibition of Hemolytic Activity in NHPs
                                  % C5                                 %
Dose            Max C5            Knockdown         Max %              Hemolysis
(mg/kg)     Knockdown     at            Hemolysis      Inhibition
                (%)               Nadir,            Inhibition         at Nadir,
                                  Mean (SD)                            Mean (SD)
2.5         96.5          94.9          82.4           74.9
                                  (1.7)***                             (8.9)^+
5.0         97.8          97.5          93.5           91.8
                                  (0.3)***                             (2.1)**

^+ p < 0.1, * p < 0.05, ** p < 0.01, *** p < 0.001
p values correspond to post hoc pairwise comparisons (under ANOVA models) of
dose groups (n=3) vs. control (n=1)


The essentially complete knockdown of C5 was well tolerated in NHPs, as
evidenced by no changes in hematology, serum chemistry, or coagulation
parameters at 24 hours after the last dose. Alnylam is continuing to optimize
its C5-targeted siRNA lead candidate, and now expects to identify its final
Development Candidate for ALN-CC5 in early 2014 and to file an Investigational
New Drug (IND) application or IND equivalent in early 2015.

In addition, in two posters titled “ALN-TMP: A subcutaneously administered
RNAi therapeutic targeting Tmprss6 for the treatment of β-Thalassemia” and “An
RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy,
Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a
Mouse Model Of β-Thalassemia Intermedia,”  Alnylam scientists presented new
pre-clinical data from the company’s ALN-TMP program. The new study showed
that weekly subcutaneous administration of ALN-TMP resulted in robust
knockdown of TMPRSS6 mRNA in mice, with about 90% knockdown (p<0.0001) at a
dose of 1.0 mg/kg. This level of knockdown was associated with a two-fold
increase in hepcidin levels (p<0.05), and a greater than 50% decrease in
transferrin saturation (p<0.001). The data also demonstrated a linear
relationship between TMPRSS6 mRNA silencing and transferrin saturation,
suggesting that ALN-TMP can modulate iron restriction in a predictable manner.
In addition, studies in a mouse model of β-thalassemia intermedia (Hbb^th3/+ 
mice) were conducted to explore the effects of ALN-TMP in combination with the
iron chelator deferiprone compared to either treatment alone. Administration
of ALN-TMP, but not deferiprone, was shown to ameliorate anemia and
extramedullary hematopoiesis, including increases in hemoglobin, decreases in
serum erythropoietin, and reduction in splenomegaly. On the other hand,
ALN-TMP and deferiprone were found to act in an additive manner toward
reducing serum and liver iron levels. These new findings suggest that combined
ALN-TMP and iron chelation therapy may provide improved management of
secondary iron overload in β-thalassemia, including thalassemia major, and
also support the potential for ALN-TMP as a therapeutic option in a broader
range of iron overload disorders.

About ALN-CC5

ALN-CC5 is an RNAi therapeutic targeting the C5 component of the complement
pathway for the treatment of complement-mediated diseases. The complement
system plays a central role in immunity as a protective mechanism for host
defense, but its dysregulation results in life-threatening complications in a
broad range of human diseases including paroxysmal nocturnal hemoglobinuria
(PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis,
neuromyelitis optica, amongst others. Complement component C5, which is
predominantly expressed in liver cells, is a genetically and clinically
validated target; loss of function human mutations are associated with an
attenuated immune response against certain infections and intravenous anti-C5
monoclonal antibody therapy has demonstrated clinical activity and
tolerability in a number of complement-mediated diseases. A subcutaneously
administered RNAi therapeutic that silences C5 represents a novel approach to
the treatment of complement-mediated diseases. ALN-CC5 utilizes Alnylam’s
proprietary GalNAc conjugate delivery platform enabling subcutaneous dose
administration.

About ALN-TMP

ALN-TMP comprises a systemically delivered RNAi therapeutic targeting
transmembrane protease, serine 6 (Tmprss6) for the treatment of β-thalassemia
and iron overload disorders. These blood disorders are associated with chronic
anemia, extra-medullary hematopoiesis, and ineffective erythropoiesis.
Tmprss6, a genetically validated target expressed on hepatocytes, functions by
cleaving hemojuvelin, resulting in reduced hepcidin levels and increased iron
mobilization. Pre-clinical animal model studies with ALN-TMP have demonstrated
corrective effects on iron overload in addition to broader disease modifying
effects including improvements in hemoglobin levels, spleen histopathology,
and globin gene expression.

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-CC5 and ALN-TMP, and its
expectations regarding selection of a Development Candidate and filing of an
Investigational New Drug (IND) application for ALN-CC5, 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, 202-955-6222 x2597
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