Alnylam Reports Positive Top-Line Results for ALN-TTRsc, a Subcutaneously Administered RNAi Therapeutic Targeting Transthyretin

  Alnylam Reports Positive Top-Line Results for ALN-TTRsc, a Subcutaneously
  Administered RNAi Therapeutic Targeting Transthyretin (TTR) for the
  Treatment of TTR-Mediated Amyloidosis

 – ALN-TTRsc Achieves Greater than 80% Knockdown of Serum TTR and is Found to
                    be Generally Safe and Well Tolerated –

 – Results Establish Human Translation of Alnylam’s Proprietary GalNAc-siRNA
 Conjugate Platform for Subcutaneous Administration of RNAi Therapeutics with
                           Wide Therapeutic Index –

 – Data to be Presented at the Annual Scientific Meeting of the Heart Failure
                      Society of America in September –

                – Company to Host and Webcast R&D Day Today –

Business Wire

CAMBRIDGE, Mass. -- July 11, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today positive top-line results from its ongoing Phase I
trial of ALN-TTRsc, a subcutaneously administered RNAi therapeutic targeting
the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis
(ATTR). The company is reporting that ALN-TTRsc achieved robust and
statistically significant (p<0.01) knockdown of serum TTR protein levels of
greater than 80% in healthy volunteer subjects, in line with results for
ALN-TTRsc previously reported in non-human primates. In addition, to date
ALN-TTRsc was found to be generally safe and well tolerated. Dose escalation
in this trial continues and results will be presented at the Annual Scientific
Meeting of the Heart Failure Society of America (HFSA), being held September
22 – 25, 2013 in Orlando, Fla. These human study results are the first to be
reported for Alnylam’s proprietary GalNAc-siRNA conjugate delivery platform,
enabling subcutaneous dosing of RNAi therapeutics with a wide therapeutic
index.

“These clinical results with ALN-TTRsc establish human translation for RNAi
therapeutics that utilize our GalNAc-siRNA conjugate delivery platform. This
platform enables subcutaneous dose administration with a wide therapeutic
index and has now become our primary approach for development of RNAi
therapeutics. As a result, we believe these data are very meaningful not only
for the continued advancement of ALN-TTRsc, but also for the continued
execution on our entire ‘Alnylam 5x15’ product strategy,” said John
Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Specifically, we are
very excited to report top-line results from the study showing statistically
significant knockdown of serum TTR to levels greater than 80% in treated
subjects, results which are in line with our non-human primate experience. We
look forward to continued advancement of our ALN-TTRsc program, including
presentation of data from the Phase I trial at the HFSA meeting in September,
start of a Phase II study in familial amyloidotic cardiomyopathy patients by
the end of this year, and – assuming positive results – start of a pivotal
Phase III trial for ALN-TTRsc in 2014.”

ATTR is caused by mutations in the TTR gene which cause abnormal amyloid
protein deposits to accumulate in various tissues including peripheral nerves
and heart, resulting in neuropathy and/or cardiomyopathy. ATTR represents a
major unmet medical need with significant morbidity and mortality; familial
amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide
and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people
worldwide. ALN-TTRsc, which is being developed for the treatment of FAC, is a
subcutaneously administered RNAi therapeutic that comprises an siRNA
conjugated to a GalNAc ligand that enables receptor-mediated delivery to the
liver. ALN-TTRsc is the first GalNAc-siRNA – and the first subcutaneously
delivered – systemic RNAi therapeutic to enter clinical development stages.
Alnylam is also developing ALN-TTR02, an intravenously administered RNAi
therapeutic targeting TTR for the treatment of FAP patients with ATTR.

The ongoing Phase I trial of ALN-TTRsc is being conducted in the U.K. as a
randomized, double-blind, placebo-controlled, single- and multi-dose,
dose-escalation study, enrolling up to 40 healthy volunteer subjects. Subjects
received single or multiple ascending subcutaneous doses of ALN-TTRsc ranging
from 1.25 to 10 mg/kg. The primary objective of the study is to evaluate the
safety and tolerability of single and multiple doses of subcutaneously
administered ALN-TTRsc. Secondary objectives include assessment of clinical
activity of the drug as measured by serum TTR levels. Upon completion of the
Phase I trial, the company plans to start a Phase II clinical study of
ALN-TTRsc in FAC patients in late 2013 and, assuming positive results, expects
to start a pivotal Phase III trial for ALN-TTRsc in FAC patients in 2014.

Pre-clinical studies have shown that subcutaneous administration of ALN-TTRsc
resulted in potent and sustained suppression of TTR. In non-human primates,
ALN-TTRsc administration resulted in an approximately 80% reduction of TTR at
doses as low as 2.5 mg/kg. In single- and multi-dose pre-clinical safety
studies in rodents and non-human primates, ALN-TTRsc was found to be generally
safe and well tolerated. Specifically, at doses as high as 300 mg/kg in
non-human primates, ALN-TTRsc was well tolerated with no clinical signs, no
adverse laboratory or histopathologic findings, no elevations in cytokines or
complement, and no significant injection site reactions; these results
demonstrate an approximately 100-fold therapeutic index for GalNAc-siRNA
conjugates.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi
company, to develop and commercialize RNAi therapeutics, including ALN-TTR02
and ALN-TTRsc, for the treatment of ATTR in Japan and the broader
Asian-Pacific region. Alnylam plans to develop and commercialize the ALN-TTR
program in North and South America, Europe, and rest of the world.

Alnylam is hosting an R&D Day today from 8:30 a.m. – 12:00 p.m. ET at the
Sofitel New York in New York City. Alnylam scientists and management will
review progress with the company’s “Alnylam 5×15” product strategy for the
development of RNAi therapeutics. The event will be webcast live on the News &
Investors section of the company’s website, www.alnylam.com. An audio replay
of the event will be available on the Alnylam website approximately 90 minutes
after the event.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and fatal disease caused by mutations in the TTR gene. TTR
protein is produced primarily in the liver and is normally a carrier for
retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to
accumulate and damage body organs and tissue, such as the peripheral nerves
and heart, resulting in intractable peripheral sensory neuropathy, autonomic
neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need
with significant morbidity and mortality; familial amyloidotic polyneuropathy
(FAP) affects approximately 10,000 people worldwide and familial amyloidotic
cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients
have a life expectancy of five to 15 years from symptom onset, and the only
treatment options for early stage disease are liver transplantation and
tafamidis (approved in Europe). The mean survival for FAC patients is
approximately 2.5 years, and there are no approved therapies. There is a
significant need for novel therapeutics to treat patients who have inherited
mutations in the TTR gene.

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 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-TTRsc, its
expectations regarding the reporting of data from its ALN-TTRsc clinical
trials, its expectations with respect to the timing and success of its
clinical trials for ALN-TTRsc, and its expectations regarding the potential
market opportunity for ALN-TTRsc, 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-TTRsc, 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 current 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 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