Alnylam Initiates Phase II Clinical Trial with ALN-TTRsc, a Subcutaneously Delivered RNAi Therapeutic Targeting Transthyretin

  Alnylam Initiates Phase II Clinical Trial with ALN-TTRsc, a Subcutaneously
  Delivered RNAi Therapeutic Targeting Transthyretin (TTR) in Development for
  the Treatment of TTR-Mediated Amyloidosis (ATTR)

– Pilot Phase II Trial Now Open for Enrollment for ATTR Patients with Familial
    Amyloidotic Cardiomyopathy (FAC) or Senile Systemic Amyloidosis (SSA);
         Study Includes a Number of Exploratory Clinical Endpoints –

 – Company Expects to Present Data in Late 2014, and Start Pivotal Phase III
        Trial with ALN-TTRsc in TTR Cardiac Amyloidosis in Late 2014 –

Business Wire

CAMBRIDGE, Mass. -- December 16, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has initiated a pilot Phase II study with
ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the
transthyretin (TTR) gene in development for the treatment of TTR-mediated
amyloidosis (ATTR). The Phase II trial, which is now open for enrollment, is
aimed at evaluating the tolerability and preliminary clinical activity of
ALN-TTRsc in TTR cardiac amyloidosis patients with familial amyloidotic
cardiomyopathy (FAC) – which is caused by autosomal dominant mutations in the
TTR gene, or senile systemic amyloidosis (SSA) – which is caused by idiopathic
accumulation of wild-type TTR in the heart. The company expects to present
data from the Phase II trial in late 2014, and assuming positive results,
begin a Phase III trial in TTR cardiac amyloidosis patients by the end of
2014.

“Our recently presented Phase I study results of ALN-TTRsc demonstrated
robust, up to 94% knockdown of serum TTR, which we believe provide an
encouraging profile of clinical activity that warrants further advancement of
this drug candidate for the treatment of TTR cardiac amyloidosis. We are
pleased to announce that we have initiated our pilot Phase II trial with
ALN-TTRsc, with the study now open for enrollment. Initiation of this Phase II
trial highlights continued execution on our ‘Alnylam 5x15’ product development
and commercialization strategy, which is focused on advancing RNAi
therapeutics toward genetically defined targets for the treatment of diseases
with high unmet medical need,” said Akshay Vaishnaw, M.D., Ph.D., Executive
Vice President and Chief Medical Officer of Alnylam. “This new study aims to
evaluate the tolerability and preliminary clinical activity of ALN-TTRsc in
patients with TTR cardiac amyloidosis. Since ALN-TTRsc achieves robust
knockdown of serum TTR, the disease-causing protein in ATTR, we believe that
this investigational agent has encouraging potential as a new therapeutic
option for patients. Further, it is notable that ALN-TTRsc is the most
advanced program in our pipeline that utilizes our GalNAc-conjugate approach
for subcutaneous delivery of RNAi therapeutics, and the first to enter Phase
II trials; as such, we are pleased with this important industry milestone with
the continued development of RNAi therapeutics that utilize this delivery
approach in clinical studies.”

ATTR is caused by mutations in the TTR gene which cause abnormal TTR 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 FAC affects at least 40,000 people worldwide. Senile systemic amyloidosis
(SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic
deposition of wild-type TTR; its prevalence is generally unknown, but is
associated with advanced age. ALN-TTRsc is an investigational drug being
developed for the treatment of TTR cardiac amyloidosis, including both FAC and
SSA, and is a subcutaneously administered RNAi therapeutic that comprises a
TTR-specific 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 advance
in clinical development. Alnylam is also developing patisiran (ALN-TTR02), an
intravenously administered RNAi therapeutic targeting TTR for the treatment of
ATTR patients with FAP.

The Phase II trial is an open-label, multi-dose study of ALN-TTRsc, designed
to enroll approximately 15 TTR cardiac amyloidosis patients with FAC or SSA.
The primary objective of the study is to evaluate the general tolerability of
ALN-TTRsc. Patients will receive 5 daily doses followed by 5 weekly doses of 5
mg/kg, with follow-up through Day 90; in the Phase I ALN-TTRsc study, this
dose resulted in an up to 93% TTR knockdown and a mean nadir knockdown of
approximately 88%, and was found to be generally safe and well tolerated.
Secondary objectives include assessment of clinical activity as measured by
knockdown of serum TTR levels and additional tests, such as cardiac imaging
(including echocardiography and cardiac MRI), circulating cardiac biomarkers
(NT-proBNP and troponins T and I), 6-minute walk test, New York Heart
Association (NYHA) classification, and measures of heart failure symptoms and
quality of life (Kansas City Cardiomyopathy Questionnaire and EQ-5D QOL).
Patients completing the Phase II trial will be eligible to participate in an
open-label extension (OLE) study for further assessment of general
tolerability and clinical activity with long-term dosing; the ALN-TTRsc Phase
II OLE study is expected to be initiated in mid-2014.

Alnylam reported positive results from a Phase I trial with ALN-TTRsc in 28
healthy volunteers at the Heart Failure Society of America 17th Annual
Scientific Meeting held in September 2013. The results of the clinical study
showed that ALN-TTRsc administration led to robust, consistent, and
statistically significant (p<0.01) knockdown of serum TTR of up to 94%.
Knockdown of TTR was found to be rapid, dose-dependent, and durable. ALN-TTRsc
was found to be generally safe and well tolerated in the study. Importantly,
these human study results were 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.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi
company, to develop and commercialize RNAi therapeutics, including patisiran
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.

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
approved 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. Senile systemic
amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused
by idiopathic deposition of wild-type TTR; its prevalence is generally
unknown, but is associated with advanced age. There is a significant need for
novel therapeutics to treat patients with TTR amyloid polyneuropathy and/or
cardiomyopathy.

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 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 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
Amanda Sellers (Media), 202-955-6222 x2597
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