Alnylam Initiates Phase I Clinical Study for ALN-TTRsc, a Subcutaneously Administered RNAi Therapeutic Targeting Transthyretin

  Alnylam Initiates Phase I Clinical Study for ALN-TTRsc, a Subcutaneously
  Administered RNAi Therapeutic Targeting Transthyretin (TTR) for the
  Treatment of TTR-Mediated Amyloidosis (ATTR)

 – ALN-TTRsc is Company’s First Subcutaneously Delivered RNAi Therapeutic to
                           Enter Clinical Trials –

                    – Data from Trial Expected Mid-2013 –

Business Wire

CAMBRIDGE, Mass. -- March 18, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has initiated dosing in its Phase I clinical
trial with ALN-TTRsc, an RNAi therapeutic targeting transthyretin (TTR) for
the treatment of TTR-mediated amyloidosis (ATTR). 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.

“RNAi therapeutics hold great promise for the treatment of ATTR since they
have demonstrated rapid, potent, and durable knockdown of TTR, the
disease-causing protein. We are advancing what we believe to be the industry
leading effort in ATTR; this includes ALN-TTRsc for the treatment of FAC and
ALN-TTR02 for the treatment of FAP which is currently enrolling patients in a
Phase II trial,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President
and Chief Medical Officer of Alnylam. “The start of this Phase I trial with
ALN-TTRsc represents the first for an RNAi therapeutic that utilizes our
proprietary GalNAc conjugate delivery platform. It also marks the first
subcutaneously delivered, systemic RNAi therapeutic for the industry. We look
forward to the continued advancement of ALN-TTRsc for the treatment of FAC.”

The 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. 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.
Alnylam expects to present data from this trial in mid-2013. Upon completion
of the Phase I trial, the company plans to start a Phase II clinical study of
ALN-TTRsc in FAC patients by the end of 2013 and, assuming positive results,
expects to start a pivotal trial for ALN-TTRsc in FAC patients in 2014.

“ATTR is a genetic disease with significant unmet medical need and limited
treatment options for patients. RNAi therapeutics are a novel and compelling
approach for the treatment of ATTR, as this novel modality has been shown to
achieve robust knockdown of serum levels of both wild-type and mutant TTR,”
said Philip Hawkins, FMedSci., Professor of Medicine, University College
London Medical School. “I am encouraged by the clinical and pre-clinical data
to date with Alnylam’s ALN-TTR program and look forward to the continued
advancement of this effort for patients suffering from either the
cardiomyopathy or polyneuropathy manifestations of this devastating disease.”

ATTR is an autosomal dominant inherited disease caused by mutations in the TTR
gene, which is expressed predominantly in the liver. 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.

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.

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. GalNAc-siRNAs are being employed in
Alnylam’s ALN-TTRsc, ALN-AT3, and ALN-AS1 RNAi therapeutic programs for the
treatment of transthyretin-mediated amyloidosis (ATTR), hemophilia and rare
bleeding disorders, and acute intermittent porphyria, respectively, among
other ‘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 for
the treatment of genetically defined diseases, including ALN-TTR for the
treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the
treatment of hemophilia and rare bleeding disorders (RBD), ALN-AS1 for the
treatment of acute intermittent porphyria (AIP), ALN-PCS for the treatment of
hypercholesterolemia, and ALN-TMP for the treatment of hemoglobinopathies. 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 a significant 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 directed toward
genetically defined targets for 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-TTR for the treatment of transthyretin-mediated
amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia and rare bleeding
disorders (RBD), ALN-AS1 for the treatment of acute intermittent porphyria
(AIP), ALN-PCS for the treatment of hypercholesterolemia, ALN-TMP for the
treatment of hemoglobinopathies, and 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-TTR02 and ALN-TTRsc, as well as other “Alnylam 5x15”
programs, its expectations with respect to the timing and success of its
clinical trials, including for ALN-TTR02 and ALN-TTRsc, its expectations
regarding the reporting of data from its ALN-TTRsc clinical trial, and its
expectations regarding 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, successfully
demonstrate the safety and efficacy of its drug candidates, including drug
candidates utilizing GalNAc-siRNA delivery, the pre-clinical and clinical
results for these product candidates, 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 Annual Report on Form
10-K for the year ended December 31, 2012 on file with the Securities and
Exchange Commission. 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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