Alnylam Advances Development Candidate for ALN-AS1, a Subcutaneously Administered RNAi Therapeutic Targeting Aminolevulinate

  Alnylam Advances Development Candidate for ALN-AS1, a Subcutaneously
  Administered RNAi Therapeutic Targeting Aminolevulinate Synthase 1 (ALAS-1)
  for the Treatment of Hepatic Porphyrias

 – New Pre-Clinical Results Presented at Oligonucleotide Therapeutics Society
 (OTS) Meeting Demonstrate that ALN-AS1 Completely Blocks Production of Toxic
 Heme Biosynthesis Intermediates that Cause Disease Symptoms and Pathology –

 – Additional Pre-Clinical Data Presented at OTS Highlight Continued Advances
   with Clinically Validated GalNAc-Conjugate Platform for Delivery of RNAi
  Therapeutics with Subcutaneous Dose Administration and a Wide Therapeutic
                                   Index –

Business Wire

CAMBRIDGE, Mass. -- October 8, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it is advancing its Development Candidate for
ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for
the treatment of hepatic porphyrias including acute intermittent porphyria
(AIP). The new pre-clinical research findings, presented at the 9^th Annual
Meeting of the Oligonucleotide Therapeutics Society being held October 6 – 8,
2013 in Naples, Italy, show that subcutaneous administration of a GalNAc-siRNA
targeting ALAS-1 leads to rapid, dose-dependent, and long-lasting knockdown of
ALAS-1 mRNA and complete inhibition of the toxic intermediates that mediate
the symptoms and pathology of AIP. Based on these findings, including results
in non-human primate studies, the company has selected its ALN-AS1 Development
Candidate and expects to file an Investigational New Drug (IND) application
for this RNAi therapeutic in 2014. ALN-AS1 is part of the company’s “Alnylam
5x15” product development and commercialization strategy, in which the company
aims to advance five genetic disease target programs into clinical
development, including programs in late stages, by the end of 2015. In
addition, the company presented new pre-clinical data with its proprietary,
clinically validated GalNAc-siRNA conjugate delivery platform for subcutaneous
delivery of RNAi therapeutics with a wide therapeutic index.

“We are very pleased to advance ALN-AS1 as a new Development Candidate in our
‘Alnylam 5x15’ pipeline, with the goal of filing an IND in 2014. Our new
pre-clinical data show that subcutaneous administration of ALN-AS1 results in
complete suppression of the toxic heme biosynthesis intermediates that cause
the symptoms and pathology of AIP,” said Rachel Meyers, Ph.D., Vice President
of Research and RNAi Lead Development at Alnylam. “ALN-AS1 now becomes our
third RNAi therapeutic utilizing our GalNAc-siRNA conjugate delivery platform
to enter development stages, extending our progress with ALN-TTRsc for the
treatment of transthyretin-mediated amyloidosis, where we intend to soon
initiate a Phase II trial, and ALN-AT3 for the treatment of hemophilia, where
we plan on filing our IND by the end of this year. With the recent clinical
validation of our GalNAc-siRNA conjugate delivery platform, we have increased
confidence that ALN-AS1 could become a transformative therapy for patients
with AIP, an ultra-rare genetic disease with enormous unmet medical need. We
very much look forward to filing our IND for this program in 2014.”

Hepatic porphyrias, including AIP, are ultra-rare orphan diseases caused by
loss-of-function mutations in enzymes involved in heme biosynthesis, leading
to accumulation of toxic heme intermediate precursors. In the case of AIP,
there are approximately 5,000 patients in the U.S. and Europe that suffer
acute, life-threatening porphyria attacks every year; there are approximately
500 patients afflicted with recurrent debilitating attacks, often occurring
once per month. Treatment options for AIP patients suffering from an attack
are limited, and include the use of heme preparations that show limited
efficacy and are associated with a number of complications. Currently, there
are no drugs available to prevent attacks from occurring. Alnylam’s approach
is to knock down ALAS-1, an enzyme upstream of porphobilinogen deaminase
(PBGD), the defective gene in AIP. RNAi-mediated silencing of hepatocyte
ALAS-1 could reduce the abnormal production of the toxic heme intermediates,
specifically aminolevulinic acid (ALA) and porphobilinogen (PBG), which
mediate the symptoms and disease pathology in AIP patients. Alnylam believes
that a subcutaneously administered RNAi therapeutic targeting ALAS-1 has the
potential to be used as a prophylactic approach to prevent attacks and also as
a therapy for acute attacks.

The new research results presented at OTS support the selection of the ALN-AS1
Development Candidate for further advancement toward clinical trials.
Specifically, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led
to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in
non-human primates, with an ED[50] of approximately 1.25 mg/kg. Further, in a
rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted
in a complete blunting of phenobarbital-induced over-production of PBG and
ALA, the toxic heme intermediates in AIP. The company now plans to initiate
IND-enabling studies with the goal of filing an IND in 2014.

In addition, Alnylam scientists presented new pre-clinical data  on the
pharmacokinetic and pharmacodynamic properties of GalNAc-siRNA conjugates.
Results showed that target gene silencing is achieved at very low levels of
liver tissue exposure. Specifically, the tissue drug level associated with 50%
target gene silencing (EC[50]) was determined to be 0.1 micrograms of
GalNAc-siRNA per gram of liver tissue. This tissue level is about 1000-fold
lower than other oligonucleotide platforms, where the EC[50] for liver target
gene knockdown is reported to be about 100 micrograms per gram of tissue (Yu
et al., Biochem Pharmacol 2009;77:910-919). In additional studies, the levels
of GalNAc-siRNA loaded into the RNA-Induced Silencing Complex (RISC) were
quantified and determined to be 0.001 microgram per gram of liver tissue,
which corresponds to about 500 to 1000 siRNA molecules per cell for
RNAi-mediated target gene knockdown. The ability of GalNAc-siRNA to achieve
target gene knockdown at low tissue exposure underscores the potential for a
wide therapeutic index for these RNAi therapeutics.

“This year’s OTS meeting highlights continued progress for oligonucleotide
therapeutics, and Alnylam is pleased to be a part of this overall endeavor. We
are particularly excited to present our advances with RNAi therapeutics that
employ our GalNAc-siRNA conjugate delivery platform for hepatocyte target gene
silencing. Indeed, we believe our recent clinical data serve to validate this
approach and also confirm a remarkable one-to-one correlation of target
knockdown in non-human primate studies as compared with human trials,” said
Muthiah (Mano) Manoharan, Ph.D., Senior Vice President of Drug Discovery at
Alnylam. “New results presented at OTS highlight the applicability of
GalNAc-siRNA conjugates across a broad range of hepatocyte-expressed target
genes. Moreover, we have demonstrated that target gene knockdown with
GalNAc-siRNA is achieved at tissue drug levels of approximately 0.1
micrograms/gram, representing an approximately 1000-fold improvement in
potency as compared with other oligonucleotide therapeutic platforms. We
believe that these findings of target gene knockdown at very low tissue
exposure could significantly improve the therapeutic index for RNA
therapeutics, and underscore our belief that GalNAc-siRNA conjugates represent
a best-in-class strategy for systemic RNA therapeutics for liver-expressed
disease genes.”

About ALN-AS1

Alnylam is developing ALN-AS1, an RNAi therapeutic targeting aminolevulinate
synthase-1 (ALAS-1) for the treatment of porphyria, including acute
intermittent porphyria (AIP). AIP is an ultra-rare autosomal dominant disease
caused by loss of function mutations in porphobilinogen deaminase (PBGD), an
enzyme in the heme biosynthesis pathway that can result in accumulation of
toxic heme precursors. Patients with AIP suffer from acute and/or recurrent
life-threatening attacks with severe abdominal pain, peripheral and autonomic
neuropathy, and neuropsychiatric manifestations. ALN-AS1 is a GalNAc-siRNA
conjugate targeting ALAS-1, a liver-expressed, rate-limiting enzyme upstream
of PBGD in the heme biosynthesis pathway. Inhibition of ALAS-1 is known to
reduce the accumulation of heme precursors that cause the clinical
manifestations of AIP. ALN-AS1 has the potential to be a therapy for the
treatment of acute porphyria attacks, as well as a prophylactic approach for
the prevention of recurrent attacks. The company has identified a Development
Candidate and intends to advance ALN-AS1 into the clinic in 2014. Alnylam
intends to directly commercialize ALN-AS1 in North and South America, Europe,
and other parts of the world, and intends to seek a partner for this program
in Japan and other Asian territories.

About Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is an ultra-rare autosomal dominant disease
caused by loss-of-function mutations in porphobilinogen deaminase (PBGD), an
enzyme in the heme biosynthesis pathway. Exposure of AIP patients to certain
drugs, dieting, or hormonal changes can trigger strong induction of
aminolevulinate synthase-1 (ALAS-1), another enzyme in the heme biosynthesis
pathway, which can lead to accumulation of heme intermediates upstream of PBGD
that precipitate attack symptoms. Patients with AIP can suffer acute and/or
recurrent life-threatening attacks with severe abdominal pain, peripheral and
autonomic neuropathy, and neuropsychiatric manifestations, and possible death
if left untreated. Approximately 5,000 patients in the U.S. and Europe suffer
acute porphyria attacks annually, and approximately 500 patients are afflicted
with recurrent debilitating attacks. Treatment options for AIP patients
suffering from an acute attack are limited; patients are treated with
intravenous heme analogues that have a slow onset and can result in severe
thrombophlebitis and iron overload. Currently there is no approved
prophylactic treatment available to prevent recurrent attacks, which often
occur monthly in women associated with menses. There exists a significant need
for therapies for AIP patients.

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 porphyria
including 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 complement component C5 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, 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: 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-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 complement component C5 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, ALN-AS1, and ALN-CC5, amongst 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-AS1,
ALN-TTRsc, and ALN-AT3, its expectations with respect to the timing and
success of clinical trials for ALN-TTRsc, its expectations with respect to the
timing of filing an IND for ALN-AS1 and ALN-AT3, and its plans with respect to
the commercial opportunity for the ALN-AS1 program, 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-AS1, 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 Quarterly
Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on
August 9, 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
 
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