Alnylam Presents Key Pre-Clinical Proof-of-Concept Data for ALN-AS1, an RNAi Therapeutic Targeting Aminolevulinate Synthase-1

  Alnylam Presents Key Pre-Clinical Proof-of-Concept Data for ALN-AS1, an RNAi
  Therapeutic Targeting Aminolevulinate Synthase-1 (ALAS-1) for the Treatment
  of Porphyria

– RNAi Therapeutics Targeting ALAS-1 Completely Block Production of Toxic Heme
    Biosynthesis Intermediates that Cause Symptoms and Disease Pathology –

Business Wire

CAMBRIDGE, Mass. -- May 17, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented key pre-clinical
proof-of-concept data from its RNAi therapeutic program targeting
aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including
acute intermittent porphyria (AIP). The new research findings were presented
at the International Congress of Porphyrins and Porphyrias being held May 16 –
18, 2013 in Lucerne, Switzerland. Specifically, Alnylam scientists and
collaborators at the Icahn School of Medicine at Mount Sinai in New York City
presented data from pre-clinical models of the human disease showing that RNAi
therapeutics targeting ALAS-1 can completely block the abnormal production of
toxic intermediates of the heme biosynthesis pathway that cause the symptoms
and disease pathology of AIP. Alnylam’s AIP drug candidate, 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.

“Our pre-clinical data clearly show that RNAi therapeutics targeting ALAS-1
can achieve potent, rapid, and durable suppression of the toxic heme
biosynthesis intermediates that cause the symptoms and disease pathology of
AIP. As such, these findings provide key, pre-clinical, proof-of-concept data
for our ALN-AS1 program, which we believe could become a transformative
therapy for patients with AIP, an ultra-rare genetic disease with enormous
unmet medical need,” said Jared Gollob, M.D., Vice President, Clinical
Research at Alnylam. “We are now extending these pre-clinical results to a
GalNAc-siRNA conjugate development candidate that enables subcutaneous dose
administration, and our current data with prototype molecules provide clear
validation of this strategy. With our ongoing efforts, we expect to finalize
selection of a GalNAc-siRNA development candidate for our ALN-AS1 program in
late 2013, leading to an investigational new drug filing for this program in
2014.”

“AIP is an ultra-rare genetic disorder caused by an inherited deficiency in
porphobilinogen deaminase that can result in accumulation of toxic
intermediates in the heme biosynthesis pathway. Patients with AIP present with
acute and/or recurrent attacks including severe, life-threatening abdominal
pain, peripheral and autonomic neuropathy, and neuropsychiatric
manifestations,” said Robert J. Desnick, M.D., Ph.D., Dean for Genetics and
Genomic Medicine and Professor and Chair Emeritus of the Department of
Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai
in New York City. “There is clear need for new therapies to treat acute
attacks and prevent recurrent attacks, and we are very encouraged by the
potential of an RNAi approach for the treatment of this debilitating,
life-threatening disease.”

“Our pre-clinical work with Alnylam has shown that RNAi-mediated silencing of
ALAS-1 results in essentially complete abrogation of the toxic heme
biosynthesis intermediates that cause the symptoms and disease pathophysiology
of AIP. In preliminary studies, we have also shown that RNAi-mediated
silencing of ALAS-1 is more effective than heme administration in the
treatment of an acute attack,” said Makiko Yasuda, M.D., Ph.D., Assistant
Professor in the Department of Genetics and Genomic Sciences at the Icahn
School of Medicine at Mount Sinai in New York City. “RNAi has the potential to
serve as a novel treatment for AIP, and we look forward to continuing our
close collaborative efforts with Alnylam on the advancement of this program to
the clinic.”

There are approximately 5,000 patients in the U.S. and Europe that 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, 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 knockdown ALAS-1, an enzyme upstream of
porphobilinogen deaminase (PBGD), in hepatocytes. 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 these patients. A
subcutaneously administered RNAi therapeutic targeting ALAS-1 could be used as
a prophylactic approach to prevent attacks and as a therapy for acute attacks.

The new research results support the advancement of RNAi therapeutics as a
promising strategy for the prevention and/or treatment of acute attacks in
patients with AIP. In the new studies, Alnylam scientists and collaborators at
Icahn School of Medicine at Mount Sinai presented findings from a mouse model
of AIP. Prophylactic administration of an ALAS-1 specific siRNA completely
protected the mice from phenobarbital-induced up-regulation of hepatic ALAS-1
mRNA and the resulting accumulation of the neurotoxic ALA and PBG heme
biosynthesis precursors. This protective effect was dose responsive and
durable, with a single dose administration resulting in a protective effect
that lasted for at least two weeks. Further, in a treatment model, a single
dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and PBG
that were elevated during a phenobarbital-induced acute attack. Further,
preliminary comparative studies show that ALAS-1 siRNA administration was more
effective than heme administration in the treatment of an acute attack.
Finally, the company presented results from its ongoing GalNAc-siRNA conjugate
efforts enabling subcutaneous dose administration. In particular, a prototype
GalNAc-siRNA targeting ALAS-1 was shown to be effective in blocking ALA and
PBG production in both prophylactic and treatment models of AIP. The company
is on track to designate a GalNAc-siRNA development candidate, ALN-AS1, in
late 2013 resulting in an investigational new drug (IND) filing in 2014.

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 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 is on track to identify a final development candidate by
late 2013 and 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 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; and
ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease, 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; and
ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease, 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 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, its expectations with
respect to the timing and success of its clinical and pre-clinical trials, the
expected timing of regulatory filings, including its plan to file an IND
application and initiate clinical trials for ALN-AS1, its expectations
regarding reporting of data from its pre-clinical studies for ALN-AS1 studies,
its plans to seek a partner for its ALN-AS1 program and other “Alnylam 5x15”
programs, and its expectations regarding the potential market opportunity for
ALN-AS1, 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, 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
 
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