Alnylam Provides Key 2013 – 2014 Goals for RNAi Therapeutics Pipeline

  Alnylam Provides Key 2013 – 2014 Goals for RNAi Therapeutics Pipeline

  - Aims to Advance ALN-TTR02 into Phase III Pivotal Trial in Transthyretin
     (TTR)-Mediated Amyloidosis (ATTR) Patients with Familial Amyloidotic
   Polyneuropathy (FAP) by Late 2013; Phase II Data Expected in Mid-2013 -

 - Plans to Initiate Exploratory Phase II Study of ALN-TTRsc in ATTR Patients
  with Familial Amyloidotic Cardiomyopathy (FAC) by Late 2013; Phase I Data
                            Expected in Mid-2013 -

 - Expects to File Investigational New Drug (IND) Application for ALN-AT3 in
Hemophilia and Rare Bleeding Disorders in Mid-2013; Start Phase I in Late 2013
                                      -

- Expands “Alnylam 5x15” Pipeline with ALN-AS1, an RNAi Therapeutic Targeting
   Aminolevulinate Synthase 1 (ALAS-1) for Treatment of Acute Intermittent
                                 Porphyria -

        - Guides to End 2012 with Approximately $225 Million in Cash -

JPMorgan Healthcare Conference 2013

Business Wire

CAMBRIDGE, Mass. -- January 6, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today its key “Alnylam 5x15™” pipeline and partner program
goals for 2013 through 2014.

“In 2012, we made tremendous progress in our RNAi therapeutic development
efforts with our ‘Alnylam 5x15’ product strategy focused on genetically
defined targets for diseases with limited treatment options for patients and
their caregivers. The next couple of years promise to be transformative for
Alnylam as we aim to advance our pipeline into Phase III, report on key
clinical data in multiple programs, and expand the breadth our ‘5x15’ pipeline
with additional clinical and pre-clinical programs,” said John Maraganore,
Ph.D., Chief Executive Officer of Alnylam. “Specifically, we aim to advance
what we believe to be the industry leading effort in ATTR, with ALN-TTR02
starting a Phase III trial for FAP patients and ALN-TTRsc entering a pilot
Phase II trial in FAC patients. In addition, we expect to report on clinical
results from Phase II and Phase I studies from these two programs
respectively, in mid-2013. Further, we are expanding our ‘5x15’ clinical
pipeline with ALN-AT3, a potential breakthrough therapy for hemophilia,
including hemophilia complicated by ‘inhibitors,’ and for other rare bleeding
disorders, where we expect to file an IND in mid-2013 and initiate a Phase I
study in late 2013. Finally, we are excited today to introduce a new ‘Alnylam
5x15’ program – ALN-AS1 for the treatment of acute intermittent porphyria, an
ultra-rare genetic disease caused by loss of function mutations in an enzyme
in the heme biosynthesis pathway that result in acute and/or recurrent
life-threatening attacks with severe abdominal pain, peripheral and autonomic
neuropathy, and neuropsychiatric manifestations. In aggregate, we believe that
execution on our ‘Alnylam 5x15’ programs and our ambitious goals for 2013 and
beyond will enable continued advancement of RNAi therapeutics as innovative
medicines for patients, resulting in value creation for our shareholders.”

“Alnylam 5x15” Product Strategy Goals

  *Advance ALN-TTR02 into Phase III Pivotal Trial in Familial Amyloidotic
    Polyneuropathy (FAP). ALN-TTR02 is an intravenously delivered RNAi
    therapeutic targeting transthyretin (TTR) for the treatment of
    TTR-mediated amyloidosis (ATTR).

       *Alnylam is currently conducting a Phase II study with ALN-TTR02 in
         patients with ATTR. The Phase II study is an open-label,
         multi-center, multi-dose, dose-escalation trial designed to enroll
         approximately 20 ATTR patients. Patients are being enrolled into
         cohorts of increasing doses and are receiving two doses of ALN-TTR02
         once every four weeks. The primary objectives of the study are to
         evaluate the safety and tolerability of multiple doses of ALN-TTR02
         and to measure clinical activity based on serial measurement of
         circulating serum TTR levels. The company expects to report results
         from this trial in mid-2013.
       *Alnylam intends to initiate an open-label extension study in mid-2013
         for longer-term treatment of patients enrolled in the Phase II study.
         The new extension study will include a number of exploratory clinical
         endpoint measurements. The company intends to provide periodic
         updates on results from the extension study starting in 2014.
       *Assuming positive results from the Phase II study, the company
         expects to initiate a Phase III pivotal trial of ALN-TTR02 in ATTR
         patients with FAP in late 2013. FAP is a serious clinical
         manifestation of ATTR that afflicts approximately 10,000 patients
         worldwide. Alnylam will provide specific details on the trial design
         following discussions with worldwide regulatory authorities.
       *Alnylam intends to directly commercialize ALN-TTR02 in North and
         South America, Europe, and other parts of the world, and has formed a
         partnership with Genzyme, a Sanofi company, to commercialize the
         product in Japan and other Asian countries.

  *Move ALN-TTRsc through Phase I Study and into Pilot Phase II Trial in
    Familial Amyloidotic Cardiomyopathy (FAC). ALN-TTRsc is an RNAi
    therapeutic targeting TTR for the treatment of ATTR and utilizes the
    company’s proprietary GalNAc-conjugate delivery approach enabling
    subcutaneous dose administration.

       *Alnylam recently filed a Clinical Trial Application (CTA) with the
         U.K. Medicines and Healthcare products Regulatory Agency (MHRA) for
         ALN-TTRsc. The Phase I trial is designed 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 ALN-TTRsc. In addition, the study will evaluate
         clinical activity of ALN-TTRsc as measured by serum TTR levels.
         Alnylam expects to begin dosing in this trial early in 2013 with data
         mid-year.
       *Assuming positive results from the Phase I trial, Alnylam aims to
         initiate an exploratory Phase II trial of ALN-TTRsc in ATTR patients
         with FAC in late 2013 leading to the start of a Phase III trial in
         FAC patients in 2014. FAC is a serious clinical manifestation of ATTR
         that afflicts approximately 40,000 patients worldwide.
       *As with ALN-TTR02, Alnylam intends to directly commercialize
         ALN-TTRsc in North and South America, Europe, and other parts of the
         world, and in partnership with Genzyme in Japan and other Asian
         countries.

  *Expand “Alnylam 5x15” Clinical Pipeline with ALN-AT3, a Potential
    Breakthrough Therapy for the Treatment of Hemophilia and Rare Bleeding
    Disorders (RBD). Alnylam is developing ALN-AT3, an RNAi therapeutic
    targeting antithrombin (AT) for the treatment of hemophilia and RBD. This
    RNAi therapeutic utilizes the company’s proprietary GalNAc-conjugate
    delivery approach enabling subcutaneous dose administration. ALN-AT3 is a
    novel therapeutic approach aimed at re-balancing the coagulation cascade
    and normalizing hemostasis in severe hemophilia A and B patients,
    including patients with “inhibitors” against their replacement factor.
    There are approximately 2,000 inhibitor patients in major markets with up
    to 5,000 patients worldwide that define the greatest unmet need in
    hemophilia A and B. In addition to hemophilia A and B which are
    characterized by a loss of function in Factors VIII and IX respectively,
    ALN-AT3 has the potential to treat RBD that are defined by deficiencies in
    other clotting factors such as Factors II, V, VII, X, and XI. It is
    estimated that there are approximately 1,000 RBD patients worldwide with
    significant or severe bleeding complications where prophylaxis is
    warranted. Alnylam plans to file an IND for ALN-AT3 in mid-2013 and to
    initiate a Phase I study in late 2013. The company expects to report data
    from this study in 2014. The company intends to directly commercialize
    ALN-AT3 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.
  *Grow “Alnylam 5x15” Pipeline with ALN-AS1, a New Therapeutic Strategy for
    the Treatment of Acute Intermittent Porphyria (AIP). Alnylam announced
    today that it has designated ALN-AS1, an RNAi therapeutic targeting
    aminolevulinate synthase 1 (ALAS-1) for the treatment of acute
    intermittent porphyria (AIP), as a new program in its “Alnylam 5x15”
    product strategy. AIP is an ultra-rare genetic 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. Approximately
    5,000 patients in the U.S. and Europe suffer AIP attacks annually, and
    approximately 500 patients are afflicted with recurrent debilitating
    attacks; patients with recurrent attacks often include women in
    association with menses. 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 expects to identify a final development
    candidate by late 2013 and advance ALN-AS1 into the clinic in 2014. The
    company has generated pre-clinical proof of concept data that will be
    presented at a scientific meeting in mid-2013. The company 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.

“Our ‘Alnylam 5x15’ product strategy is focused on potential breakthrough
medicines for high unmet need indications with concentrated market access and
strong patient advocacy,” said Barry Greene, President and Chief Operating
Officer of Alnylam. “With the progress we have made in our pipeline, including
plans to initiate our ALN-TTR02 Phase III pivotal trial at the end of this
year, we are now establishing a commercial strategy to drive maximal value.
Specifically, we plan to directly commercialize our core ‘5x15’ products –
ALN-TTR02, ALN-TTRsc, ALN-AT3, and ALN-AS1 – in North and South America,
Europe, and other territories, while partnering for development expertise and
market access in Japan and other Asian markets. We will also continue to
advance other pipeline assets, including our RNAi therapeutic program
targeting PCSK9, with existing or future partnerships we aim to form.”

  *Advance Additional “Alnylam 5x15” Pipeline Programs through Partnerships.
    Alnylam will continue to advance its additional “Alnylam 5x15” programs,
    including: ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment
    of severe hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting
    TMPRSS6 for the treatment of hemoglobinopathies; and ALN-AAT, an RNAi
    therapeutic targeting the mutant Z-allele in alpha-1-antitrypsin (AAT)
    deficiency for the treatment of AAT deficiency-associated liver disease,
    amongst other programs. Specifically, the company intends to advance these
    programs with new partnerships it intends to form.  Alnylam has also
    elected to suspend further advancement of ALN-HPN, an RNAi therapeutic
    targeting the hepcidin pathway for the treatment of refractory anemia, in
    order to focus on other higher priority pipeline programs.

Partner Program Goals

  *Support Partner-Based Efforts for Advancement of Additional Clinical-Stage
    RNAi Therapeutic Programs. Alnylam has completed a Phase IIb clinical
    study with ALN-RSV01 for the treatment of respiratory syncytial virus
    (RSV) infection in lung transplant patients. The company has met with
    regulatory authorities in the U.S. and Europe and, together with its
    partner Cubist, expects to communicate an update on future plans in early
    2013. ALN-RSV01 is partnered with Kyowa Hakko in Japan and other major
    markets in Asia. Alnylam will also continue to support its partner
    Ascletis as it advances ALN-VSP, an RNAi therapeutic for the treatment of
    liver cancers towards the clinic in China.

“Alnylam’s solid cash position, combined with our focused pipeline efforts,
ensure that our investments in 2013 will be directed toward the highest
value-creating activities that we believe exist within our ‘Alnylam 5x15’
pipeline,” said Michael Mason, Vice President, Finance and Treasurer of
Alnylam. “Today, we are guiding to end 2012 with approximately $225 million in
cash. We will provide financial guidance for 2013 in connection with our
year-end 2012 financial results in February.”

Alnylam management will present a company overview at the 31st Annual J.P.
Morgan Healthcare Conference on Wednesday, January 9, 2013 at 8:00 a.m. PT
(11:00 a.m. ET) at the Westin St. Francis Hotel in San Francisco, Calif. A
live audio webcast of the presentation will be available on the News &
Investors section of the company’s website, www.alnylam.com. A replay of the
presentation will be available on the Alnylam website within 48 hours after
the event.

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, ALN-PCS for the treatment of severe
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 and Genzyme. 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 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 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for
development and commercialization of novel RNAi therapeutics to address
genetically defined 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
severe 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.

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
thyroid hormone and 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. As a result, there is a significant need for novel therapeutics to
treat patients who have inherited mutations in the TTR gene.

About Hemophilia and Rare Bleeding Disorders

Hemophilias are hereditary disorders caused by genetic deficiencies of various
blood clotting factors, resulting in recurrent bleeds into joints, muscles,
and other major internal organs. Hemophilia A is defined by loss-of-function
mutations in factor VIII, and there are greater than 40,000 registered
patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function
mutations in factor IX, affects greater than 9,500 registered patients in the
U.S. and Europe. Standard treatment for hemophilia patients involves
replacement of the missing clotting factor either as prophylaxis or on-demand
therapy. However, a significant number of hemophilia A patients will develop
an antibody to their replacement factor – a very serious complication; these
‘inhibitor’ patients become refractory to standard replacement therapy. There
are approximately 2,000 inhibitor patients in major markets and up to 5,000
patients worldwide. Other rare bleeding disorders (RBD) are defined by
congenital deficiencies of other blood coagulation factors including factors
II, V, VII, X, and XI, with an estimated 1,000 RBD patients worldwide in need
of routine prophylaxis. There exists a significant need for novel therapeutics
to treat severe hemophilia patients and patients with RBDs.

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; some patients are given
intravenous heme analogues that must be administered through a central venous
catheter, but these have a slow onset and can result in severe
thrombophlebitis, iron overload and resistance to treatment over time.
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-siRNAs 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. Notably, GalNAc-siRNAs are being employed in
Alnylam’s ALN-TTRsc and ALN-AT3 RNAi therapeutic programs for the treatment of
transthyretin-mediated amyloidosis (ATTR) and hemophilia and rare bleeding
disorders, respectively, both of which the company expects to have in clinical
trials in 2013. GalNAc-siRNAs are a proprietary Alnylam delivery platform.

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-TTR02 and ALN-TTRsc,
ALN-AT3, ALN-AS1, ALN-PCS, ALN-TMP, ALN-AAT, ALN-VSP, and ALN-RSV01, 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 IND or IND equivalent applications and initiate clinical trials
for ALN-TTR02, ALN-TTRsc, ALN-AT3, and ALN-AS1, its expectations regarding
reporting data from its ongoing and planned clinical studies, including its
studies for ALN-TTR02, ALN-TTRsc, ALN-AT3, and ALN-AS1, its plans to seek
collaborations for its ALN-AT3, ALN-AS1, ALN-PCS, ALN-TMP, and ALN-AAT
programs, as well as other research programs and technologies, and its
expected cash position as of December 31, 2012, 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, and the successful defense of litigation, as well as
those risks more fully discussed in the “Risk Factors” section of its most
recent quarterly report on Form 10-Q 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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