Alnylam Reports Positive Clinical Results – with up to 94% Knockdown of Serum Transthyretin (TTR) – for ALN-TTRsc, a

  Alnylam Reports Positive Clinical Results – with up to 94% Knockdown of
  Serum Transthyretin (TTR) – for ALN-TTRsc, a Subcutaneously Delivered RNAi
  Therapeutic for the Treatment of TTR-Mediated Amyloidosis (ATTR)

  –ALN-TTRsc Clinical Activity Establishes New Benchmark for Consistent TTR
                       Knockdown of Approximately 90% –

– Multiple Doses of ALN-TTRsc Found to be Generally Safe and Well Tolerated in
                               Phase I Study –

 – Results Establish Human Translation of Alnylam’s Proprietary GalNAc-siRNA
 Conjugate Platform for Subcutaneous Administration of RNAi Therapeutics with
                           Wide Therapeutic Index –

   – Company to Host Conference Call at 8:00 a.m. Today to Discuss Clinical
                                  Results –

Business Wire

CAMBRIDGE, Mass. -- September 23, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today positive interim results from its Phase I clinical
trial of ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the
transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR).
The data are being presented today at the Heart Failure Society of America
17^th Annual Scientific Meeting being held September 22 – 25, 2013 in Orlando,
Fla. Results show that ALN-TTRsc administration led to robust, consistent, and
statistically significant (p<0.01) knockdown of serum TTR protein levels of up
to 94%. In addition, knockdown of TTR, the disease causing protein in ATTR,
was found to be rapid, dose dependent, and durable. To date, ALN-TTRsc has
been found to be generally safe and well tolerated in this study. These human
data are the first to be presented for Alnylam’s proprietary GalNAc-siRNA
conjugate delivery platform, enabling subcutaneous dosing of RNAi therapeutics
with a wide therapeutic index, and demonstrate human translation for this
platform. Moreover, these results establish a new benchmark for consistent TTR
knockdown of approximately 90% for RNA therapeutics in development for the
treatment of ATTR.

“These new ALN-TTRsc results are a major milestone in our ATTR program, as
well as our entire pipeline of RNAi therapeutics. Specifically, we have
demonstrated robust, up to 94% knockdown of circulating TTR with a very
encouraging safety profile. We believe this level of consistent TTR knockdown
is exceptional and unmatched, and we now aim to advance ALN-TTRsc in future
clinical studies with the goal of achieving approximately 90% TTR knockdown to
maximize clinical efficacy,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President and Chief Medical Officer of Alnylam. “These new data support our
belief that ALN-TTRsc has the potential to be an important therapeutic for the
treatment of familial amyloidotic cardiomyopathy (FAC) – a disease for which
there are no approved therapies. With these results in hand, we are well
positioned for continued execution on this program, which includes the
initiation of a pilot Phase II study in FAC patients by the end of this year,
and – assuming positive results – start of a pivotal Phase III trial with
ALN-TTRsc by the end of 2014.”

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 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.
Alnylam is also developing ALN-TTR02, an intravenously administered RNAi
therapeutic targeting TTR for the treatment of ATTR patients with FAP.

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.
In an initial single-ascending dose phase of the study, subjects (n=16)
received subcutaneous doses of placebo or ALN-TTRsc from 1.25 to 10 mg/kg. In
the multiple-ascending dose phase of the study, subjects (n=12) received 10
subcutaneous doses of placebo or ALN-TTRsc from 2.5 to 10 mg/kg. Upon
completion of this Phase I trial, the company expects to start a pilot Phase
II clinical study of ALN-TTRsc in FAC patients in late 2013 and, assuming
positive results, plans to start a pivotal Phase III trial with ALN-TTRsc in
FAC patients in 2014.

Interim data from the 28 subjects enrolled and analyzed in this study to date
showed that single- and multi-dose administration of ALN-TTRsc resulted in
rapid, dose-dependent, consistent, and durable knockdown of serum TTR levels.
In the multi-dose cohorts (n=12), there was a statistically significant
knockdown of serum TTR at doses of 2.5 mg/kg (p<0.01), 5.0 mg/kg (p<0.001),
and 10.0 mg/kg (p<0.001) as compared to placebo (results are shown in the
table below). At a dose of 5.0 mg/kg, ALN-TTRsc administration resulted in an
up to 93.3% knockdown of serum TTR and a mean TTR knockdown of 87.5% at nadir.
At a dose of 10.0 mg/kg, ALN-TTRsc administration led to an up to 94.0%
knockdown of serum TTR and a mean TTR knockdown of 92.4% at nadir.

                                                        
Summary of ALN-TTRsc Clinical Activity Results with Multi-Dose Administration
                                                                     
Dose Group        Placebo       2.5 (n=3)    5.0         10 (n=3)
(mg/kg)              (n=3)                            (n=3)
Mean knockdown                        58.2 ±          87.5 ±         92.4 ±
at nadir (% ±     7.8 ± 8.6     11.1**       7.2 ***     1.5***
SD)
Maximum TTR       15.8          70.6         93.3        94.0
knockdown (%)
                                                                     

** p < 0.01 vs. placebo
***p < 0.001 vs. placebo
p values from ANCOVA models including baseline TTR and dose groups as factors

Analysis of the TTR knockdown in humans as compared to results obtained in
non-human primates showed a closely correlated, essentially one-to-one
relationship on a mg/kg basis (r^2=0.83, p<0.001). These results confirm human
translation for Alnylam’s GalNAc-siRNA conjugate platform, which is also being
employed in the company’s programs in hemophilia, porphyria,
complement-mediated diseases, hypercholesterolemia, beta-thalassemia, and
alpha-1-antitrypsin deficiency, amongst others.

In this study as reported to date, single and multiple doses of ALN-TTRsc were
found to be generally safe and well tolerated. There were no significant
adverse events associated with drug at doses through 10.0 mg/kg. All adverse
events were deemed mild or moderate in severity. Injection site reactions were
observed in a minority of subjects receiving ALN-TTRsc (24%) or placebo (14%).
These were reported as being clinically mild and consisted of transient
erythema associated in a minority of cases with edema and/or pain. In all
cases, these reactions were self-limiting and resolved within approximately
two hours of onset. There were no study discontinuations, flu-like symptoms,
or changes in cytokines, C-reactive protein (CRP), liver function tests, renal
function, or hematologic parameters.

“I am very encouraged by these new clinical activity and safety data with
ALN-TTRsc. Specifically, I am impressed with the potent, rapid, and durable
knockdown as well as the favorable safety profile observed to date,” said
Professor Philip N. Hawkins, National Amyloidosis Centre, Division of
Medicine, and University College London Medical School, Royal Free Hospital.
“Clearly, the ability of this RNAi therapeutic to achieve a consistent,
approximately 90% knockdown of TTR sets a new benchmark that I believe has the
potential to translate into meaningful clinical benefit for patients. I very
much look forward to the continued advancement of RNAi therapeutics in
clinical trials for the treatment of ATTR – both FAP and FAC – as there are
currently very few options for patients suffering from this debilitating,
progressive disease.”

“We are in the midst of very exciting times at Alnylam, with a steady flow of
pre-clinical and clinical data that reflect the strong potential of RNAi
therapeutics as an emerging class of innovative medicines. These new Phase I
clinical results with ALN-TTRsc establish human translation for RNAi
therapeutics that utilize our GalNAc-siRNA conjugate delivery platform. This
platform enables subcutaneous dose administration with a wide therapeutic
index and has now become our primary approach for execution on our ‘Alnylam
5x15’ product strategy,” said John Maraganore, Ph.D., Chief Executive Officer
of Alnylam. “Importantly, we believe these new results demonstrate an
unmatched level of efficacy for RNA therapeutics with a consistent,
approximately 90% target gene knockdown via subcutaneous dose administration,
in addition to a very promising safety profile. As a result, we believe these
data are very meaningful not only for the continued advancement of ALN-TTRsc,
but also for the continued execution on our entire ‘Alnylam 5x15’ product
strategy. Through this strategy, we believe that we are building a compelling
opportunity for shareholder value creation with a modular and reproducible
approach for development and, ultimately, commercialization of innovative
medicines for genetically defined diseases.”

In 2012, 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.

Conference Call Information

Management will discuss these Phase I clinical data with ALN-TTRsc on Monday,
September 23, 2013 at 8:00 a.m. ET. A slide presentation will also be
available on the News & Investors page of the company’s website,
www.alnylam.com, to accompany the conference call. To access the call, please
dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes
prior to the start time and refer to conference ID 68228737. A replay of the
call will be available beginning at 11:00 a.m. ET on Monday, September 23,
2013. To access the replay, please dial 855-859-2056 (domestic) or
404-537-3406 (international), and refer to conference ID 68228737.

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.

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;
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 the C5 component of the complement pathway 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, 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;
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 the C5 component of the complement pathway 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-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 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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