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Alnylam Scientists Present Pre-clinical Data with ALN-CC5, an RNAi Therapeutic Targeting Complement Component C5 for the

  Alnylam Scientists Present Pre-clinical Data with ALN-CC5, an RNAi
  Therapeutic Targeting Complement Component C5 for the Treatment of
  Complement-Mediated Diseases

   – New Research Presented at 6^th International Conference on Complement
  Therapeutics Demonstrates Potent, Dose-Dependent, and Durable Silencing of
Serum C5 and Inhibition of Complement Hemolytic Activity by Approximately 90%
                                      –

       – ALN-CC5 Advanced as New “Alnylam 5x15” Program Using Company’s
GalNAc-Conjugate Delivery Technology Enabling Subcutaneous Dose Administration
                                      –

   – Company Expands Pipeline Guidance and Expects to Nominate Development
                           Candidate by Late 2013 –

Business Wire

CAMBRIDGE, Mass. -- June 20, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data with
ALN-CC5, an RNAi therapeutic targeting complement component C5. These data
were presented at the 6^th International Conference on Complement Therapeutics
being held June 18 - 23, 2013 in Kos, Greece. The complement system plays a
central role in immunity as a protective mechanism for host defense, but its
dysregulation results in serious, life-threatening complications in a broad
range of human diseases including paroxysmal nocturnal hemoglobinuria (PNH),
atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis
optica, amongst others. C5 is a genetically and clinically validated target;
loss of function human mutations are associated with an attenuated immune
defense against certain infections and intravenously administered anti-C5
monoclonal antibody therapy has demonstrated clinical activity and
tolerability in a number of complement-mediated diseases. In a presentation
titled “Development of an RNAi Therapeutic Silencing the C5 Component of
Complement,” Alnylam scientists presented pre-clinical results showing potent,
dose-dependent, and durable RNAi-mediated knockdown of serum C5 and inhibition
of complement-mediated hemolytic activity of approximately 90% with a
subcutaneously administered RNAi therapeutic. Alnylam believes that ALN-CC5 –
part of the company’s “Alnylam 5x15” product strategy – represents a novel
approach for the treatment of complement-mediated diseases; the company
expects to nominate a development candidate for clinical advancement in late
2013.

“C5 is a genetically and clinically validated target that exemplifies the
potential of Alnylam’s ‘5x15’ product strategy for innovative new medicines.
First, C5 is predominantly expressed in liver, where we have established
clinical activity and tolerability for RNAi therapeutics. In addition, our
clinical development plan for an RNAi therapeutic targeting C5 will be
facilitated by serum biomarkers in Phase I trials and a relatively streamlined
and focused path for advanced development,” said Rachel Meyers, Ph.D., Vice
President, Research and RNAi Lead Development at Alnylam. “Indeed, we believe
that a subcutaneously administered RNAi therapeutic targeting C5 could
represent an important advance for the treatment of a broad range of
complement-mediated diseases.”

New data presented at the scientific meeting showed that a GalNAc-siRNA
conjugate targeting the C5 mRNA resulted in potent, dose-dependent, and
durable silencing of C5 liver mRNA, knockdown of C5 serum protein levels, and
inhibition of complement-mediated hemolysis activity. Specifically, a
prototype GalNAc-siRNA conjugate targeting C5 showed a single dose ED50 for C5
knockdown of approximately 0.6 mg/kg in rodent models. In multi-dose
experiments, subcutaneous administration of the GalNAc-siRNA conjugate
resulted in approximately 90% knockdown of serum C5 levels at doses of ≥1.25
mg/kg. Additional multi-dose experiments showed that the current lead
candidate siRNA could achieve an approximately 90% inhibition of
complement-mediated hemolytic activity in the rat at subcutaneous doses of 5
mg/kg; these effects were rapid, dose-dependent, and durable for weeks after
cessation of treatment. The company is performing additional optimization of
the GalNAc-siRNA conjugate lead molecule and expects to nominate its ALN-CC5
development candidate in late 2013.

“The complement system plays a central role in immunity as part of host
defense. However, dysregulation of this pathway can lead to life-threatening
complications in a wide range of human diseases including PNH, aHUS,
myasthenia gravis, neuromyelitis optica, amongst others,” said Akshay
Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer at
Alnylam. “We are excited about these pre-clinical data showing potent,
dose-dependent, and durable knockdown of serum C5 with about 90% inhibition of
hemolysis activity using a subcutaneously administered RNAi therapeutic. We
believe that if these results can extend in the clinical setting, they could
represent a very promising therapeutic strategy and new treatment option for
patients with complement-mediated diseases.”

About ALN-CC5

ALN-CC5 is an RNAi therapeutic targeting the C5 component of the complement
pathway for the treatment of complement-mediated diseases. The complement
system plays a central role in immunity as a protective mechanism for host
defense, but its dysregulation results in life-threatening complications in a
broad range of human diseases including paroxysmal nocturnal hemoglobinuria
(PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis,
neuromyelitis optica, amongst others. Complement component C5, which is
predominantly expressed in liver cells, is a genetically and clinically
validated target; loss of function human mutations are associated with an
attenuated immune response against certain infections and intravenous anti-C5
monoclonal antibody therapy has demonstrated clinical activity and
tolerability in a number of complement-mediated diseases. A subcutaneously
administered RNAi therapeutic that silences C5 represents a novel approach to
the treatment of complement-mediated diseases. ALN-CC5 utilizes Alnylam’s
proprietary GalNAc conjugate delivery platform enabling subcutaneous dose
administration.

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, 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-CC5, its expectations with
respect to the timing of naming a development candidate for ALN-CC5, its
expectations regarding reporting of data from its pre-clinical studies for
ALN-CC5 studies, its plans to seek a partner for certain of its “Alnylam 5x15”
programs, and its expectations regarding the potential market opportunity for
ALN-CC5, 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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