Alnylam Presents Key Scientific Data on Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Technology

  Alnylam Presents Key Scientific Data on Enhanced Stabilization Chemistry
  (ESC)-GalNAc-Conjugate Technology

    – ESC-GalNAc-Conjugate Platform Enables Subcutaneous Delivery of RNAi
  Therapeutics with Increased Potency and Durability, and a Wide Therapeutic
                                   Index –

Business Wire

CAMBRIDGE, Mass. -- May 11, 2014

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today that it is presenting key scientific data on its
Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform.
Specifically, the company will be presenting data showing that chemical
modifications of siRNA that enhance in vitro stability result in higher liver
exposure in vivo and lead to a significantly increased potency and durability
of effect in pre-clinical studies. As compared with the “standard template
chemistry” (STC)-GalNAc-conjugate approach used in ALN-TTRsc – a
subcutaneously administered RNAi therapeutic targeting transthyretin (TTR) for
the treatment of TTR cardiac amyloidosis – ESC-GalNAc-siRNA conjugates
demonstrated a 10-fold increased potency in non-human primate (NHP) studies,
and a durability of effect that supports once-monthly or potentially even less
frequent subcutaneous dosing regimens. The ESC-GalNAc-conjugate technology is
being used in a wide range of Alnylam development programs, including ALN-AT3
– an RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders – which is currently in a Phase 1
clinical study.

“Our ESC-GalNAc-conjugate delivery platform enables subcutaneous dosing of
RNAi therapeutics with increased potency and durability, and a wide
therapeutic index. Importantly, we have demonstrated that increased siRNA
stability is the key to realizing these potency and durability improvements.
In addition, our data suggest that further improvements in potency and
durability might be realized in human studies based on an attenuated nuclease
environment. Accordingly, we believe that once-monthly and possibly less
frequent subcutaneous dose regimens could be achieved in our clinical pipeline
programs with this technology,” said Muthiah (Mano) Manoharan, Ph.D., Senior
Vice President, Drug Discovery of Alnylam. “We look forward to sharing
additional pre-clinical and clinical results in the weeks and months to come,
where we expect to build on data sets that are defining what we believe will
be a very attractive product profile for our RNAi therapeutics, including the
ability to clamp down disease targets in a predictable, sustainable, and
durable manner.”

In a presentation at the TIDES 2014 meeting, being held May 12 – 15, 2014 in
Providence, Rhode Island, Alnylam scientists presented new data on the
company’s ESC-GalNAc-conjugate delivery platform. Metabolic profiling studies
were performed in vitro and showed that chemically modified siRNA using an
STC-GalNAc-conjugate approach were prone to significant exonuclease and
endonuclease degradation. More extensive, yet targeted, chemical modifications
were introduced, including the use of chemistries that prevent exonuclease
degradation at the 5’-end of the siRNA sense and antisense strands and
improved resistance towards endonuclease degradation at the inter-nucleotide
linkages for both strands. These additional modifications resulted in a marked
increase in in vitro metabolic stability. In in vivo studies where ESC-GalNAc
siRNA were compared with STC-GalNAc siRNA, the enhanced stabilization resulted
in markedly prolonged liver tissue exposure with a nearly 30-fold increase in
area under the curve (AUC) values. In turn, the higher level of tissue
exposure was associated with an over 10-fold increase in in vivo potency as
measured toward target gene knockdown and a marked prolongation in durability
of effect. Of interest, a comparative analysis in NHP and human studies of the
efficacy and durability of ALN-TTRsc – an STC-GalNAc siRNA – revealed a
significantly lower degradation rate in humans and a prolonged durability of
target knockdown. These data suggest that ESC-GalNAc-siRNA conjugates could
show even greater durability in human studies, providing further support for
once-monthly and possibly even less frequent subcutaneous dosing regimens.

Finally, the preliminary safety of ESC-GalNAc-siRNA conjugates was evaluated
in rodent and NHP toxicology studies. An ESC-GalNAc conjugate – ALN-PCSsc –
was administered as five weekly subcutaneous doses of up to 300 mg/kg. At all
doses tested, the siRNA was found to be well tolerated, with no adverse
in-life findings, no significant changes in clinical pathology values (e.g.,
LFTs), and no adverse histopathology findings including at the injection
sites. In these initial toxicology studies, the no adverse effect level
(NOAEL) was determined to be greater than 300 mg/kg in both species. These
data indicate that the improved potency and durability of ESC-GalNAc-siRNA
conjugates do not appear to be associated with any negative safety

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc

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. Alnylam’s Enhanced
Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous
dosing with increased potency and durability, and a wide therapeutic index.
This delivery platform is being employed in several of Alnylam’s genetic
medicine programs, including programs in clinical development.

About 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 as
genetic medicines, including programs as part of the company’s “Alnylam 5x15™”
product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics
directed toward genetically defined targets for the treatment of serious,
life-threatening diseases with limited treatment options for patients and
their caregivers. These include: patisiran (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 TTR cardiac
amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile
systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting
antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders
(RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic
targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic
porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi
therapeutic targeting PCSK9 for the treatment of hypercholesterolemia;
ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the
treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed
hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic
targeting apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; and other programs yet to be disclosed. As part of its
“Alnylam 5x15” strategy, as updated in early 2014, the company expects to have
six to seven genetic medicine product candidates in clinical development -
including at least two programs in Phase 3 and five to six programs with human
proof of concept - by the end of 2015. The company’s demonstrated commitment
to RNAi therapeutics has enabled it to form major alliances with leading
companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda,
Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines
Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna
Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds
an equity position in Regulus Therapeutics Inc., a company focused on
discovery, development, and commercialization of microRNA therapeutics.
Alnylam scientists and collaborators have published their research on RNAi
therapeutics in over 200 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

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam’s future
expectations, plans and prospects, including without limitation, Alnylam’s
views with respect to the potential for RNAi therapeutics and its Enhanced
Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, and its
expectations regarding its “Alnylam 5x15” product strategy, 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 manage operating expenses, 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 most recent Quarterly Report on Form 10-Q filed
with the Securities and Exchange Commission (SEC) 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.


Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
Liz Bryan, 202-955-6222 x2526
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