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 consequences.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-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. 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 www.alnylam.com.
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.
Copyright Business Wire 2014