Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today the publication of a peer-reviewed article in
the Journal of the American Chemical Society describing the
discovery of GalNAc-conjugated siRNA as a novel strategy for delivery of
RNAi therapeutics. The paper, titled “Multivalent
N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes
and Elicits Robust RNAi-Mediated Gene Silencing,” (Nair et al.,
J. Am. Chem. Soc., doi:10.1021/ja505986a) documents the
pioneering discovery of GalNAc-siRNA conjugates as a novel delivery
approach for potent and durable knockdown of hepatocyte-expressed
disease targets in vivo. GalNAc-siRNA conjugates are a clinically
validated, proprietary Alnylam delivery platform and are designed to
achieve targeted delivery of RNA therapeutics to hepatocytes through
uptake by the asialoglycoprotein receptor (ASGPR). This targeted
delivery platform enables specific, potent and durable knockdown of
hepatocyte-expressed disease genes with subcutaneous dosing and a wide
therapeutic index. GalNAc-conjugates have emerged as a promising
strategy for the delivery of RNA therapeutics in advanced pre-clinical
and initial clinical studies.
“This publication as a JACS ‘Communication’ documents the
landmark discovery by Alnylam scientists of GalNAc-conjugates as a
potent and durable approach for subcutaneous administration of RNAi
therapeutics with a wide therapeutic index. Indeed, our scientists
championed the application of GalNAc-conjugates for delivery of RNA
therapeutics, including siRNAs, and we believe that this approach has
emerged as the optimal strategy across the entire industry for RNA
therapeutics targeting hepatocyte-expressed disease genes,” said Muthiah
(Mano) Manoharan, Ph.D., Senior Vice President, Drug Discovery at
Alnylam. “Over the last two years, we’ve now witnessed a steady flow of
advanced pre-clinical and clinical data on GalNAc-conjugates for RNA
therapeutics. This includes our Phase 1 and Phase 2 data on revusiran
with an up to 98.2% knockdown of the disease-causing transthyretin
protein; initial top-line clinical data for ALN-AT3 – our
investigational RNAi therapeutic targeting antithrombin for the
treatment of hemophilia – showing significant target gene knockdown at
doses as low as 0.03 mg/kg; and non-human primate data for our PCSK9 and
complement C5 programs showing potent and durable effects supportive of
once-monthly, and possibly once-quarterly, low volume, subcutaneous dose
administration regimens. In addition, our clinical and non-clinical
safety data continue to support what we believe to be a wide therapeutic
index for this delivery modality. Moreover, we’re now pleased to see
this approach being advanced by our licensees at Regulus Therapeutics,
showing impressive clinical data with RG-101 in hepatitis C, and at
Isis, with encouraging pre-clinical data on GalNAc-conjugated antisense
oligonucleotides. In sum, we’re proud to have pioneered this important
innovation in the RNA therapeutics field, and we look forward to
realizing the full impact of our science on the treatment of human
disease.”
Alnylam’s GalNAc-siRNA conjugate platform is a clinically validated
delivery technology that is being employed in essentially all of
Alnylam’s RNAi therapeutic pipeline programs. Recently, the company
presented positive
initial Phase 2 data with revusiran (ALN-TTRsc), a GalNAc-conjugated
RNAi therapeutic targeting transthyretin (TTR) in development for the
treatment of TTR cardiac amyloidosis; revusiran is a first generation
GalNAc-conjugate that utilizes Standard Template Chemistry (STC). In the
Phase 2 multi-dose study, revusiran demonstrated clinical activity with
an up to 98.2% knockdown of serum TTR – the disease-causing protein –
and was found to be generally well tolerated in patients with TTR
cardiac amyloidosis and advanced disease burden. The Phase 2 results
support advancement of revusiran in a Phase 3 randomized, double-blind,
placebo-controlled study in TTR cardiac amyloidosis, and the company
expects to start the study before year’s end.
Earlier this year, Alnylam reported positive
top-line clinical results with ALN-AT3, an investigational RNAi
therapeutic targeting antithrombin (AT) for the treatment of hemophilia
and rare bleeding disorders; ALN-AT3 employs a second generation
GalNAc-conjugate chemistry termed “Enhanced Stabilization Chemistry,” or
“ESC.” In the first part of a Phase 1 clinical study, where ALN-AT3 was
administered at low doses to healthy human volunteers, a single 0.03
mg/kg subcutaneous dose resulted in an up to 32% knockdown of serum AT
and increases in thrombin generation. These clinical results suggest
that ESC-GalNAc conjugates have a greater than 50-fold enhanced potency
in humans as compared with STC-GalNAc conjugates due to enhanced
stability in humans. Alnylam expects to present initial data
from the ALN-AT3 Phase 1 study, including results in human volunteers
and the first, lowest dose cohort of hemophilia subjects, at the
American Society of Hematology meeting being held from December 6 – 9,
2014.
In addition, Alnylam has presented extensive non-human primate data with
other ESC-GalNAc-siRNA conjugates, including ALN-PCSsc
– an investigational RNAi therapeutic targeting PCSK9 for the treatment
of hypercholesterolemia – and ALN-CC5
– an investigational RNAi therapeutic targeting complement C5 for the
treatment of complement-mediated diseases. Recently, the company has
filed and received approval for a Clinical Trial Application (CTA) to
initiate a Phase 1 study of ALN-PCSsc in normal human volunteers with
elevated LDL-C; the company expects to start the Phase 1 study by the
end of 2014 and plans to report initial clinical data in mid-2015. In
the case of ALN-CC5, Alnylam remains on track to file a CTA by the end
of 2014, and expects to report initial clinical data in mid-2015.
In addition to data on siRNA conjugates, additional proof-of-concept for
GalNAc-conjugates as a potent delivery platform for RNA therapeutics was
recently reported by Regulus Therapeutics with positive interim clinical
data with RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122
for the treatment of hepatitis C virus (HCV) infection. As
reported by Regulus, interim results from an ongoing clinical study
demonstrated that treatment with a single subcutaneous dose of 2 mg/kg
of RG-101 as monotherapy resulted in significant and sustained
reductions in HCV RNA, as well as a mean viral load reduction of 4.1 log10
at day 29; RG-101 was reported to be well tolerated in the study.
Regulus has a license to Alnylam’s GalNAc-conjugate technology in the
field of microRNA therapeutics through the companies’ 2007 license
agreement. Further, Isis Pharmaceuticals has reported successful
adoption of GalNAc-conjugated antisense oligonucleotides (ASOs) in
pre-clinical studies. Isis has obtained a license to Alnylam’s
GalNAc-conjugate technology in the field of single-stranded
oligonucleotide therapeutics, including ASOs, through the companies’
2004 license agreement.
Alnylam has obtained broad intellectual property protection for its
GalNAc-conjugate delivery platform for RNA therapeutics. Amongst other
issued and granted patents, the Manoharan et al. patent (US
8,828,956) includes claims directed to compositions including those
comprising a modified RNA agent linked to a biantennary or triantennary
ligand. Specifically, the patent includes claims that broadly cover
single-stranded or double-stranded chemically modified RNA therapeutics
conjugated with an N-acetylgalactosamine (GalNAc) ligand,
independent of length, sequence, or disease target.
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 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, durability, and a
wide therapeutic index, and is being employed in several of Alnylam’s
genetic medicine programs, including programs in clinical development.
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) targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR)
in patients with familial amyloidotic polyneuropathy (FAP); revusiran
(ALN-TTRsc) 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 targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD);
ALN-CC5 targeting complement component C5 for the treatment of
complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid
synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including
acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the
treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin
(AAT) for the treatment of AAT deficiency-associated liver disease;
ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment
of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders; ALN-ANG targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting
apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia;
ALN-AGT targeting angiotensinogen (AGT) for the treatment of
hypertensive disorders of pregnancy (HDP), including preeclampsia;
ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary
hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus
(HDV) genome for the treatment of HDV infection; ALN-PDL targeting
programmed death ligand 1 (PD-L1) for the treatment of chronic liver
infections; 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, and The Medicines Company. In early
2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product
geographic alliance on Alnylam's genetic medicine programs in the rare
disease field. Specifically, Alnylam will lead development and
commercialization of programs in North America and Europe, while Genzyme
will develop and commercialize products in the rest of world. In
addition, Alnylam and Genzyme will co-develop and co-commercialize
revusiran in North America and Europe. 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, 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 release concerning Alnylam’s future
expectations, plans and prospects, including without limitation,
Alnylam’s views with respect to the potential for RNAi therapeutics,
including revusiran (ALN-TTRsc) for the treatment of TTR cardiac
amyloidosis, ALN-AT3 for the treatment of hemophilia and rare bleeding
disorders, ALN-PCSsc for the treatment of hypercholesterolemia, and
ALN-CC5 for the treatment of complement-mediated diseases, the timing of
submitting regulatory filings, beginning clinical studies, and reporting
data, its expectations regarding the potency and therapeutic index of
GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry
(ESC)-GalNAc conjugates, its expectations regarding its “Alnylam 5x15”
product strategy, and its plans regarding commercialization of RNAi
therapeutics, 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 manage operating
expenses, 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.
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