Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today that it presented new data related
to its overall delivery research efforts including the rational design
of Mimetic Lipoprotein Particles, or MLPs, a novel technology for the
systemic delivery of small interfering RNAs, or siRNAs, the molecules
that mediate RNAi. In addition, Alnylam scientists and collaborators
presented additional new data on systemic delivery and provided an
update on RNA activation (RNAa) technology. These new data were
presented at the 5th Oligonucleotide Therapeutics Society/19th
Antisense Joint Symposium held November 3-6, 2009 in Fukuoka, Japan.
"Delivery of siRNAs remains one of the most important objectives in our
efforts to advance RNAi therapeutics to patients,” said Victor
Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished
Alnylam Fellow. "Accordingly, we are very excited by our new efforts in
the rational design of MLPs, a whole new strategy for systemic delivery.
Indeed, MLPs are designed to harness natural physiologic pathways in
their delivery of siRNAs and they represent an important convergence of
Alnylam’s research on conjugate- and lipid nanoparticle-based delivery
strategies. In addition to our continued efforts on a wide range of
other delivery technologies, this new line of research continues to
demonstrate Alnylam’s scientific leadership in RNAi.”
In a poster titled "Lipophilic siRNA Delivery by Reconstituted
Lipoprotein Particles In Vivo” Tomoko Nakayama, Ph.D., Associate
Director, Research at Alnylam, presented for the first time the rational
design and characterization of MLPs as an RNAi delivery platform. MLPs
were designed to mimic the physiologic properties of endogenous
lipoprotein particles and were engineered using recombinant human
apolipoprotein A1 (rh-apoA1) or recombinant human apolipoprotein E
(rh-apoE), phosphatidylcholine, and a cholesterol-conjugated siRNA
(chol-siRNA). The resulting MLPs had biophysical properties comparable
to normal high-density lipoprotein (HDL, or "good” cholesterol)
particles including a mean diameter size of approximately 10 nm. The
stoichiometry for siRNA:particle loading ratio was observed to be 1:1.
The reported in vivo studies were performed in mice using MLPs
with chol-siRNAs targeting apolipoprotein B (apoB), the major
apolipoprotein involved in the metabolism of low-density lipoprotein
(LDL, or "bad”) cholesterol. Administration of the MLP resulted in
silencing of the apoB mRNA by up to 80% with an associated 50 to 80%
reduction in levels of plasma apoB protein and cholesterol in mice.
These data also demonstrated significant improvements in the potency of
apoB silencing when using MLP-delivery of siRNAs as compared with use of
chol-siRNAs alone. The study further demonstrated that apoE-MLP was more
effective in delivering siRNAs than apoA-MLPs, at least as measured for
the silencing of the liver-expressed target gene.
In addition, Dr. Muthiah Manoharan, Alnylam’s Vice President, Drug
Discovery, gave a talk titled "Chemical Strategies for Delivering RNAi”
in which he presented new research on lipid nanoparticle and
conjugate-based delivery of siRNA. The new data showed continued
improvement in the in vivo potency of siRNA delivered by lipid
nanoparticles (LNPs), where the median effective dose (ED50)
for gene silencing was achieved at microgram/kilogram dose levels.
Further, quantitation of siRNA revealed the ability to achieve ED50
target gene silencing at tissue levels of approximately one
nanogram/gram tissue.
"The resulting research efforts of our scientists and collaborators
continue to represent what we believe is remarkable progress on delivery
of RNAi therapeutics,” said Dr. Manoharan. "Importantly, with the novel
LNP formulations we have discovered, we are now on a research trajectory
for in vivo gene silencing potency of siRNA at single-digit
microgram/kilogram dose levels. Further, we have now documented for the
first time that the siRNA tissue levels required for gene silencing are
approximately one nanogram/gram tissue, highlighting the power of
harnessing a natural, catalytic mechanism.”
Further, Alnylam scientists and collaborator Dr. Masayuki Matsui from
the laboratory of Dr. David R. Corey, Professor in the Departments of
Pharmacology & Biochemistry, University of Texas Southwestern Medical
Center (UTSW) at Dallas, presented new data on their RNAa research
efforts in a poster titled "Activation of LDL Receptor Gene Expression
by Promoter-Targeted Duplex RNAs.” In these studies, double-stranded
"anti-gene” RNAs (agRNAs) targeting the promoter region of the LDL
receptor (LDLR) were discovered that increase LDLR expression up to
four-fold. The action of agRNAs was dose-dependent and durable for about
one week. In functional studies, LDLR activation by agRNAs was found to
result in increased binding of fluorescently labeled LDL particles to
hepatocyte-derived cells in a culture system and to have additive
effects together with the action of lovastatin in upregulation of LDLR
protein levels. RNAa with agRNAs targeting the LDLR promoter could
define a novel approach for the treatment of hypercholesterolemia.
Other presentations from Alnylam scientists at the OTS meeting include
the following.
-
A presentation titled "Development of an RNAi Therapeutic Targeting
KSP and VEGF for the Treatment of Liver Cancers” by Dinah Sah, Ph.D.,
Vice President, Research, CNS and Oncology, which provided an overview
of the progress Alnylam has made to date with its ALN-VSP program
which is in a Phase I clinical trial in patients with advanced solid
tumors with liver involvement, including hepatocellular carcinoma
(HCC).
-
A presentation by Alnylam Scientific Advisory Board member and
collaborator, Judy Lieberman, M.D., Ph.D., Senior Investigator of the
Immune Disease Institute and Professor of Pediatrics, Harvard Medical
School. The presentation, titled "Silencing sexual transmission of
HSV-2 and HIV,” detailed the progress to date to develop an RNAi
topical microbicide to provide protection from the transmission of the
herpes simplex virus-2 (HSV-2) and for human immunodeficiency virus
(HIV).
-
A poster presented by Alnylam scientists titled "Conjugation
strategies for RNAs using click chemistry,” which describes approaches
to improve cellular uptake of siRNAs by conjugating lipophilic
molecules, carbohydrates, and polyamines to appropriate sites of RNA
molecules.
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 RNAs (siRNAs), 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 applying its
therapeutic expertise in RNAi to address significant medical needs, many
of which cannot effectively be addressed with small molecules or
antibodies, the current major classes of drugs. Alnylam is leading the
translation of RNAi as a new class of innovative medicines with
peer-reviewed research efforts published in the world’s top scientific
journals including Nature, Nature Medicine, and Cell.
The company is leveraging these capabilities to build a broad pipeline
of RNAi therapeutics; its most advanced program is in Phase II human
clinical trials for the treatment of respiratory syncytial virus (RSV)
infection and is partnered with Cubist and Kyowa Hakko. In addition, the
company is developing RNAi therapeutics for the treatment of a wide
range of disease areas, including liver cancers, hypercholesterolemia,
Huntington’s disease, and TTR amyloidosis. The company’s leadership
position in fundamental patents, technology, and know-how relating to
RNAi has enabled it to form major alliances with leading companies
including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko,
and Cubist. To reflect its outlook for key scientific, clinical, and
business initiatives, Alnylam established "RNAi 2010” in January
2008 which includes the company’s plan to significantly expand the scope
of delivery solutions for RNAi therapeutics, have four or more programs
in clinical development, and to form four or more new major business
collaborations, all by the end of 2010. Alnylam is a joint owner of
Regulus Therapeutics, a joint venture focused on the discovery,
development, and commercialization of microRNA therapeutics. Founded in
2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For
more information, please visit http://www.alnylam.com.
Alnylam Forward-Looking Statement
Various statements in this release concerning Alnylam’s future
expectations, plans and prospects, 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 the company's ability to
successfully research and develop products and to successfully prosecute
and enforce its patents around the world, as well as those risks more
fully discussed in the "Risk Factors” section of its most recent
quarterly report on Form 10-Q on file with the Securities and Exchange
Commission. 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 does not
assume any obligation to update any forward-looking statements.
