Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today that it has discovered a key
mechanism related to the systemic delivery of RNAi therapeutics using
lipid nanoparticles (LNPs). The new pre-clinical research was presented
at the "Advances in Biopharmaceuticals” Keystone Symposium held January
8-13, 2010 in Midway, Utah, and was performed in collaboration with
scientists at the Max Planck Institute of Molecular Cell Biology and
Genetics. The new data document a key mechanism for endogenous targeting
of LNPs to the liver, provide alternative targeting strategies for the
hepatic delivery of RNAi therapeutics, and highlight potential targeting
approaches for delivery to non-hepatic tissues and cell types.
"A key achievement this past year was our progress in systemic delivery
of RNAi therapeutics, the critical scientific determinant for
advancement of this promising new class of medicines to patients,” said
Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President,
Distinguished Alnylam Fellow. "As noted recently, one dimension of our
progress is evidenced by the discovery of novel LNP compositions that
have markedly enhanced potency with efficacy achieved at microgram per
kilogram dose levels. Today, we’re very pleased to announce our
discovery of a key mechanism for systemic delivery by LNPs, a finding
that reveals a very promising new frontier for RNAi therapeutics with
targeted delivery.”
"We’re very excited about our new findings as they provide critical
mechanistic insights for the continued advancement of LNPs as a platform
for systemic delivery of RNAi therapeutics,” said Akin Akinc, Ph.D.,
Associate Director, Research at Alnylam. "Indeed, we have demonstrated
that the endogenous protein apolipoprotein E (ApoE) mediates the liver
uptake of certain LNPs in a manner that mimics physiologic mechanisms
for lipoprotein metabolism. Further, we’ve demonstrated the ability to
engineer exogenous targeting of LNPs to yet another liver receptor,
pointing to the broader opportunity of targeting LNPs to distinct cell
types and tissues beyond the liver.”
The new in vitro and in vivo research findings establish
the role of ApoE as an endogenous targeting ligand for neutrally charged
ionizable LNPs (iLNPs), but not certain cationic LNPs (cLNPs), and
demonstrate an alternative targeting strategy for the hepatic delivery
of RNAi therapeutics using the carbohydrate N-acetylgalactosamine
(GalNAc) as an exogenous ligand. Data from these studies showed:
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in cultured liver cells, ApoE dramatically enhanced both the
cellular uptake and silencing activity of siRNAs formulated in iLNPs;
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in an ApoE knockout mouse model, iLNPs demonstrated a complete loss of
activity due to the absence of ApoE as an endogenous targeting ligand;
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however, in vivo activity was found to be fully restored
through the addition of an exogenous source of ApoE (recombinant ApoE,
or "r-ApoE”) when the protein was pre-mixed with iLNPs prior to their
co-administration;
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specifically, the data showed that as little as 0.03 mg/kg of
r-ApoE was able to fully restore the activity of an siRNA
formulated in an iLNP; and,
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alternatively, in the same ApoE knockout model, silencing activity was
found to be restored by the use of an exogenous GalNAc ligand that
targets the iLNP to the asialoglycoprotein receptor (ASGR) expressed
on hepatocytes, with as little as 0.15 mole% GalNAc ligand being
sufficient to give near maximal activity.
LNP formulations represent one of several approaches Alnylam is pursuing
for systemic delivery of RNAi therapeutics. Additional approaches
include novel lipidoid formulations, including cLNPs; mimetic
lipoprotein particles (MLPs); siRNA conjugation strategies; and
single-stranded RNAi; amongst others. Alnylam is currently enrolling
patients in a Phase I clinical program with its systemic RNAi
therapeutic ALN-VSP for the treatment of liver cancers. In addition,
Alnylam intends to initiate a Phase I trial in the first half of 2010
for an additional systemic RNAi therapeutic, ALN-TTR for the treatment
of transthyretin (TTR)-mediated amyloidosis. ALN-VSP and ALN-TTR both
utilize a first generation LNP formulation known as stable nucleic
acid-lipid particles (SNALP), which contains an ionizable lipid, and is
developed in collaboration with Tekmira Pharmaceuticals Corp.
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. RNAi
therapeutics target the cause of diseases by potently silencing specific
messenger RNAs (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 Kirin. In
addition, the company is developing RNAi therapeutics for the treatment
of a wide range of disease areas, including liver cancers, TTR
amyloidosis, hypercholesterolemia, and Huntington’s disease. 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 Kirin, 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 and Isis are joint owners of Regulus Therapeutics Inc., a
company focused on the discovery, development, and commercialization of
microRNA-based therapeutics. Founded in 2002, Alnylam maintains
headquarters in Cambridge, Massachusetts. For more information, please
visit 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
discover and develop novel drug candidates, successfully demonstrate
efficacy and safety of its drug candidates in human clinical trials, 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.
