Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, today announced the publication of new data in the
journal Nature Biotechnology by Alnylam scientists and
collaborators from Tekmira Pharmaceuticals Corporation, AlCana
Technologies, Inc., and The University of British Columbia (UBC). The
new study employed a rational design approach for the discovery of novel
lipids that can be incorporated into lipid nanoparticles (LNPs) for
systemic delivery of RNAi therapeutics. This new research complements
the combinatorial chemistry-based approach recently described by Alnylam
scientists in the Proceedings of the National Academy of Sciences
(PNAS) (Love et al. (January 11, 2010) Proc. Natl Acad.
Sci. USA, 10.1073/pnas.0910603106), and highlights the power of
using multiple parallel approaches for optimizing LNPs.
"We are very excited by our continued progress in discovering new LNP
compositions that provide dramatic improvements in the systemic delivery
of RNAi therapeutics,” said Victor Kotelianski, M.D., Ph.D., D.Sc.,
Senior Vice President, Distinguished Alnylam Fellow. "As compared with
our recent paper from our MIT collaboration just last month, this new
paper highlights the results of an entirely different approach using
rational design for lipid discovery. When formulated with siRNAs, these
new lipids form highly potent LNPs that augment Alnylam’s platform of
second generation LNPs. We believe that these discoveries will define
major new opportunities for Alnylam for the advancement of our pipeline.”
The new paper (Semple et al., Nature Biotechnology advance online
publication, 17 January 2010 (doi:10.1038/nbt.1602)) describes the
discovery of a novel lipid, known as "KC2,” based on a medicinal
chemistry effort to explore the structure-activity relationships in the
lipid "DLinDMA,” which is used in certain first generation LNPs such as
Tekmira’s stable nucleic acid-lipid particles (SNALP) formulations. A
large number of novel lipids were synthesized to probe the relationship
of lipid structure, such as the alkyl chain, linker, and head group
moieties, with function as determined by screening for in vivo
gene silencing activity. Additional measurements were performed to
characterize the ability of the novel lipids to mediate certain
physicochemical changes in lipid bilayers consistent with needed
disruption of endosomal membranes. In order to explore its suitability
for systemic delivery, the novel KC2 lipid was formulated with siRNA in
an LNP formulation. Specifically, the in vivo data showed that:
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gene silencing in rodents was achieved following a single injection at
doses as low as 0.01mg/kg;
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potent and selective silencing of the clinically relevant gene
transthyretin (TTR) was achieved at doses as low as 0.1 mg/kg in
non-human primates; and,
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the formulation was found to be well tolerated in both rodents and
non-human primates.
"We’ve been successful in using distinct, albeit complementary
strategies for new lipid discovery that has led to the creation of a
robust second generation LNP platform for use in Alnylam’s systemic
delivery efforts,” said Antonin de Fougerolles, Ph.D., Vice President
Research. "The novel KC2-containing LNPs described in the current paper
demonstrate potent gene silencing efficacy with siRNA at very low
microgram per kilogram doses in several species including non-human
primates. We fully expect that the significantly improved potency of
these second generation LNPs will yield important advantages for
advancement of RNAi therapeutics including lowered material
requirements, improved therapeutic index, and expanded scope of delivery
beyond the liver.”
LNP formulations represent one of several approaches Alnylam is pursuing
for systemic delivery of RNAi therapeutics. Additional approaches
include novel lipidoid formulations, 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-TTR01 for the treatment of TTR-mediated amyloidosis. ALN-VSP and
ALN-TTR01 both utilize a first generation SNALP formulation developed in
collaboration with Tekmira Pharmaceuticals Corporation.
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 Kirin. In
addition, the company is developing RNAi therapeutics for the treatment
of a wide range of disease areas, including liver cancers, TTR-mediated
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. 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
successfully discover and develop novel drug candidates, successfully
and 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.
