Alnylam Presents Pre-clinical Data from Hypercholesterolemia, Liver Cancer, Ebola,...

Alnylam Presents Pre-clinical Data from Hypercholesterolemia, Liver Cancer, Ebola, and Progressive Multifocal Leukoencephalopathy (PML) Programs at RNAi Keystone Symposium

New Data Highlight Broad Applications of RNAi Therapeutics and
Continued Progress in Advancing Pipeline of Innovative Medicines

New Results Also Document Significant Advancements in Systemic
Delivery of RNAi Therapeutics
CAMBRIDGE, Mass.--(Business Wire)--
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today that it presented pre-clinical
data at the "RNAi, MicroRNA, and Non-Coding RNA" Keystone Symposium
held March 25-30, 2008 in Whistler, British Columbia. Alnylam and its
collaborators presented data from Alnylam's therapeutic programs
including hypercholesterolemia, liver cancer, Ebola, and PML, as well
as an update on delivery approaches for the systemic delivery of RNAi
therapeutics.

"Alnylam scientists and collaborators continue to make significant
progress with RNAi therapeutics in important areas of unmet medical
need. We are encouraged by the data continuing to emerge from our
hypercholesterolemia, Ebola, liver cancer, and PML programs which show
potent and specific in vivo efficacy mediated by an RNAi mechanism,"
said Victor Kotelianski, M.D., Ph.D., Vice President, Research at
Alnylam. "We are also excited by our progress in optimizing siRNAs for
systemic delivery, including our recent data regarding heart and
muscle delivery. We believe that these cumulative data demonstrate
Alnylam's scientific leadership and commitment in translating the
science of RNAi into a new class of innovative medicines."

Hypercholesterolemia

Alnylam is developing a systemically delivered RNAi therapeutic
for the treatment of hypercholesterolemia targeting PCSK9, a
well-validated gene involved in the metabolism of LDL cholesterol
("bad cholesterol"). In a poster titled "RNAi Therapeutics Targeting
PCSK9 Acutely Lower Cholesterol from Mice to Non-Human Primates,"
Alnylam scientists presented in vivo data demonstrating that an RNAi
therapeutic targeting the PCSK9 gene significantly decreased LDL
cholesterol in three pre-clinical animal models - mouse, rat and
non-human primate.

Data presented at the meeting from studies in rodent models
include the following:

-- an RNAi therapeutic targeting PCSK9 demonstrated statistically
significant dose- dependent silencing of PCSK9 mRNA and
lowered total cholesterol by 40 to 50 percent as compared with
control, non-specific siRNAs; and,

-- the effects on cholesterol lowering was mediated by a three to
five fold increase in LDL receptor levels with no effect on
hepatic triglycerides and hepatic cholesterol; these data
further support the belief that RNAi therapeutics targeting
PCSK9 are unlikely to result in steatosis (fatty liver).

In non-human primate models, data presented include the following
as compared to a control siRNA:

-- RNAi-mediated gene silencing was associated with rapid
reductions in LDL cholesterol levels by 40 to 60 percent of
pre-dose levels;

-- circulating apolipoprotein B (apoB) levels - a constituent of
the LDL particle - decreased by 30 to 40 percent of pre-dose
levels;

-- after a single intravenous injection, the RNAi therapeutic
showed a durable biological effect with levels of LDL
cholesterol decreased for up to three weeks; and,

-- therapeutic efficacy was observed with an overall decreased
ratio of total cholesterol to HDL cholesterol ("good
cholesterol") - a result which has been shown in humans to
correlate with clinical benefit.

Liver Cancer

Alnylam is developing a systemically delivered RNAi therapeutic,
ALN-VSP, for the treatment of liver cancers and potentially other
solid tumors. ALN-VSP comprises two siRNAs in a lipid particle
formulation. These two siRNAs target separate genes involved in the
growth and development of tumors: kinesin spindle protein, or KSP, and
vascular endothelial growth factor, or VEGF. In a talk titled
"Translating RNAi," Muthiah Manoharan, Ph.D., Vice President, Drug
Discovery at Alnylam presented in vivo data from its ALN-VSP program
which were generated in collaboration with Protiva, using their stable
nucleic acid-lipid particles, or SNALP, technology.

Pre-clinical data with ALN-VSP, as compared to a control
non-specific siRNA, in a mouse model of liver cancer demonstrated the
following:

-- significant dose-dependent silencing of both KSP and VEGF
derived from the human tumor;

-- evidence of tumor cell cycle arrest due to KSP silencing
documented histologically;

-- reduction in overall tumor growth as measured by
quantification of a tumor-specific gene; and

-- marked reduction in the size of liver tumors in VSP-treated
animals as observed by gross pathology.

Alnylam BioDefense(TM)/Ebola

Alnylam is developing an RNAi therapeutic directed against the
Ebola virus, which can cause a severe, often fatal infection, and
poses a potential biological safety risk and bioterrorism threat. In a
poster titled "RNAi Therapeutics for the Treatment of Ebola Virus
Infection," pre-clinical data were presented on this program, which
utilizes an optimized RNAi therapeutic formulated in a lipid particle
for systemic delivery. This work was done in collaboration with
Tekmira using their lipid particle delivery formulation technology.

Pre-clinical data presented include the following:

-- potent siRNAs with in vitro anti-viral activity have been
identified against all genes in the Ebola genome;

-- a greater than 95 percent decrease in viral titer was seen
when an RNAi therapeutic targeting one of these genes, VP35,
was administered to mice infected with Ebola; and,

-- the VP35 siRNA, as compared with a control non-specific siRNA,
was able to protect both mice and guinea pigs from lethal
Ebola infection.

Alnylam is working with the United States Army Medical Research
Institute of Infectious Diseases (USAMRIID), an organization which is
uniquely experienced in the handling, safety, and security
requirements of specialized biological agents. Alnylam produces drug
candidates which are then sent to USAMRIID for in vitro and in vivo
testing against the Ebola virus. The National Institute of Allergy and
Infectious Diseases (NIAID), a component of the National Institutes of
Health (NIH), is funding this work through a federal contract (No.
HHSN266200600012C).

Progressive Multifocal Leukoencephalopathy (PML)

Alnylam is developing an RNAi therapeutic for the potential
treatment of PML, in collaboration with Biogen Idec. PML is caused by
infection of the central nervous system with a virus called "JC virus"
and can occur in certain immune-suppressed patients, including those
receiving immunomodulatory therapies. In a poster titled "Developing
RNAi Therapeutics Targeting JCV for Treatment of PML," Alnylam
scientists presented results showing that potential JCV RNAi
therapeutic candidates targeting different JCV transcripts have been
identified and showed potent inhibition of secondary PML infection in
vitro, both prophylactically and post-infection. Because there is no
established animal model of PML, Alnylam is delivering its RNAi
therapeutic to normal oligodendrocytes, the primary site of JCV
infection in vivo.

Additional pre-clinical data presented from this program included
the following:

-- JCV siRNAs are stable in human cerebrospinal fluid (CSF) with
half-lives greater than 48 hours, and do not produce unwanted
cytokine responses;

-- in a rodent model, siRNAs in vivo were successfully delivered
and silenced an endogenous oligodendrocyte target (CNP) in a
specific manner as compared with a control non-specific siRNA;

-- direct central nervous system (CNS) delivery of siRNA in the
rodent model silenced the CNP mRNA by approximately 75
percent, as compared with a control non-specific siRNA, and
was durable for up to one week;

-- CNP silencing was found to be mediated by an RNAi mechanism as
measured by 5'RACE; and

-- in a non-human primate model, direct infusion of an siRNA into
the CNS silenced the CNP mRNA by 55 percent.

Alnylam believes these findings further support the use of RNAi as
a potential therapeutic approach for the treatment of PML.

Delivery

"As we continue to develop novel delivery solutions for RNAi
therapeutics, we are excited by the new data around chemical
modifications for improved efficacy, safety and delivery," said
Muthiah Manoharan, Ph.D., Vice President, Drug Discovery at Alnylam.
"In addition, we are also encouraged by the use of simple
Intralipid(TM) formulations using cholesterol-conjugated siRNAs and
antagomirs which showed promising muscle delivery. Indeed, these data,
with our collaborator Markus Stoffel, suggest an exciting convergence
of conjugation and formulation approaches for systemic delivery of
RNAi therapeutics."

In the talk titled "Translating RNAi," Dr. Manoharan also
presented new data related to the effective delivery of RNAi
therapeutics. Dr. Manoharan showed that among the numerous
carbohydrate modifications to improve the drug-like properties of
siRNAs, 2'-Fluoro modifications consistently provided increased target
binding affinity, endonuclease stability, and, importantly, reduced
immune response. In addition, it is the only modification compared to
other carbohydrate modifications, including locked nucleic acid, or
LNA, that preserves RISC activity when used in both sense and
antisense strands.

Data presented included the following:

-- 2'-Fluoro modified siRNAs are significantly more stable,
thermodynamically and to nucleases in biological fluids, and
can increase the efficacy of siRNAs approximately 2-fold in
vivo; and

-- a 2'-Fluoro modified siRNA targeting Factor VII was found to
produce no immuno-stimulatory response, whereas a
corresponding unmodified siRNA could stimulate IFN-alpha and
TNF-alpha in vitro.

Alnylam has exclusive access to the use of 2'-Fluoro chemistries
for RNAi therapeutics through its 2004 agreement with Isis
Pharmaceuticals, Inc.

In addition, data were presented related to new delivery
approaches for the delivery of RNAi therapeutics. Specifically:

-- a new cationic lipid was developed in collaboration with
Tekmira; a substantial increase in potency of siRNA-containing
lipid particles containing this lipid was observed suggesting
the potential to develop new lipid-based formulations for
systemic delivery of siRNAs with markedly improved potency;

-- PEG conjugation can facilitate delivery of siRNAs to the
intestine; and

-- Alnylam's new lipid particle formulations with new cationic
lipids and PEG modifications continue to improve the
therapeutic potential of siRNAs and antagomirs.

Finally, in a talk titled, "RNAi Based Therapy," Markus Stoffel,
M.D., Ph.D., Professor for Metabolic Diseases at the Institute of
Molecular Systems Biology, Swiss Federal Institute of Technology in
Zurich, member of the Alnylam Scientific Advisory Board and long-term
collaborator of Alnylam, presented new data utilizing
cholesterol-conjugated siRNAs that are co-formulated with commercially
available Intralipid(TM). These new cholesterol-conjugated
siRNA:Intralipid formulations showed distribution to heart and muscle.
Similar results were obtained with single-stranded,
cholesterol-conjugated olionucleotides targeting microRNAs, also
called "antagomirs," including silencing of microRNAs in heart and
muscle.

About RNA Interference (RNAi)

RNAi 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, and 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. In addition, the company is
developing RNAi therapeutics for the treatment of a wide range of
disease areas, including hypercholesterolemia, liver cancers, 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, and Roche. To reflect its outlook for key
scientific, clinical, and business initiatives, Alnylam has
established "RNAi 2010" 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 LLC, 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, visit
www.alnylam.com.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future
expectations, plans, and prospects, including its views with respect
to the robustness, scope, and predictive value of the data presented
at the Keystone Symposium, 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 risks related to:
Alnylam's approach to discover and develop novel drugs, which is
unproven and may never lead to marketable products; Alnylam's ability
to fund and the results of further pre-clinical and clinical trials;
obtaining, maintaining and protecting intellectual property utilized
by its products; Alnylam's ability to enforce its patents against
infringers and to defend its patent portfolio against challenges from
third parties; Alnylam's ability to obtain additional funding to
support its business activities; Alnylam's dependence on third parties
for development, manufacture, marketing, sales, and distribution of
products; the successful development of Alnylam's product candidates,
all of which are in early stages of development; obtaining regulatory
approval for products; competition from others using technology
similar to Alnylam's and others developing products for similar uses;
Alnylam's dependence on collaborators; and its short operating
history; as well as those risks more fully discussed in the "Risk
Factors" section of our most recent report on Form 10-K 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.

Investors:
Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
or
Media:
KMorrisPR
Kathryn Morris, 845-635-9828

Copyright Business Wire 2008