Alnylam Files Clinical Trial Application to Initiate a Phase I Study for ALN-TTRsc, a Subcutaneously Administered RNAi

  Alnylam Files Clinical Trial Application to Initiate a Phase I Study for
  ALN-TTRsc, a Subcutaneously Administered RNAi Therapeutic Targeting
  Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR)

    – Company Expects to Initiate Phase I Study in Early 2013 with Data in
                                  Mid-2013 –

Business Wire

CAMBRIDGE, Mass. -- January 3, 2013

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has filed a Clinical Trial Application (CTA)
with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to
initiate a Phase I clinical trial with ALN-TTRsc, an RNAi therapeutic
targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis
(ATTR). ALN-TTRsc is a subcutaneously administered RNAi therapeutic that
comprises an siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc)
ligand. 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. ALN-TTRsc is
the first GalNAc-siRNA to enter clinical development stages. Following
approval of the CTA, Alnylam expects to initiate a Phase I study with
ALN-TTRsc early in 2013 with data expected to be reported in mid-2013.

“RNAi therapeutics hold great promise for the treatment of ATTR due to their
ability of achieving rapid, potent, and durable knockdown of TTR, the
disease-causing protein. At Alnylam, we are committed to advancing an industry
leading effort for patients with ATTR. Accordingly we are advancing both
ALN-TTR02, an intravenously administered RNAi therapeutic currently in a Phase
II clinical trial in patients, and now ALN-TTRsc, a subcutaneously
administered RNAi therapeutic,” said Akshay Vaishnaw, M.D., Ph.D., Executive
Vice President and Chief Medical Officer of Alnylam. “This CTA filing for
ALN-TTRsc marks our first for an RNAi therapeutic that utilizes our
proprietary GalNAc conjugate delivery platform enabling subcutaneous dose
administration. Our pre-clinical studies with ALN-TTRsc have confirmed the
ability of achieving over 80% TTR knockdown at single digit mg/kg doses with a
very wide therapeutic index. We very much look forward to the continued
advancement of ALN-TTRsc, including the start of this Phase I clinical trial
in healthy volunteers early in the year with data expected mid-year.”

ATTR is an autosomal dominant inherited disease caused by mutations in the TTR
gene, which is expressed predominantly in the liver and results in the
accumulation of pathogenic deposits of mutant and wild-type TTR protein in
multiple extra-hepatic tissues, including the peripheral nervous system,
gastrointestinal tract, and heart. Pre-clinical studies have shown that
subcutaneous administration of ALN-TTRsc resulted in potent and sustained
suppression of TTR. In non-human primates, ALN-TTRsc was administered in a
loading dose regimen of once a day for five days, followed by a maintenance
dose regimen of once a week for four weeks resulting in an approximately 80%
reduction of TTR at doses as low as 2.5 mg/kg. TTR knockdown was achieved
rapidly, with nadir TTR levels observed at about day 14. Suppression of TTR of
approximately 80% was sustained with the weekly maintenance dose, and recovery
to baseline levels was observed at day 40 after the last dose. At an ED[80]
dose of 2.5 mg/kg and based on solubility of the GalNAc-siRNA, subcutaneous
administration of ALN-TTRsc is expected to be achieved in human studies at a
dose volume of approximately 1 mL. In single dose and multi-dose pre-clinical
safety studies in rodents and non-human primates, ALN-TTRsc was found to be
generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg
in non-human primates, ALN-TTRsc was well tolerated with no clinical signs, no
adverse laboratory or histopathologic findings, no elevations in cytokines or
complement, and no significant injection site reactions.

“ATTR presents a tremendous unmet medical need and is an example of a disease
caused by overproduction of a mutant protein. RNAi therapeutics represent a
novel and compelling approach for the treatment of ATTR, as they have been
shown to achieve robust knockdown of serum levels of both wild-type and mutant
TTR,” said Philip Hawkins, FMedSci., Professor of Medicine, University College
London Medical School. “I am encouraged by the clinical data to date with
ALN-TTR02 and the pre-clinical data shown with ALN-TTRsc. As such, I look
forward to the clinical translation of this new RNAi therapeutic, as it
represents a promising potential treatment option for patients suffering from
this disease.”

As per the filed CTA, the Phase I trial of ALN-TTRsc is planned to be
conducted in the U.K. as a randomized, double-blind, placebo-controlled,
single- and multi-dose, dose-escalation study, enrolling up to 40 healthy
volunteer subjects. The primary objective of the study is to evaluate the
safety and tolerability of single and multiple doses of subcutaneously
administered ALN-TTRsc. Secondary objectives include assessment of clinical
activity of the drug as measured by serum TTR levels.

About Transthyretin-Mediated Amyloidosis
Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and fatal disease caused by mutations in the TTR gene. TTR
protein is produced primarily in the liver and is normally a carrier for
thyroid hormones and retinol binding proteins. Mutations in TTR cause abnormal
amyloid proteins to accumulate and damage body organs and tissue, such as the
peripheral nerves and heart, resulting in intractable peripheral sensory
neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a
major unmet medical need with significant morbidity and mortality; familial
amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide
and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people
worldwide. FAP patients have a life expectancy of five to 15 years from
symptom onset, and the only treatment options for early stage disease are
liver transplantation and tafamidis (approved in Europe). The mean survival
for FAC patients is approximately 2.5 years, and there are no approved
therapies. As a result, there is a significant need for novel therapeutics to
treat patients who have inherited mutations in the TTR gene.

About GalNAc Conjugates
GalNAc-siRNAs are designed to achieve targeted delivery of RNAi therapeutics
to hepatocytes through uptake by the asialoglycoprotein receptor. Research
findings demonstrate potent and durable target gene silencing, as well as a
wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from
multiple ‘Alnylam 5x15’ programs. Notably, GalNAc-siRNAs are being employed in
Alnylam’s ALN-TTRsc and ALN-AT3 RNAi therapeutic programs for the treatment of
transthyretin-mediated amyloidosis (ATTR) and hemophilia and rare bleeding
disorders, respectively, both of which the company expects to have in clinical
trials in 2013. GalNAc-siRNAs are a proprietary Alnylam delivery platform.

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 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 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 for
the treatment of genetically defined diseases, including ALN-TTR for the
treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the
treatment of hemophilia, ALN-PCS for the treatment of severe
hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and
ALN-TMP for the treatment of hemoglobinopathies. As part of its “Alnylam
5x15^TM” strategy, the company expects to have five RNAi therapeutic products
for genetically defined diseases in clinical development, including programs
in advanced stages, on its own or with a partner by the end of 2015. Alnylam
has additional partnered programs in clinical or development stages, including
ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection,
ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of
Huntington’s disease. The company’s leadership position on RNAi therapeutics
and intellectual property have enabled it to form major alliances with leading
companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda,
Kyowa Hakko Kirin, Cubist, Ascletis, Monsanto and Genzyme. In addition,
Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on
discovery, development, and commercialization of microRNA therapeutics;
Regulus has formed partnerships with GlaxoSmithKline, Sanofi, AstraZeneca and
Biogen Idec. Alnylam has also formed Alnylam Biotherapeutics, a division of
the company focused on the development of RNAi technologies for applications
in biologics manufacturing, including recombinant proteins and monoclonal
antibodies. Alnylam’s VaxiRNA™ platform applies RNAi technology to improve the
manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in
this effort. Alnylam scientists and collaborators have published their
research on RNAi therapeutics in over 100 peer-reviewed papers, including many
in the world’s top scientific journals such as Nature, Nature Medicine, Nature
Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in
Cambridge, Massachusetts. For more information, please visit

About “Alnylam 5x15™”
The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for
development and commercialization of novel RNAi therapeutics to address
genetically defined diseases with high unmet medical need. Products arising
from this initiative share several key characteristics including: a
genetically defined target and disease; the potential to have a major impact
in a high unmet need population; the ability to leverage the existing Alnylam
RNAi delivery platform; the opportunity to monitor an early biomarker in Phase
I clinical trials for human proof of concept; and the existence of clinically
relevant endpoints for the filing of a new drug application (NDA) with a
focused patient database and possible accelerated paths for commercialization.
By the end of 2015, the company expects to have five such RNAi therapeutic
programs in clinical development, including programs in advanced stages, on
its own or with a partner. The “Alnylam 5x15” programs include ALN-TTR for the
treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the
treatment of hemophilia, ALN-PCS for the treatment of severe
hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and
ALN-TMP for the treatment of hemoglobinopathies. Alnylam intends to focus on
developing and commercializing certain programs from this product strategy
itself in the United States and potentially certain other countries; the
company will seek development and commercial alliances for other core programs
both in the United States and in other global territories.

Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam’s future expectations,
plans and prospects, including without limitation, statements regarding
Alnylam’s views with respect to the potential for RNAi therapeutics and its
proprietary GalNAc-siRNA delivery platform, its expectations regarding the
development of ALN-TTR02, ALN-TTRsc, and ALN-AT3, the filing of a CTA with the
MHRA to initiate a Phase I clinical trial with ALN-TTRsc and the expected
timing of regulatory clearance and clinical trial initiation for ALN-TTRsc,
its expectations with respect to the timing and success of its clinical
trials, including for ALN-TTR02, ALN-TTRsc, and ALN-AT3, its expectations
regarding the reporting of data from its ALN-TTRsc clinical trial, and its
expectations regarding its “Alnylam 5x15” product strategy, 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, successfully
demonstrate the safety and efficacy of its drug candidates, including drug
candidates utilizing GalNAc-siRNA delivery, the pre-clinical and clinical
results for these product candidates, which may not support further
development of such product candidates, actions of regulatory agencies, which
may affect the initiation, timing and progress of clinical trials for such
product candidates, obtaining, maintaining and protecting intellectual
property, obtaining regulatory approval for products, competition from others
using technology similar to Alnylam’s and others developing products for
similar uses, and Alnylam’s ability to establish and maintain strategic
business alliances and new business initiatives, 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.


Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
Amanda Sellers (Media), 202-955-6222 x2597
Press spacebar to pause and continue. Press esc to stop.