Alnylam Announces New RNAi Therapeutic Program for the Treatment of Hepatitis B Virus (HBV) Infection and Reports an Up to 2.3

  Alnylam Announces New RNAi Therapeutic Program for the Treatment of
  Hepatitis B Virus (HBV) Infection and Reports an Up to 2.3 Log10 Reduction
  of HBV Surface Antigen (HBsAg) in Chronically Infected Chimpanzees

 – New ALN-HBV Program Stems from Alnylam’s Acquisition of Sirna Therapeutics
                                 from Merck –

– Alnylam Expects to Nominate ALN-HBV Development Candidate (DC) with Enhanced
  Stabilization Chemistry (ESC)-GalNAc-Conjugate Delivery Platform by End of
 2014; File Investigational New Drug Application (IND) around Year-End 2015 -

Business Wire

CAMBRIDGE, Mass. -- May 12, 2014

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today that it has named a new program to its pipeline:
ALN-HBV for the treatment of hepatitis B virus (HBV) infection. The new
ALN-HBV program derives from the company’s January 2014 acquisition of Merck’s
RNAi assets, including their Sirna Therapeutics subsidiary. HBV infection
afflicts 400 million people worldwide, with 1 to 2 million people in the U.S.,
and is a leading cause of liver disease and hepatocellular carcinoma (HCC)
worldwide. Despite the use of nucleoside analog inhibitors of viral DNA
synthesis and interferon therapies, less than 10% of patients achieve a
cure^1. Reduction in HBV surface antigen (HBsAg) levels of over 0.5 log10 is
the single best predictor of immunologic cure^2. An RNAi therapeutic targeting
the HBV genome could have the potential to achieve a “functional cure” by
effectively decreasing expression of tolerogenic HBsAg, in addition to
inhibiting all steps of the HBV life cycle. In the most comprehensive
proof-of-concept pre-clinical study results presented to date with an RNAi
therapeutic for the treatment of HBV, Alnylam reported significant, multi-log
reductions in HBV surface antigen (HBsAg) and HBV viral titers, and showed
evidence for an immune-mediated therapeutic effect in chronically infected
chimpanzees.

“Alnylam’s new ALN-HBV program is a mature, pre-clinical asset acquired
through the company’s acquisition of Sirna from Merck. We are very encouraged
by the data we are presenting for the first time today, which we believe
constitute the most robust proof-of-concept pre-clinical data to date with an
RNAi therapeutic for the treatment of HBV,” said Laura Sepp-Lorenzino, Ph.D.,
Vice President, Entrepreneur-in-Residence at Alnylam, and Project Leader of
the ALN-HBV program. “We believe our ALN-HBV RNAi therapeutic represents a
powerful mechanism for inhibiting all steps of the HBV life cycle:
replication, assembly, secretion of virus, and secretion of sub-viral
antigens. The Development Candidate for our ALN-HBV program will employ our
Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, enabling
subcutaneous dose administration with improved potency and durability, and a
wide therapeutic index. We believe that an ESC-GalNAc conjugate can emerge as
the best-in-class approach for RNA therapeutics targeting HBV, and we expect
to name our ALN-HBV Development Candidate by the end of this year and file an
IND or IND equivalent around the end of 2015.”

The new data are being presented at the TIDES 2014 meeting, being held May 12
– 15 in Providence, Rhode Island. The results were from a model of chronically
infected chimpanzees (N=4) showing that RNAi therapeutics targeting a
conserved region of the HBV genome could have the potential of achieving a
functional cure. First, potent siRNAs that target highly conserved regions of
the HBV genome were designed and synthesized. When administered as a single
0.25 mg/kg dose in a lipid nanoparticle (LNP) formulation in chronically
infected chimpanzees, the RNAi therapeutic showed an over 2 log10 reduction in
circulating viral DNA in the highest titer animal and a mean 1.9 log10
decrease in viral DNA. These effects were confirmed to be RNAi specific by use
of a control LNP-encapsulated siRNA, and to be mediated by an RNAi mechanism
of action as detected by 5’RACE. In multi-dose, dose-escalation studies in the
chronically infected animals, doses of 0.125 to 0.5 mg/kg achieved an over 4
log10 reduction of circulating viral DNA and an up to 2.3 log10 reduction in
HBsAg; a mean 2.9 log10 reduction and a mean 2.0 log10 reduction were achieved
in HBV DNA and HBsAg, respectively. In one animal with greater than five-fold
elevated alanine aminotransferase (ALT) levels at baseline, administration of
the RNAi therapeutic was associated with a complete normalization of elevated
transaminase levels. Of interest, two of four animals showed mildly elevated
liver transaminase levels of about two-to-three fold approximately one-to-two
months post dosing that included increases in interferon-gamma and
interleukin-6, suggestive of potential “therapeutic flares” related to immune
clearance of infected hepatocytes.

“HBV infection is a major global health issue, affecting approximately 400
million people. As a leading cause of liver disease and liver cancer
worldwide, significant unmet need exists for novel HBV therapies,” said Graham
Foster, Ph.D., FRCP, Professor of Hepatology at Queen Mary University of
London. “Because of its unique mechanism of action to inhibit key steps in the
viral life cycle, an RNAi approach targeting the HBV genome could offer the
potential for significant efficacy in the treatment of HBV, and a potential
route to a functional cure.”

Alnylam plans to advance an ESC-GalNAc-siRNA conjugate targeting the HBV
genome for its ALN-HBV program. An ESC-GalNAc-siRNA conjugate will enable
subcutaneous dose administration with improved potency and durability, and a
wide therapeutic index. The company expects to select a Development Candidate
(DC) in late 2014 and plans to file an IND or IND equivalent around year end
2015.

About Hepatitis B Virus (HBV) Infection

Hepatitis B is the most common serious liver infection in the world.
Worldwide, 2 billion people (1 out of 3 people) have been infected with
hepatitis B and 400 million people have become chronically infected. An
estimated 1 million people die each year from hepatitis B and its
complications worldwide; about 5,000 of those are in the U.S. The clinical
manifestations are severe. Worldwide, chronic infection with hepatitis causes
80% of all hepatocellular carcinoma (HCC) and more than 500,000 people die
each year from this lethal cancer. About 5% of the population are chronic
carriers of HBV, and nearly 25% of all carriers develop serious liver diseases
such as chronic hepatitis, cirrhosis, and HCC. HBV infection causes more than
1 million deaths every year. With today’s medicines, the cure rate for chronic
HBV infection is less than 10%. An RNAi therapeutic targeting the HBV genome
has the potential to achieve a “functional cure” by inhibiting all steps of
the HBV life cycle.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc
Conjugates

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. Alnylam’s Enhanced
Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous
dosing with increased potency and durability, and a wide therapeutic index.
This delivery platform is being employed in several of Alnylam’s genetic
medicine programs, including programs in clinical development.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi
therapeutic products using LNP technology.

About 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 as
genetic medicines, including programs as part of the company’s “Alnylam 5x15™”
product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics
directed toward genetically defined targets for the treatment of serious,
life-threatening diseases with limited treatment options for patients and
their caregivers. These include: patisiran (ALN-TTR02), an intravenously
delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of
TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic
polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic
targeting TTR for the treatment of ATTR in patients with TTR cardiac
amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile
systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting
antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders
(RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic
targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic
porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi
therapeutic targeting PCSK9 for the treatment of hypercholesterolemia;
ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the
treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed
hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic
targeting apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; and other programs yet to be disclosed. As part of its
“Alnylam 5x15” strategy, as updated in early 2014, the company expects to have
six to seven genetic medicine product candidates in clinical development -
including at least two programs in Phase 3 and five to six programs with human
proof of concept - by the end of 2015. Alnylam is also developing ALN-HBV, an
RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the
treatment of HBV infection. The company’s demonstrated commitment to RNAi
therapeutics has enabled it to form major alliances with leading companies
including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko
Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and
Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics,
a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity
position in Regulus Therapeutics Inc., a company focused on discovery,
development, and commercialization of microRNA therapeutics. Alnylam
scientists and collaborators have published their research on RNAi
therapeutics in over 200 peer-reviewed papers, including many in the world’s
top scientific journals such as Nature, Nature Medicine, Nature Biotechnology,
Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002,
Alnylam maintains headquarters in Cambridge, Massachusetts. For more
information, please visit www.alnylam.com.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam’s future
expectations, plans and prospects, including without limitation, Alnylam’s
views with respect to the potential for RNAi therapeutics, including ALN-HBV
for treatment of HBV, its expectations with respect to further advancing
ALN-HBV in development, the filing of an IND application for ALN-HBV, its
expectations with respect to the timing and success of clinical trials with
ALN-HBV, its expectations regarding the potential market opportunity for
ALN-HBV, its expectations regarding its “Alnylam 5x15” product strategy, and
its plans regarding commercialization of RNAi therapeutics, 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 manage operating expenses, Alnylam’s ability to discover
and develop novel drug candidates and delivery approaches, successfully
demonstrate the efficacy and safety of its drug candidates, the pre-clinical
and clinical results for its product candidates, which may not support further
development of product candidates, actions of regulatory agencies, which may
affect the initiation, timing and progress of clinical trials, obtaining,
maintaining and protecting intellectual property, Alnylam’s ability to enforce
its patents against infringers and defend its patent portfolio against
challenges from third parties, obtaining regulatory approval for products,
competition from others using technology similar to Alnylam’s and others
developing products for similar uses, Alnylam’s ability to obtain additional
funding to support its business activities and establish and maintain
strategic business alliances and new business initiatives, Alnylam’s
dependence on third parties for development, manufacture, marketing, sales and
distribution of products, the outcome of litigation, and unexpected
expenditures, as well as those risks more fully discussed in the “Risk
Factors” filed with Alnylam’s most recent Quarterly Report on Form 10-Q filed
with the Securities and Exchange Commission (SEC) and in other filings that
Alnylam makes with the SEC. 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 explicitly disclaims
any obligation to update any forward-looking statements.

^1 Perrillo, R., "The benefits and risks of interferon therapy for hepatitis
B" Hepatology 49: S103-111 (2009)

^2 Seto WK, Wong DK, Fung J, et al. A large case-control study on the
predictability of hepatitis B surface antigen levels three years before
hepatitis B surface antigen seroclearance. Hepatology 56: 812-819 (2012);

Contact:

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
or
Media
Spectrum
Liz Bryan, 202-955-6222 x2526
 
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