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 cure1.
Reduction in HBV surface antigen (HBsAg) levels of over 0.5 log10 is the
single best predictor of immunologic cure2. 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);
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