Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, and The Alpha-1 Project (TAP), the venture philanthropy
subsidiary of the Alpha-1 Foundation, announced today that they have
entered into a collaboration agreement for the continued advancement of
ALN-AAT, a subcutaneously administrated RNAi therapeutic in development
for the treatment of alpha-1 antitrypsin (AAT) deficiency-associated
liver disease. TAP’s mission is to work with patients, academia,
pharmaceutical and biotech companies, and public health organizations in
the pursuit of cures and therapies for chronic obstructive pulmonary
disease (COPD) and liver disease caused by AAT deficiency. TAP is
partially funding research activities for ALN-AAT. Detailed financial
terms of the research agreement were not disclosed. Alnylam remains on
track to file an investigational new drug (IND) application for this
program in mid-2015.
“We have assembled what we believe to be the industry’s most robust
pre-clinical data package supporting advancement of ALN-AAT – an
‘Enhanced Stabilization Chemistry’ or ‘ESC’-GalNAc-siRNA conjugate
targeting AAT – including results in rodent models that demonstrate
knockdown of the disease-causing Z-allele and significant lowering of
the mutant protein (Z-AAT) burden in the liver, with associated
improvements in liver function, as seen by normalization of the
proliferative index, improved liver pathology, attenuated tissue
fibrosis, and decreased incidence of liver tumor formation. In addition,
we believe we have confirmed the activity of ALN-AAT in non-human
primate models and expect our Development Candidate to achieve human
target gene knockdown at doses less than 1 mg/kg with a once-monthly
dose regimen or better. Since our GalNAc-siRNA platform is clinically
validated based on results from other Alnylam RNAi therapeutic programs,
we have a high level of confidence that ALN-AAT can achieve potent
knockdown of the disease-causing Z-allele protein with subcutaneous dose
administration and a favorable safety profile,” said Akshay Vaishnaw,
M.D., Ph.D., Executive Vice President and Chief Medical Officer of
Alnylam. “Accordingly, we are fully committed to the continued
advancement of our RNAi therapeutic to patients with AAT deficiency with
associated liver disease. This new recognition from TAP, part of the
leading patient advocacy group for people afflicted with AAT deficiency,
brings our efforts closer to patients in need and to their caregivers.
We continue to expect that we will file our IND or IND equivalent for
ALN-AAT in mid-2015.”
ALN-AAT is one of Alnylam’s genetic medicine programs, which are RNAi
therapeutics directed toward genetically defined targets for the
treatment of diseases with high unmet medical need. Alnylam pioneered
the application of RNAi therapeutics toward genetically defined targets
expressed in the liver as part of the company’s “Alnylam 5x15” product
strategy. AAT deficiency-associated liver disease is caused by
accumulation of mutant AAT protein (“Z-allele” or “Z-AAT”) in liver
tissue with subsequent liver injury, fibrosis, cirrhosis, and, in some
cases, hepatocellular carcinoma. It is estimated that approximately
10,000 to 20,000 people with AAT deficiency in the U.S. and E.U. have
associated liver pathology.
“I applaud Alnylam for its efforts to develop a therapeutic for Alphas
with liver disease, as there are few options available for them today.
The Alpha-1 community is in desperate need of a treatment to improve the
quality of life for both pediatric and adult liver patients,” said John
Walsh, CEO and co-founder of the Alpha-1 Foundation.
Pre-clinical data from Alnylam’s ALN-AAT program were first presented
at the Annual Meeting of the American Association for the Study of Liver
Diseases (AASLD, “The Liver Meeting”) in November 2013 and were most
recently updated
at Digestive Disease Week (DDW) in May 2014. Amongst other results
presented, these data in rodent studies showed that administration of
ALN-AAT was associated with a potent and dose-dependent knockdown of
serum AAT (a surrogate for AAT knockdown in the liver) with a
single-dose ED50 of 0.5 mg/kg. In multi-dose rodent
experiments, subcutaneous administration at 0.5 mg/kg resulted in
approximately 90% knockdown of serum AAT. In addition, initial
single-dose NHP results were performed showing dose-dependent knockdown
of serum AAT with an ED50 of less than 3 mg/kg; these results
are expected to support a multi-dose ED50 of less than 0.3
mg/kg. ALN-AAT employs Alnylam’s ESC-GalNAc-conjugate technology,
enabling subcutaneous administration with a wide therapeutic index.
Alnylam’s GalNAc-siRNA conjugate platform has been clinically validated
for both activity and tolerability through the company’s ALN-TTRsc (an
RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR
cardiac amyloidosis; currently in Phase 2) and ALN-AT3 (an RNAi
therapeutic targeting antithrombin for the treatment of hemophilia and
rare bleeding disorders; currently in Phase 1) programs.
“TAP is very pleased to collaborate with Alnylam Pharmaceuticals. Their
cutting-edge work on a therapy for liver disease brings us closer to
finding a cure for Alpha-1 Antitrypsin Deficiency, thus fulfilling our
mission,” said Jean-Marc Quach, Executive Director for The Alpha-1
Project.
About Alpha-1 Antitrypsin (AAT) and AAT Deficiency
Alpha-1 antitrypsin deficiency is an autosomal disorder that results in
disease of the lungs and liver. AAT is a liver-produced serine
proteinase inhibitor with the primary function of protecting the lungs
from neutrophil elastase and other irritants that cause inflammation. In
the liver, misfolding of the mutant Z-AAT protein hinders its normal
release into the blood thereby causing it to aggregate in hepatocytes,
leading to liver injury, fibrosis, cirrhosis, and hepatocellular
carcinoma (HCC). A deficient serum level of the protein can render the
lungs susceptible to emphysema. About 95% of people with alpha-1
antitrypsin deficiency are homozygous and carry two copies of the
abnormal Z allele (PiZZ). There are estimated to be approximately
200,000 people who are PiZZ in the U.S. and major European countries,
and of these, at least 10% have an associated liver pathology caused by
the misfolded protein encoded by the pathogenic Z-allele. Treatment for
lung disease associated with AAT deficiency consists of routine
emphysema care and, in some instances, augmentation therapy, which
utilizes purified AAT from the plasma of healthy donors to increase
circulating and airway levels of AAT to help restore its function in the
lungs. The only treatment options presently available for patients with
cirrhosis caused by mutant AAT accumulation in the liver are supportive
care and, in the case of advanced cirrhosis, liver transplantation.
RNAi-mediated inhibition of AAT in AAT-deficient PiZZ patients may
represent a promising new way to treat this rare disease.
About The Alpha-1 Project
Mission statement: The Alpha-1 Project will work with patients,
academia, pharmaceutical and biotech companies, and public health
organizations in the relentless pursuit of cures and therapies for COPD
and liver disease caused by Alpha-1 Antitrypsin Deficiency. For more
information, visit www.thealpha-1project.com.
The Alpha-1 Project is a wholly-owned for-profit subsidiary of the
Alpha-1 Foundation. For more information on the Foundation, visit www.alpha-1foundation.org.
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, durability, and a
wide therapeutic index, and is being employed in several of Alnylam’s
genetic medicine programs, including programs in clinical development.
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 5x15TM” 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
aminolevulinic acid 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.
About “Alnylam 5x15™” and Genetic Medicines
The “Alnylam 5x15” strategy, launched in January 2011, establishes a
path for development and commercialization of novel RNAi therapeutics as
genetic medicines. Alnylam’s genetic medicine programs are RNAi
therapeutics directed toward genetically defined targets for the
treatment of diseases with high unmet medical need. These programs share
several key characteristics including: a genetically defined target and
disease expressed in the liver; the potential to have a major impact in
a high unmet need population; the ability to leverage the existing
Alnylam RNAi platform with clinically proven delivery to the liver; the
opportunity to monitor an early biomarker in Phase 1 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.
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. The “Alnylam 5x15” programs
include: patisiran (ALN-TTR02), an intravenously delivered RNAi
therapeutic targeting transthyretin (TTR) in development for the
treatment of TTR-mediated amyloidosis (ATTR) in patients with familial
amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered
RNAi therapeutic targeting TTR in development 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) in development for the
treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an
RNAi therapeutic targeting complement component C5 in development for
the treatment of complement-mediated diseases; ALN-AS1, an RNAi
therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) in
development for the treatment of hepatic porphyrias including acute
intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting
PCSK9 in development 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 in development 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, a subcutaneously administered RNAi therapeutic targeting
apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; and other programs yet to be disclosed. In 2014,
Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic
alliance on Alnylam's genetic medicine programs. Specifically, Alnylam
will lead development and commercialization of programs in North America
and Europe, while Genzyme will develop and commercialize products in the
rest of world. In addition, Alnylam and Genzyme will co-develop and
co-commercialize ALN-TTRsc in North America and Europe.
Alnylam Forward-Looking Statements
Various statements in this 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-AAT for the treatment of AAT deficiency-associated liver
disease, its expectations with respect to timing of regulatory filings
for ALN-AAT, the potential therapeutic opportunities for ALN-AAT, its
expectations regarding its “Alnylam 5x15” product strategy, and its
plans regarding commercialization of RNAi therapeutics, including
ALN-AAT, 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.
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