– Company Expects to Present Initial Clinical
Results in Early 2016 –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today that it has initiated a Phase
1/2 clinical trial with ALN-AAT, a subcutaneously administered
investigational RNAi therapeutic targeting alpha-1 antitrypsin
(AAT) for the treatment of AAT deficiency-associated liver disease
(alpha-1 liver disease). The Phase 1/2 trial will be conducted
initially in normal healthy volunteers, and, then, in patients with
alpha-1 liver disease. Initiation of this trial is based on
encouraging pre-clinical data presented at the Digestive Disease
Week (DDW) meeting May 16 – 19, 2015. The company expects to
present initial clinical data from this trial in early 2016.
“We believe ALN-AAT has the potential to be a transformative
therapy for patients with alpha-1 liver disease, an increasingly
recognized clinical manifestation of alpha-1 antitrypsin deficiency
where liver transplantation is the only available treatment option.
Our pre-clinical results, including new data presented at this
year’s DDW meeting, demonstrate that monthly subcutaneous dosing of
ALN-AAT achieves robust knockdown of serum AAT – the
disease-causing protein – of up to 93% in NHPs, with highly durable
effects and a wide therapeutic index. We are aiming to replicate
these results in our Phase 1/2 study,” said Akshay Vaishnaw, M.D.,
Ph.D., Executive Vice President of R&D and Chief Medical
Officer of Alnylam. “ALN-AAT is now the seventh clinical program in
our rapidly growing pipeline of investigational RNAi therapeutics.
We expect to share initial data from the Phase 1/2 trial in early
2016.”
“There is great unmet need for any specific treatment for
patients with alpha-1-antitrypsin deficiency and liver disease,
which is caused by misfolding of the mutated Z-antitrypsin protein;
accumulation of the misfolded protein in liver cells causes
irreversible hepatocyte damage which leads to advanced liver
disease in many. Alpha-1 liver disease can manifest as cholestasis,
chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and
occurs in both children and adults where it is currently managed
with supportive care or, in the case of liver failure, with liver
transplantation,” said Professor Graeme Alexander, Consultant
Hepatologist, Cambridge University Hospitals, Cambridge, UK. “I am
encouraged by the pre-clinical data with ALN-AAT, and hope these
results can be repeated in patient studies. This investigational
RNAi therapeutic has the potential to become an important treatment
option for the management of alpha-1 antitrypsin deficiency related
liver disease.”
ALN-AAT is a subcutaneously administered investigational RNAi
therapeutic that utilizes Alnylam’s proprietary ESC-GalNAc-siRNA
conjugate delivery technology. ESC-GalNAc-siRNA conjugates are
designed to achieve targeted delivery of RNAi therapeutics to
hepatocytes through uptake by the asialoglycoprotein receptor, and
enable subcutaneous dosing with increased potency and durability
and a wide therapeutic index.
As per the filed CTA, the Phase 1/2 trial of ALN-AAT is a
randomized, single-blind, placebo-controlled study being conducted
in three parts. Parts A and B are single-dose (Part A) and
multi-dose (Part B), dose-escalation studies, designed to enroll up
to a total of 48 healthy adult volunteers. Part C will be a
multi-dose study designed to enroll up to a total of 24 adults with
alpha-1 liver disease and mild-to-moderate liver fibrosis. The
primary objective of the study is to evaluate safety and
tolerability of single and multiple subcutaneous doses of ALN-AAT.
Secondary objectives include evaluation of pharmacokinetics and
clinical activity for ALN-AAT as measured by knockdown of serum
AAT. In addition, biopsies will be obtained from subjects with
alpha-1 liver disease to quantify the effects of treatment on
levels of periodic acid-Schiff (PAS)-stained globules, a measure of
misfolded AAT accumulation observed in the livers of alpha-1 liver
disease patients.
“The Alpha-1 community is in clear need of a treatment option to
improve the disease course and quality of life for both children
and adults with Alpha-1 liver disease,” said John Walsh, CEO
and co-founder of the Alpha-1 Foundation. “We are all pleased with
Alnylam’s progress to date with ALN-AAT, and will continue to
closely follow this program through the course of its clinical
development.”
Genzyme Alliance
In January 2014, Alnylam and Genzyme, a Sanofi company,
formed an alliance to accelerate and expand the development and
commercialization of RNAi therapeutics across the world. The
alliance is structured as a multi-product geographic alliance in
the field of rare diseases. Alnylam retains product rights
in North America and Western Europe, while Genzyme
obtained the right to access certain programs in Alnylam's current
and future Genetic Medicines pipeline, including ALN-AAT, in the
rest of the world. In certain defined instances, Genzyme has
co-development/co-commercialization and/or global product rights.
Genzyme's rights are structured as an opt-in that is triggered upon
achievement of human proof-of-principle.
About Alpha-1 Antitrypsin (AAT), AAT Deficiency, and Alpha-1
Liver Disease
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. About 95% of people with alpha-1 antitrypsin
deficiency are homozygous and carry two copies of the abnormal Z
allele (PiZZ) which expresses the Z-AAT protein. 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). There are estimated to be approximately 120,000
individuals with the PiZZ mutation in the U.S. and major European
countries, and of these, about 10% have an associated liver
pathology (alpha-1 liver disease) caused by the misfolded Z-AAT
protein. The only treatment options presently available for alpha-1
liver disease patients are supportive care and, in the case of
advanced cirrhosis, liver transplantation. RNAi-mediated inhibition
of AAT in people with alpha-1 liver disease 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 and durability, and a wide
therapeutic index. This delivery platform is being employed in
nearly all of Alnylam's pipeline 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. Alnylam’s pipeline of investigational RNAi therapeutics
is focused in 3 Strategic Therapeutic Areas (STArs): Genetic
Medicines, with a broad pipeline of RNAi therapeutics for the
treatment of rare diseases; Cardio-Metabolic Disease, with a
pipeline of RNAi therapeutics toward genetically validated,
liver-expressed disease targets for unmet needs in cardiovascular
and metabolic diseases; and Hepatic Infectious Disease, with a
pipeline of RNAi therapeutics that address the major global health
challenges of hepatic infectious diseases. In early 2015, Alnylam
launched its “Alnylam 2020” guidance for the advancement and
commercialization of RNAi therapeutics as a whole new class of
innovative medicines. Specifically, by the end of 2020, Alnylam
expects to achieve a company profile with 3 marketed products, 10
RNAi therapeutic clinical programs – including 4 in late stages of
development – across its 3 STArs. The company’s demonstrated
commitment to RNAi therapeutics has enabled it to form major
alliances with leading companies including Merck, Medtronic,
Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and
Genzyme, a Sanofi company. 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, New England
Journal of Medicine, and The Lancet. Founded in 2002, Alnylam
maintains headquarters in Cambridge, Massachusetts. For more
information about Alnylam’s pipeline of investigational RNAi
therapeutics, please visit www.alnylam.com.
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 regarding the
reporting of initial data from its ALN-AAT Phase 1/2 clinical
study, its expectations regarding the potential market opportunity
for ALN-AAT, its expectations regarding its STAr pipeline growth
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 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 be replicated or
continue to occur in other subjects or in additional studies or
otherwise 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 manage operating expenses, 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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Alnylam Pharmaceuticals, Inc.Michael Mason,
617-551-8327Vice President, Finance and
TreasurerorMedia:SpectrumLiz Bryan, 202-955-6222 x2526
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