– Company Guides that it Plans to Initiate
Phase 1/2 Trial in Late 2015 and Report Initial Clinical Results in
Early 2016 –
– New Pre-Clinical Data with ALN-AAT Presented
at Digestive Disease Week (DDW) Meeting, Showing Robust Knockdown
of Serum AAT of Up to 93% with Monthly Subcutaneous Dosing in
Non-Human Primates and a Wide Therapeutic Index –
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 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). As per the CTA filing, the intended clinical study of
ALN-AAT will be performed in normal healthy volunteers, and, then,
in subjects with alpha-1 liver disease. ALN-AAT now becomes the
company’s sixth clinical stage program in its Genetic Medicine
Strategic Therapeutic Area (STAr), the seventh clinical pipeline
program overall, and the fifth clinical program employing the
company’s Enhanced Stabilization Chemistry (ESC)-GalNAc delivery
technology. Consistent with previous guidance, the company expects
that following approval of the CTA, it will initiate the Phase 1/2
study in late 2015, with initial data expected to be reported in
early 2016. In addition, Alnylam scientists presented new
pre-clinical data in an oral presentation at the Digestive Disease
Week (DDW) meeting, held May 16 – 19, 2015 in Washington, D.C.
Amongst other reported research findings, new data showed a robust
knockdown of serum AAT of up to 93% in non-human primates (NHPs)
with monthly subcutaneous dosing and a wide therapeutic index.
“We believe ALN-AAT holds considerable promise as a novel
therapeutic approach for the treatment of alpha-1 liver disease, an
increasingly recognized clinical manifestation of
alpha-1-antitrypsin deficiency where there is a significant unmet
need and 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 doses 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. In earlier
reported and recently updated studies, we’ve demonstrated that
ALN-AAT can reduce liver levels of mutant AAT, improve
histopathology associated with mutant AAT expression, and reduce
liver fibrosis and the incidence of tumor formation in a mouse
model of alpha-1 liver disease,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President of R&D and Chief Medical Officer of
Alnylam. “The filing of this new CTA also highlights the
reproducible and modular features of Alnylam’s platform, as ALN-AAT
now becomes our sixth clinical stage program in our Genetic
Medicine STAr, our seventh clinical pipeline program overall, and
the fifth clinical program employing our ESC-GalNAc delivery
technology. We very much look forward to the continued advancement
of this program toward the clinic, consistent with our guidance
where we expect to start the Phase 1/2 trial in late 2015, with
initial clinical results expected to be reported in early
2016.”
“Alpha-1 liver disease is caused by expression of the mutant ‘Z
allele’ of the AAT gene and misfolding of the Z-AAT protein, which
then accumulates in liver cells and causes cellular damage.
Individuals who are homozygous for the mutant Z allele make up
approximately 95% of all people with AAT deficiency liver disease.
These individuals have a lifetime risk of liver disease of 10% to
50%, which can manifest as cholestatic disease, chronic hepatitis,
cirrhosis, and hepatocellular carcinoma. Severe liver disease can
occur in both children and adults and is currently managed with
supportive care, or in the case of liver failure, with liver
transplantation. Clearly, there is a very high unmet need for novel
therapies for alpha-1 liver disease,” said Jeffrey Teckman,
M.D., Professor in the Department of Pediatrics and
Director of Pediatric Gastroenterology and Hepatology at Saint
Louis University School of Medicine. “I am encouraged by the
pre-clinical data with ALN-AAT, and if these results extend in
clinical studies, I believe that this investigational RNAi
therapeutic has the potential to become an important treatment
option for the management of alpha-1 liver disease. I am also
pleased with Alnylam’s commitment to advance this candidate to
clinical stages, bringing a new potential treatment option forward
for patients.”
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 will be a randomized, single-blind,
placebo-controlled study conducted in three parts. Parts A and B
will be 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 in
adults with the PiZZ mutation in their AAT gene and with
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 of ALN-AAT 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 AAT misfolding
observed in the livers of alpha-1 liver disease patients.
In an oral presentation at DDW, Alnylam scientists presented new
data demonstrating an up to 93% knockdown of serum AAT (mean 90 ±
2%) following monthly subcutaneous dosing with ALN-AAT in NHPs at a
dose of 3 mg/kg. This level of knockdown was highly durable,
lasting for greater than 30 days following the final dose. Further,
ALN-AAT was found to have a wide therapeutic index based on results
from GLP toxicology studies. Specifically, 13-week studies were
performed in the rat and NHP with q2W doses and showed No Adverse
Effect Levels (NOAELs) of greater than or equal to 50 mg/kg and 150
mg/kg, respectively; these dose levels were the top doses in both
studies. In addition, study results were reported from a transgenic
mouse model of alpha-1 liver disease, where mice overexpress the
human Z-AAT protein. A single subcutaneous dose of ALN-AAT led to
dose-dependent, durable and reversible knockdown of Z-AAT, with an
ED50 of ~0.5 mg/kg, with mean Z-AAT knockdown of greater than 90%
achieved following a single subcutaneous dose of 3mg/kg. As
previously presented, sustained reduction of Z-AAT in aged
transgenic mice with established liver disease led to improvement
in tissue pathology, decrease in fibrosis, decrease in number of
proliferating hepatocytes, and reduction in tumor burden as
measured by both number and size of tumors.
“We 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 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, including
the filing of this CTA, and we look forward to following the
progress of this program through the course of its clinical
development.”
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 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 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,
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Bryan, 202-955-6222 ext. 2526 (Media)
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