Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it is advancing its Development Candidate
(DC) for ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin
(AAT) in development for the treatment of AAT deficiency-associated
liver disease. New pre-clinical
data were presented in a Late-Breaking Abstract Session at Digestive
Disease Week (DDW), held May 3 – 6, 2014 in Chicago, Illinois. 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. 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 12,000 people with AAT
deficiency in the U.S. and E.U. have associated liver pathology. The
company now plans to initiate IND-enabling studies with the goal of
filing an IND or IND equivalent for ALN-AAT in mid-2015.
“Our pre-clinical research efforts have now led to the selection of a DC
in our ALN-AAT program, which is part of our genetic medicine pipeline.
This is important progress since we believe ALN-AAT holds considerable
promise as a novel therapeutic approach for the treatment of liver
disease associated with AAT deficiency, an increasingly recognized
problem where there is significant unmet need. Our pre-clinical results,
including new data presented at the DDW meeting, demonstrate that RNAi
therapeutics targeting 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
disease; additional data have been generated in non-human primates,”
said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead
Development at Alnylam. “We very much look forward to the continued
advancement of this program toward the clinic, including the expected
filing of an IND in mid-2015. As such, ALN-AAT is positioned to become
our seventh program in clinical development by the end of 2015,
consistent with the up-scaled “Alnylam 5x15” guidance that we provided
earlier this year.”
As previously presented at the 64th Annual Meeting of the
American Association for the Study of Liver Diseases (AASLD, “The Liver
Meeting”) in November 2013 and as updated at DDW, studies were performed
in transgenic mice overexpressing the human Z-AAT protein. Subcutaneous
administration of a GalNAc-siRNA conjugate targeting AAT (GalNAc-AAT)
resulted in rapid, potent, dose-dependent, and durable knockdown of
liver Z-AAT protein and improved liver histopathology as measured by
reduced number of Z-AAT liver globules. As measured in serum samples,
knockdown of human Z-AAT exceeded 95%. In addition, experiments were
performed in aged mice (25-46 weeks old) with advanced, established
liver disease; animals were treated with placebo or GalNAc-AAT
administered by subcutaneous injection every other week for 18 weeks.
GalNAc-AAT treatment resulted in significant (p < 0.05) improvement in
liver pathology and function as evidenced by decreased levels of Col1a2
(a marker of fibrosis), PTPRC (a marker of immune cell infiltration),
and BrdU incorporation (a measure of cell proliferation) relative
to PBS-treated animals. Further, GalNAc-AAT treatment resulted in a
significant reduction (p < 0.05) in the incidence of liver tumors
associated with Z-AAT overexpression (1/6, 16.7%) when compared to those
mice treated with PBS (4/6, 66.7%). Optimization of GalNAc-siRNA
conjugates led to the selection of the final DC for the ALN-AAT program.
The ALN-AAT DC employs Alnylam’s Enhanced Stabilization Chemistry (ESC)
GalNAc-conjugate technology, which enables subcutaneous dosing with
increased potency, durability, and a wide therapeutic index. In rodent
studies, ALN-AAT showed potent and dose-dependent knockdown of serum AAT
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. Finally, initial single-dose
non-human primate studies were performed showing dose-dependent
knockdown of serum AAT – a surrogate for AAT knockdown in the liver –
with an ED50 of less than 3 mg/kg; these results are expected
to support a multi-dose ED50 of less than 1 mg/kg, consistent
with other ESC-GalNAc-siRNA conjugates.
“AAT deficiency-associated liver disease is caused by the mutant ‘Z
allele' of the AAT gene, whose protein misfolds, accumulates in liver
cells, and causes cellular damage. People that are homozygous for the
mutant Z allele make up approximately 95% of patients with AAT
deficiency. These individuals have a lifetime risk of liver disease of
10% to 50%, which manifests as cholestatic disease, chronic hepatitis,
cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur
in 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 AAT-deficient patients
with liver disease,” said Jeffrey Teckman, M.D., Professor in the
Department of Pediatrics and Director of 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 could
become an important treatment option for the management of liver disease
in people with AAT deficiency.”
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
120,000 people who are PiZZ in the U.S. and major European countries,
and of these, about 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 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
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 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.
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 aminolevulinate 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 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 alpha-1 antitrypsin
deficiency-associated liver disease, its expectations with respect to
the filing of an IND application for ALN-AAT, its expectations regarding
the potential market opportunity for ALN-AAT, 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
Annual Report on Form 10-K 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.
Copyright Business Wire 2014