Alnylam Advances Development Candidate for ALN-AS1, a Subcutaneously Administered RNAi Therapeutic Targeting Aminolevulinate Synthase 1 (ALAS-1) for the Treatment of Hepatic Porphyrias
Oct 08, 2013
— New Pre-Clinical Results Presented at Oligonucleotide Therapeutics
Society (OTS) Meeting Demonstrate that ALN-AS1 Completely Blocks
Production of Toxic Heme Biosynthesis Intermediates that Cause Disease
Symptoms and Pathology —
— Additional Pre-Clinical Data Presented at OTS Highlight Continued
Advances with Clinically Validated GalNAc-Conjugate Platform for
Delivery of RNAi Therapeutics with Subcutaneous Dose Administration and
a Wide Therapeutic Index —
CAMBRIDGE, Mass.--(BUSINESS WIRE)--
Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it is advancing its Development Candidate
for ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1
(ALAS-1) for the treatment of hepatic porphyrias including acute
intermittent porphyria (AIP). The new pre-clinical research findings,
presented at the 9th Annual Meeting of the Oligonucleotide
Therapeutics Society being held October 6 — 8, 2013 in Naples, Italy,
show that subcutaneous administration of a GalNAc-siRNA targeting ALAS-1
leads to rapid, dose-dependent, and long-lasting knockdown of ALAS-1
mRNA and complete inhibition of the toxic intermediates that mediate the
symptoms and pathology of AIP. Based on these findings, including
results in non-human primate studies, the company has selected its
ALN-AS1 Development Candidate and expects to file an Investigational New
Drug (IND) application for this RNAi therapeutic in 2014. ALN-AS1 is
part of the company's "Alnylam 5x15" product development and
commercialization strategy, in which the company aims to advance five
genetic disease target programs into clinical development, including
programs in late stages, by the end of 2015. In addition, the company
presented new pre-clinical data with its proprietary, clinically
validated GalNAc-siRNA conjugate delivery platform for subcutaneous
delivery of RNAi therapeutics with a wide therapeutic index.
"We are very pleased to advance ALN-AS1 as a new Development Candidate
in our ‘Alnylam 5x15' pipeline, with the goal of filing an IND in 2014.
Our new pre-clinical data show that subcutaneous administration of
ALN-AS1 results in complete suppression of the toxic heme biosynthesis
intermediates that cause the symptoms and pathology of AIP," said Rachel
Meyers, Ph.D., Vice President of Research and RNAi Lead Development at
Alnylam. "ALN-AS1 now becomes our third RNAi therapeutic utilizing our
GalNAc-siRNA conjugate delivery platform to enter development stages,
extending our progress with ALN-TTRsc for the treatment of
transthyretin-mediated amyloidosis, where we intend to soon initiate a
Phase II trial, and ALN-AT3 for the treatment of hemophilia, where we
plan on filing our IND by the end of this year. With the recent clinical
validation of our GalNAc-siRNA conjugate delivery platform, we have
increased confidence that ALN-AS1 could become a transformative therapy
for patients with AIP, an ultra-rare genetic disease with enormous unmet
medical need. We very much look forward to filing our IND for this
program in 2014."
Hepatic porphyrias, including AIP, are ultra-rare orphan diseases caused
by loss-of-function mutations in enzymes involved in heme biosynthesis,
leading to accumulation of toxic heme intermediate precursors. In the
case of AIP, there are approximately 5,000 patients in the U.S. and
Europe that suffer acute, life-threatening porphyria attacks every year;
there are approximately 500 patients afflicted with recurrent
debilitating attacks, often occurring once per month. Treatment options
for AIP patients suffering from an attack are limited, and include the
use of heme preparations that show limited efficacy and are associated
with a number of complications. Currently, there are no drugs available
to prevent attacks from occurring. Alnylam's approach is to knock down
ALAS-1, an enzyme upstream of porphobilinogen deaminase (PBGD), the
defective gene in AIP. RNAi-mediated silencing of hepatocyte ALAS-1
could reduce the abnormal production of the toxic heme intermediates,
specifically aminolevulinic acid (ALA) and porphobilinogen (PBG), which
mediate the symptoms and disease pathology in AIP patients. Alnylam
believes that a subcutaneously administered RNAi therapeutic targeting
ALAS-1 has the potential to be used as a prophylactic approach to
prevent attacks and also as a therapy for acute attacks.
The new
research results presented at OTS support the selection of the
ALN-AS1 Development Candidate for further advancement toward clinical
trials. Specifically, multi-dose administration of a GalNAc-siRNA
targeting ALAS-1 led to rapid, dose-dependent, and long-lasting
knockdown of the ALAS-1 mRNA in non-human primates, with an ED50
of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1
administration at doses as low as 2.5 mg/kg resulted in a complete
blunting of phenobarbital-induced over-production of PBG and ALA, the
toxic heme intermediates in AIP. The company now plans to initiate
IND-enabling studies with the goal of filing an IND in 2014.
In addition, Alnylam scientists presented new
pre-clinical data on the pharmacokinetic and pharmacodynamic
properties of GalNAc-siRNA conjugates. Results showed that target gene
silencing is achieved at very low levels of liver tissue exposure.
Specifically, the tissue drug level associated with 50% target gene
silencing (EC50) was determined to be 0.1 micrograms of
GalNAc-siRNA per gram of liver tissue. This tissue level is about
1000-fold lower than other oligonucleotide platforms, where the EC50
for liver target gene knockdown is reported to be about 100 micrograms
per gram of tissue (Yu et al., Biochem Pharmacol
2009;77:910-919). In additional studies, the levels of GalNAc-siRNA
loaded into the RNA-Induced Silencing Complex (RISC) were quantified and
determined to be 0.001 microgram per gram of liver tissue, which
corresponds to about 500 to 1000 siRNA molecules per cell for
RNAi-mediated target gene knockdown. The ability of GalNAc-siRNA to
achieve target gene knockdown at low tissue exposure underscores the
potential for a wide therapeutic index for these RNAi therapeutics.
"This year's OTS meeting highlights continued progress for
oligonucleotide therapeutics, and Alnylam is pleased to be a part of
this overall endeavor. We are particularly excited to present our
advances with RNAi therapeutics that employ our GalNAc-siRNA conjugate
delivery platform for hepatocyte target gene silencing. Indeed, we
believe our recent clinical data serve to validate this approach and
also confirm a remarkable one-to-one correlation of target knockdown in
non-human primate studies as compared with human trials," said Muthiah
(Mano) Manoharan, Ph.D., Senior Vice President of Drug Discovery at
Alnylam. "New results presented at OTS highlight the applicability of
GalNAc-siRNA conjugates across a broad range of hepatocyte-expressed
target genes. Moreover, we have demonstrated that target gene knockdown
with GalNAc-siRNA is achieved at tissue drug levels of approximately 0.1
micrograms/gram, representing an approximately 1000-fold improvement in
potency as compared with other oligonucleotide therapeutic platforms. We
believe that these findings of target gene knockdown at very low tissue
exposure could significantly improve the therapeutic index for RNA
therapeutics, and underscore our belief that GalNAc-siRNA conjugates
represent a best-in-class strategy for systemic RNA therapeutics for
liver-expressed disease genes."
About ALN-AS1
Alnylam is developing ALN-AS1, an RNAi therapeutic targeting
aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria,
including acute intermittent porphyria (AIP). AIP is an ultra-rare
autosomal dominant disease caused by loss of function mutations in
porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis
pathway that can result in accumulation of toxic heme precursors.
Patients with AIP suffer from acute and/or recurrent life-threatening
attacks with severe abdominal pain, peripheral and autonomic neuropathy,
and neuropsychiatric manifestations. ALN-AS1 is a GalNAc-siRNA conjugate
targeting ALAS-1, a liver-expressed, rate-limiting enzyme upstream of
PBGD in the heme biosynthesis pathway. Inhibition of ALAS-1 is known to
reduce the accumulation of heme precursors that cause the clinical
manifestations of AIP. ALN-AS1 has the potential to be a therapy for the
treatment of acute porphyria attacks, as well as a prophylactic approach
for the prevention of recurrent attacks. The company has identified a
Development Candidate and intends to advance ALN-AS1 into the clinic in
2014. Alnylam intends to directly commercialize ALN-AS1 in North and
South America, Europe, and other parts of the world, and intends to seek
a partner for this program in Japan and other Asian territories.
About Acute Intermittent Porphyria
Acute intermittent porphyria (AIP) is an ultra-rare autosomal dominant
disease caused by loss-of-function mutations in porphobilinogen
deaminase (PBGD), an enzyme in the heme biosynthesis pathway. Exposure
of AIP patients to certain drugs, dieting, or hormonal changes can
trigger strong induction of aminolevulinate synthase-1 (ALAS-1), another
enzyme in the heme biosynthesis pathway, which can lead to accumulation
of heme intermediates upstream of PBGD that precipitate attack symptoms.
Patients with AIP can suffer acute and/or recurrent life-threatening
attacks with severe abdominal pain, peripheral and autonomic neuropathy,
and neuropsychiatric manifestations, and possible death if left
untreated. Approximately 5,000 patients in the U.S. and Europe suffer
acute porphyria attacks annually, and approximately 500 patients are
afflicted with recurrent debilitating attacks. Treatment options for AIP
patients suffering from an acute attack are limited; patients are
treated with intravenous heme analogues that have a slow onset and can
result in severe thrombophlebitis and iron overload. Currently there is
no approved prophylactic treatment available to prevent recurrent
attacks, which often occur monthly in women associated with menses.
There exists a significant need for therapies for AIP patients.
About 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. Research
findings demonstrate potent and durable target gene silencing, as well
as a wide therapeutic index, with subcutaneously administered
GalNAc-siRNAs from multiple "Alnylam 5x15" programs.
About RNA Interference (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 toward genetically defined targets for the
treatment of serious, life-threatening diseases with limited treatment
options for patients and their caregivers. These include: 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 familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an
RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi
therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the
treatment of porphyria including acute intermittent porphyria (AIP);
ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for
the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT,
an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the
treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi
therapeutic targeting complement component C5 for the treatment of
complement-mediated diseases, amongst other programs. As part of its
"Alnylam 5x15TM" strategy, the company expects to have five
RNAi therapeutic products for genetically defined diseases in clinical
development, including programs in advanced stages, on its own or with a
partner by the end of 2015. Alnylam has additional partnered programs in
clinical or development stages, including ALN-RSV01 for the treatment of
respiratory syncytial virus (RSV) infection and ALN-VSP for the
treatment of liver cancers. The company's leadership position on RNAi
therapeutics and intellectual property have enabled it to form major
alliances with leading companies including Merck, Medtronic, Novartis,
Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, Ascletis,
Monsanto, Genzyme, and The Medicines Company. In addition, Alnylam holds
an equity position in Regulus Therapeutics Inc., a company focused on
discovery, development, and commercialization of microRNA therapeutics.
Alnylam has also formed Alnylam Biotherapeutics, a division of the
company focused on the development of RNAi technologies for applications
in biologics manufacturing, including recombinant proteins and
monoclonal antibodies. Alnylam's VaxiRNA™ platform applies RNAi
technology to improve the manufacturing processes for vaccines;
GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and
collaborators have published their research on RNAi therapeutics in over
100 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™"
The "Alnylam 5x15" strategy, launched in January 2011, establishes a
path for development and commercialization of novel RNAi therapeutics
toward genetically defined targets for the treatment of diseases with
high unmet medical need. Products arising from this initiative share
several key characteristics including: a genetically defined target and
disease; the potential to have a major impact in a high unmet need
population; the ability to leverage the existing Alnylam RNAi delivery
platform; the opportunity to monitor an early biomarker in Phase I
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. By the end of 2015, the company expects to have five
such RNAi therapeutic programs in clinical development, including
programs in advanced stages, on its own or with a partner. The "Alnylam
5x15" programs include: 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
familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic
targeting antithrombin (AT) for the treatment of hemophilia and rare
bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting
aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria
including acute intermittent porphyria (AIP); ALN-PCS, an RNAi
therapeutic targeting PCSK9 for the treatment of hypercholesterolemia;
ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi
therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT
deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting
complement component C5 for the treatment of complement-mediated
diseases, amongst other programs. Alnylam intends to focus on developing
and commercializing certain programs from this product strategy itself
in North and South America, Europe, and other parts of the world; these
include ALN-TTR, ALN-AT3, ALN-AS1, and ALN-CC5, amongst other programs.
Alnylam Forward-Looking Statements
Various statements in this press release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's expectations regarding its "Alnylam 5x15" product strategy,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-AS1, ALN-TTRsc, and ALN-AT3, its expectations with respect
to the timing and success of clinical trials for ALN-TTRsc, its
expectations with respect to the timing of filing an IND for ALN-AS1 and
ALN-AT3, and its plans with respect to the commercial opportunity for
the ALN-AS1 program, 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, including ALN-AS1, 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 Quarterly
Report on Form 10-Q filed with the Securities and Exchange Commission
(SEC) on August 9, 2013 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.
Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice
President, Investor Relations and Corporate Communications
or
Spectrum
Amanda
Sellers (Media), 202-955-6222 x2597
Source: Alnylam Pharmaceuticals, Inc.
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