Alnylam Presents Key Pre-Clinical Proof-of-Concept Data for ALN-AS1, an RNAi Therapeutic Targeting Aminolevulinate Synthase-1 (ALAS-1) for the Treatment of Porphyria
May 17, 2013
— RNAi Therapeutics Targeting ALAS-1 Completely Block Production of
Toxic Heme Biosynthesis Intermediates that Cause Symptoms and Disease
Pathology —
CAMBRIDGE, Mass.--(BUSINESS WIRE)--
Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a
leading RNAi therapeutics company, announced today that it has presented
key pre-clinical proof-of-concept data from its RNAi therapeutic program
targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of
porphyria including acute intermittent porphyria (AIP). The new research
findings were presented at the International Congress of Porphyrins and
Porphyrias being held May 16 — 18, 2013 in Lucerne, Switzerland.
Specifically, Alnylam scientists and collaborators at the Icahn School
of Medicine at Mount Sinai in New York City presented data from
pre-clinical models of the human disease showing that RNAi therapeutics
targeting ALAS-1 can completely block the abnormal production of toxic
intermediates of the heme biosynthesis pathway that cause the symptoms
and disease pathology of AIP. Alnylam's AIP drug candidate, 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.
"Our pre-clinical data clearly show that RNAi therapeutics targeting
ALAS-1 can achieve potent, rapid, and durable suppression of the toxic
heme biosynthesis intermediates that cause the symptoms and disease
pathology of AIP. As such, these findings provide key, pre-clinical,
proof-of-concept data for our ALN-AS1 program, which we believe could
become a transformative therapy for patients with AIP, an ultra-rare
genetic disease with enormous unmet medical need," said Jared Gollob,
M.D., Vice President, Clinical Research at Alnylam. "We are now
extending these pre-clinical results to a GalNAc-siRNA conjugate
development candidate that enables subcutaneous dose administration, and
our current data with prototype molecules provide clear validation of
this strategy. With our ongoing efforts, we expect to finalize
selection of a GalNAc-siRNA development candidate for our ALN-AS1
program in late 2013, leading to an investigational new drug filing for
this program in 2014."
"AIP is an ultra-rare genetic disorder caused by an inherited deficiency
in porphobilinogen deaminase that can result in accumulation of toxic
intermediates in the heme biosynthesis pathway. Patients with AIP
present with acute and/or recurrent attacks including severe,
life-threatening abdominal pain, peripheral and autonomic neuropathy,
and neuropsychiatric manifestations," said Robert J. Desnick, M.D.,
Ph.D., Dean for Genetics and Genomic Medicine and Professor and Chair
Emeritus of the Department of Genetics and Genomic Sciences at the Icahn
School of Medicine at Mount Sinai in New York City. "There is clear need
for new therapies to treat acute attacks and prevent recurrent attacks,
and we are very encouraged by the potential of an RNAi approach for the
treatment of this debilitating, life-threatening disease."
"Our pre-clinical work with Alnylam has shown that RNAi-mediated
silencing of ALAS-1 results in essentially complete abrogation of the
toxic heme biosynthesis intermediates that cause the symptoms and
disease pathophysiology of AIP. In preliminary studies, we have also
shown that RNAi-mediated silencing of ALAS-1 is more effective than heme
administration in the treatment of an acute attack," said Makiko Yasuda,
M.D., Ph.D., Assistant Professor in the Department of Genetics and
Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New
York City. "RNAi has the potential to serve as a novel treatment for
AIP, and we look forward to continuing our close collaborative efforts
with Alnylam on the advancement of this program to the clinic."
There are approximately 5,000 patients in the U.S. and Europe that
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, 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 knockdown
ALAS-1, an enzyme upstream of porphobilinogen deaminase (PBGD), in
hepatocytes. 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 these patients. A subcutaneously
administered RNAi therapeutic targeting ALAS-1 could be used as a
prophylactic approach to prevent attacks and as a therapy for acute
attacks.
The new
research results support the advancement of RNAi therapeutics as a
promising strategy for the prevention and/or treatment of acute attacks
in patients with AIP. In the new studies, Alnylam scientists and
collaborators at Icahn School of Medicine at Mount Sinai presented
findings from a mouse model of AIP. Prophylactic administration of an
ALAS-1 specific siRNA completely protected the mice from
phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and the
resulting accumulation of the neurotoxic ALA and PBG heme biosynthesis
precursors. This protective effect was dose responsive and durable, with
a single dose administration resulting in a protective effect that
lasted for at least two weeks. Further, in a treatment model, a single
dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and
PBG that were elevated during a phenobarbital-induced acute attack.
Further, preliminary comparative studies show that ALAS-1 siRNA
administration was more effective than heme administration in the
treatment of an acute attack. Finally, the company presented results
from its ongoing GalNAc-siRNA conjugate efforts enabling subcutaneous
dose administration. In particular, a prototype GalNAc-siRNA targeting
ALAS-1 was shown to be effective in blocking ALA and PBG production in
both prophylactic and treatment models of AIP. The company is on track
to designate a GalNAc-siRNA development candidate, ALN-AS1, in late 2013
resulting in an investigational new drug (IND) filing in 2014.
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 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 is on track to
identify a final development candidate by late 2013 and 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 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 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; and ALN-AAT, an RNAi
therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT
deficiency liver disease, 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, and Cell. 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 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; and ALN-AAT, an RNAi therapeutic targeting
alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver
disease, 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, and ALN-AS1; the company will seek global
development and commercial alliances for other programs.
Alnylam Forward-Looking Statements
Various statements in this 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, its expectations with respect to the timing and
success of its clinical and pre-clinical trials, the expected timing of
regulatory filings, including its plan to file an IND application and
initiate clinical trials for ALN-AS1, its expectations regarding
reporting of data from its pre-clinical studies for ALN-AS1 studies, its
plans to seek a partner for its ALN-AS1 program and other "Alnylam 5x15"
programs, and its expectations regarding the potential market
opportunity for ALN-AS1, 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 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 current
report on Form 10-Q filed with the Securities and Exchange Commission
(SEC) on May 7, 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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