– Additional Phase 1 Clinical Results with
ALN-TTRsc and Results from Pre-Clinical Chronic Toxicology Studies
Confirm Clinical Activity and Wide Therapeutic Index –
– ALN-GO1, an RNAi Therapeutic Targeting
Glycolate Oxidase (GO) in Development for the Treatment of Primary
Hyperoxaluria Type 1 (PH1), Advanced as New Program –
– New Pre-Clinical Research Demonstrates
Potential for Needle-Less Administration of RNAi Therapeutics with
Inhalation for Knockdown of Liver Targets –
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi
therapeutics company, announced today that it presented new data
from multiple clinical and pre-clinical studies at the 10th Annual
Meeting of the Oligonucleotide Therapeutics Society (OTS), held
October 12 – 15, 2014 in San Diego. Among multiple presentations,
the company presented additional data from its Phase 1 trial with
ALN-TTRsc, an investigational RNAi therapeutic targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis
(ATTR) in patients with TTR cardiac amyloidosis, showing rapid,
dose-dependent, stable, and durable knockdown of serum TTR of up to
96.2%. In addition, Alnylam scientists presented pre-clinical data
from a new program, ALN-GO1, an investigational RNAi therapeutic
targeting glycolate oxidase (GO) in development for the treatment
of primary hyperoxaluria type 1 (PH1), showing efficacy in rodent
disease models. Finally, new pre-clinical research was presented
demonstrating that delivery of Enhanced Stabilization Chemistry
(ESC)-GalNAc-siRNA conjugates to the lung achieves similar plasma
exposure, efficacy, and duration of liver gene silencing as
achieved by subcutaneous delivery. This finding opens up the
possibility for needle-less administration of RNAi therapeutics via
inhalation for knockdown of liver disease genes.
“Our Phase 1 study of ALN-TTRsc was the first to demonstrate
clinical activity and tolerability for RNAi therapeutics using our
proprietary GalNAc-conjugate delivery platform that enables
subcutaneous administration with a wide therapeutic index. These
new data extend our previous presentation by including results from
a 7.5 mg/kg cohort where we observe a mean max TTR knockdown of
87.9%. In addition, we have now completed our chronic toxicology
studies with ALN-TTRsc, including 6-month rat and 9-month non-human
primate studies, which confirmed the wide safety margin established
in previous, shorter duration studies. Importantly, we believe
these new toxicology results provide additional de-risking for our
broader GalNAc-conjugate platform, where we continue to see
favorable tolerability results in pre-clinical and clinical studies
across an increasing number of programs,” said Akshay Vaishnaw,
M.D., Ph.D., Executive Vice President and Chief Medical Officer of
Alnylam. “We are currently conducting a Phase 2 trial of ALN-TTRsc
in ATTR patients with TTR cardiac amyloidosis, and we look forward
to sharing initial data at a meeting to be held during the American
Heart Association meeting on November 15. We remain on track to
initiate an open-label extension (OLE) study with ALN-TTRsc in the
coming weeks, and expect to begin enrolling patients in our Phase 3
trial in TTR cardiac amyloidosis by the end of this year.”
Updated data were presented from the Phase 1 trial of ALN-TTRsc
performed in healthy volunteers. Initial results were presented at
the Heart Failure Society of America 17th Annual Scientific Meeting
in September 2013, and showed robust, consistent, and statistically
significant (p < 0.01) knockdown of serum TTR protein levels of
up to 94%. The new results include TTR knockdown data for an
additional cohort (N=6) receiving doses of 7.5 mg/kg, showing a
mean max TTR knockdown of 87.9% and a maximum TTR knockdown of
96.2%. As described before, ALN-TTRsc was generally well tolerated
with mild or moderate injection site reactions as the most frequent
adverse event, consistent with results from previous cohorts. In
addition to the updated clinical data, results from new
pre-clinical toxicology data with ALN-TTRsc were presented. Data
from 6-month toxicology studies in rats and 9-month toxicology
studies in non-human primates (NHPs) showed that chronic dosing
with ALN-TTRsc was generally well tolerated. In the 6-month rat
study, the No Observed Adverse Effect Level (NOAEL) for ALN-TTRsc
was determined to be 30 mg/kg, with adverse findings observed at
the 100 mg/kg dose including hepatocyte vacuolation with associated
minor increases in liver transaminases (less than or equal to 1.6
times control animals); all were reversed after a three-month
non-dosing recovery period. The NOAEL in the rat 6-month study was
unchanged from that determined in a previously conducted 6-week
study, showing the absence of any cumulative toxicologic effects.
In the 9-month NHP study, all doses – including the top dose of 200
mg/kg – were generally well tolerated with no meaningful changes in
any hematology and laboratory parameters. The NOAEL will be
determined upon completion of histopathology, but is expected to be
greater than or equal to 200 mg/kg. The completion of these
toxicology studies enables the advancement of ALN-TTRsc into a
Phase 3 clinical trial, which is expected to begin by the end of
this year, and supports the potential filing of the drug
candidate’s New Drug Application (NDA). ALN-TTRsc is currently
being evaluated in an open-label, multi-dose pilot Phase 2 clinical
trial in ATTR patients with TTR cardiac amyloidosis. Alnylam
expects to present initial results from the Phase 2 study at a
meeting to be held during the American Heart Association meeting in
November.
“We are pleased to share a number of new advances from our
research efforts. First, we are announcing a new program, ALN-GO1,
for the treatment of primary hyperoxaluria type 1 (PH1), an
ultra-orphan disease where a defect in glyoxylate metabolism in the
liver results in oxalate deposition in the kidney and leads to
end-stage renal disease. Pre-clinical data in rodent models of PH1
show that ALN-GO1, an ESC-GalNAc conjugate siRNA targeting
glycolate oxidase (GO), achieves robust knockdown of liver GO and
substantial reduction in urinary oxalate levels. We plan to
identify an ALN-GO1 Development Candidate in mid-2015 and expect to
file an investigational new drug application in 2016,” said Rachel
Meyers, Ph.D., Vice President of Research and RNAi Lead Development
at Alnylam. “We are also excited about our work demonstrating the
potential for inhalational delivery of GalNAc-siRNA conjugates.
Specifically, our new pre-clinical results show that delivery of
GalNAc-siRNA conjugates to the lung achieves a comparable level and
duration of hepatic target gene knockdown to that observed with
subcutaneous injection. We believe that this could allow for the
potential development of RNAi therapeutics that employ a
needle-less, non-invasive dosing paradigm.”
Alnylam scientists and collaborators presented pre-clinical data
from the new program, ALN-GO1, in development for the treatment of
PH1. PH1 is an autosomal recessive disorder of glyoxylate
metabolism, where hepatic detoxification of glyoxylate is impaired
due to mutation of the AGXT gene, which encodes the liver
peroxisomal alanine-glyoxylate aminotransferase (AGT) enzyme,
resulting in excessive oxylate production. Excess oxalate in PH1
patients is unable to be fully excreted by the kidneys leading to
the formation of recurrent kidney stones and the deposition of
calcium oxalate crystals in the kidneys and urinary tract. Renal
damage is caused by a combination of tubular toxicity from oxalate,
nephrocalcinosis, and renal obstruction by stones. Compromised
kidney function exacerbates the disease as oxalate is released into
systemic circulation where it may accumulate and crystalize in
bones, eyes, skin, heart, and central nervous system, leading to
severe illness and death. About 50% of patients will have kidney
failure by age 15, and about 80% will have end stage renal disease
by age 301. The prevalence of PH1 reported in Europe ranges from 1
to 9 per million. Higher values are reported in specific
populations with a high rate of consanguinity. Many patients are
diagnosed under the age of 10 years2. Current treatment options are
very limited and although combined organ transplantation of liver
and kidneys has been successful, this is risky and limited due to
organ availability. The enzyme glycolate oxidase (GO) works
upstream of AGT to oxidize glycolate to glyoxylate. Human genetics
show that a loss of function mutation in the production of GO
results in a 20-fold increase in the amount of glycolate in urine,
but no other clinical symptoms, suggesting that knockdown of GO may
starve the disrupted pathway of glyoxylate and thereby reduce the
oxalate burden in patients with PH1. A panel of ESC-GalNAc-siRNA
conjugates targeting GO were screened in vitro for their ability to
silence the GO mRNA. The most potent of these were further
evaluated in vivo with subcutaneous dosing, and an ESC-GalNAc-siRNA
targeting GO was identified that yielded a single-dose ED50 of 1.25
mg/kg and a multi-dose ED50 of 0.3 mg/kg. In addition, this
compound demonstrated therapeutic efficacy in rodent models of PH1,
as indicated by a significant decrease in levels of urinary oxalate
of up to 79%. As noted above, Alnylam plans to select a Development
Candidate for ALN-GO1 by mid-2015 and to file an investigational
new drug (IND) application in 2016.
Finally, Alnylam scientists presented new pre-clinical data
demonstrating the potential for needle-less administration of
ESC-GalNAc-siRNA conjugates via inhalation to achieve knockdown of
liver gene targets. In mouse studies, ESC-GalNAc-siRNA conjugates
targeting the TTR and Factor VII (FVII) mRNAs were shown to achieve
comparable knockdown activity in mouse liver when delivered through
use of a Microsprayer® device as compared to subcutaneous
injection. In addition, the duration of liver gene knockdown and
pharmacokinetics for systemic exposure were found to be similar for
GalNAc-siRNA administered to the lung as compared with results
obtained from subcutaneous dosing. These data provide proof of
concept for inhalation as a needle-less, non-invasive approach for
administration of RNAi therapeutics targeting liver disease
genes.
About ATTR
Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited,
progressively debilitating, and often fatal disease caused by
mutations in the TTR gene. TTR protein is produced primarily in the
liver and is normally a carrier of vitamin A. Mutations in TTR
cause abnormal amyloid proteins to accumulate and damage body
organs and tissue, such as the peripheral nerves and heart,
resulting in intractable peripheral sensory neuropathy, autonomic
neuropathy, and/or cardiomyopathy. ATTR represents a major unmet
medical need with significant morbidity and mortality; familial
amyloidotic polyneuropathy (FAP) affects approximately 10,000
people worldwide and familial amyloidotic cardiomyopathy (FAC) is
estimated to affect at least 40,000 people worldwide. FAP patients
have a life expectancy of 5 to 15 years from symptom onset, and the
only approved treatment options for early stage disease are liver
transplantation, and tafamidis (approved in Europe). FAC is fatal
within 2.5 to 5 years of diagnosis and treatment is currently
limited to supportive care. Senile systemic amyloidosis (SSA) is a
non-hereditary form of TTR cardiac amyloidosis caused by idiopathic
deposition of wild-type TTR; its prevalence is generally unknown,
but is associated with advanced age. There is a significant need
for novel therapeutics to treat patients with TTR amyloid
polyneuropathy and/or cardiomyopathy.
About Primary Hyperoxaluria Type 1 and ALN-GO1
Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive
disorder of glyoxylate metabolism. When this metabolic pathway is
impaired in PH1, a loss of function in the enzyme that metabolizes
glyoxylate into glycine and pyruvate in the liver results in its
conversion to oxylate instead. The enzyme glycolate oxidase (GO)
works upstream of this defect to oxidize glycolate to glyoxylate.
Human genetics shows that a loss of function mutation in the
production of GO results in a 20-fold increase in the amount of
glycolate in the urine, but no other clinical symptoms, suggesting
that knockdown of GO may starve the disrupted pathway of glyoxylate
and thereby reduce the oxalate burden in patients with PH1. Excess
oxalate in PH1 patients can cause severe kidney damage through
recurrent painful kidney stones and the formation and deposition of
calcium oxalate crystals in the kidneys and urinary tract.
Compromised kidney function exacerbates the disease as oxalate is
released into systemic circulation where it may accumulate and
crystalize in bones, eyes, skin, heart, and central nervous system,
leading to severe illness and death. Most patients present early in
life, and greater than 50% of patients progress to end stage renal
disease (ESRD) before the age 30. ALN-GO1 is a subcutaneously
administered RNAi therapeutic that silences GO. ALN-GO1 utilizes
Alnylam's ESC-GalNAc conjugate technology, which enables
subcutaneous dosing with increased potency and durability and a
wide therapeutic index.
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
5x15™” 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 aminolevulinic acid 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-associated liver disease; ALN-HBV, an RNAi therapeutic
targeting the hepatitis B virus (HBV) genome for the treatment of
HBV infection; 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; ALN-AGT, an RNAi therapeutic
targeting angiotensinogen (AGT) for the treatment of hypertensive
disorders of pregnancy (HDP), including preeclampsia; ALN-GO1, an
RNAi therapeutic targeting glycolate oxidase (GO) for the treatment
of Primary Hyperoxaluria Type 1 (PH1); 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, and The Medicines Company. In
early 2014, Alnylam and Genzyme, a Sanofi company, formed a
multi-product geographic alliance on Alnylam's genetic medicine
programs in the rare disease field. 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. 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, 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.
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-TTRsc for the treatment of
transthyretin (TTR)-mediated amyloidosis (ATTR) and ALN-GO1 for the
treatment of Primary Hyperoxaluria Type 1 (PH1), the timing of
regulatory filings for ALN-TTRsc and ALN-GO1, the timing of
clinical studies, including the reporting of data from clinical
studies, the potential therapeutic opportunities for ALN-GO1, the
potential for needle-less administration of RNAi therapeutics, as
well as its expectations regarding its “Alnylam 5x15” product
strategy, and its plans regarding commercialization of RNAi
therapeutics, including ALN-TTRsc and ALN-GO1, 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 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.
1 Oxaloxis & Hyperoxaluria Foundation
2 Mayo Clinic Hyperoxaluria Center Registry
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations and Corporate
CommunicationsorMedia:SpectrumLiz Bryan, 202-955-6222 ext. 2526
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