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
Copyright Business Wire 2014