– New Non-Human Primate Data on ALN-PCSsc Show
Clamped Knockdown of PCSK9 up to 92% and LDL-C Reductions of up to
77% with Monthly Subcutaneous Dosing Regimen; Phase 1 Study
with ALN-PCSsc on Track to Start This Year with Initial Data
Expected in Mid-2015 –
– New Pre-Clinical Data Presented for ALN-AC3
Targeting Apolipoprotein C3, and ALN-ANG Targeting ANGPTL3,
Supports Advancement of Both Programs for the Treatment of Genetic
and Acquired Dyslipidemias –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today that it has presented new
pre-clinical data from its investigational RNAi therapeutic
programs toward genetically validated targets in development for
the treatment of cardiovascular metabolic diseases, including:
ALN-PCSsc targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-AC3 targeting apolipoprotein C3 (apoC3)
for the treatment of hypertriglyceridemia; and ALN-ANG targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia. These new
data are being presented at the American Heart Association (AHA)
Scientific Sessions 2014 in a poster presentation titled
“Development of Monthly to Quarterly Subcutaneous Administration of
RNAi Therapeutics Targeting the Metabolic Disease Genes PCSK9,
ApoC3 and ANGPTL3.” Among other data, Alnylam presented new
pre-clinical multi-dose data in non-human primates (NHPs) with over
six months of dosing for ALN-PCSsc showing robust and clamped
knockdown of PCSK9 of up to 92% and reductions in LDL-C of up to
77% with a once-monthly subcutaneous dosing regimen. Recently,
Alnylam filed and received approval for a Clinical Trial
Application (CTA) for ALN-PCSsc, and now expects to start the Phase
1 trial before year’s end with initial clinical data expected in
mid-2015.
“ALN-PCSsc is a first-in-class PCSK9 synthesis inhibitor that we
believe represents an innovative, differentiated, and
well-validated approach for the treatment of hypercholesterolemia.
Our new non-human primate studies confirm the potential for a
once-monthly, and possibly once-quarterly, low volume subcutaneous
dose regimen. Further, the mechanism of action for ALN-PCSsc
enables LDL-C lowering independent of baseline PCSK9 plasma levels,
which we believe could result in additive or even synergistic
activity in combination with statins. Together with our partners at
The Medicines Company, we look forward to the start of our Phase 1
clinical trial in the coming weeks, with initial data expected in
mid-2015,” said Rachel Meyers, Ph.D., Vice President, Research and
RNAi Lead Development at Alnylam. “We also presented new data at
AHA on our ALN-AC3 and ALN-ANG programs, which expand our pipeline
of investigational RNAi therapeutics toward genetically validated
targets for cardio-metabolic diseases. Indeed, we see this as an
attractive area for continued investment by Alnylam given the
significant disease burden and unmet need for new medicines, the
large number of liver-expressed disease-causing genes important in
cardio-metabolic disease, and the emerging tolerability, activity,
and durability profile of our GalNAc-conjugate platform.”
ALN-PCSsc is a subcutaneously administered RNAi therapeutic that
utilizes Alnylam’s proprietary Enhanced Stabilization Chemistry
(ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA
conjugates are designed to achieve targeted delivery of RNAi
therapeutics to hepatocytes through uptake by the
asialoglycoprotein receptor, and enable subcutaneous dosing with
increased potency and durability and a wide therapeutic index. The
new pre-clinical NHP studies showed that monthly subcutaneous
administration of ALN-PCSsc resulted in PCSK9 knockdown of up to
92% and LDL-C lowering, in the absence of statin co-administration,
of up to 77%; mean maximum knockdown of PCSK9 was 83.2% +/- 7.2%,
and mean maximum LDL-C reduction was 59.0% +/- 13.3%. As a PCSK9
synthesis inhibitor, ALN-PCSsc showed rapid, durable, and clamped
knockdown of PCSK9 and reduction of LDL-C, which contrasts with the
cyclical variation in LDL-C observed with monthly dose regimens of
anti-PCSK9 monoclonal antibodies (Stein, Curr Opin Lipidol 2013,
24:510-517). Based on current human translational data with
ESC-GalNAC-conjugates, the projected human dose levels are expected
to be less than 1 mg/kg at a subcutaneous injection volume of less
than 1 mL administered once-monthly. In aggregate, these
pre-clinical data are supportive of a once-monthly, and possibly
once-quarterly, dosing regimen for ALN-PCSsc, which the company
believes could represent a highly competitive target product
profile.
Alnylam’s CTA for a Phase 1 trial with ALN-PCSsc has been
approved and the company now expects to initiate this study before
the end of this year, with initial data expected to be reported in
mid-2015. The Phase 1 trial of ALN-PCSsc will be conducted as a
randomized, single-blind, placebo-controlled, single- and
multi-dose, dose-escalation study. The study is designed to enroll
up to 76 healthy volunteer subjects with elevated baseline LDL-C (≥
100 mg/dL), with subjects randomized 3:1, drug:placebo. The study
will be performed in two phases: a single ascending dose (SAD)
phase and a multiple dose (MD) phase. In the MD phase, subjects
will receive two doses of either ALN-PCSsc or placebo administered
four weeks apart. The MD phase will also include subjects both on
and off statin co-medication. The primary objective of the Phase 1
study is to evaluate the safety and tolerability of ALN-PCSsc.
Secondary objectives include assessment of clinical activity as
determined by knockdown of plasma PCSK9 levels and serum LDL-C
levels, as well as pharmacokinetics of ALN-PCSsc. In support of the
approved CTA, Alnylam has completed toxicology studies in rodents
and NHPs. In both species, the no observed adverse effect level
(NOAEL) was determined to exceed 250 mg/kg, the top dose in both
studies, with no adverse findings in clinical, hematology,
laboratory chemistry, and histopathology assessments. Alnylam is
collaborating with The Medicines Company on the advancement of
ALN-PCSsc.
Alnylam also presented data from its ALN-AC3 program at AHA.
ALN-AC3 is a subcutaneously administered investigational RNAi
therapeutic targeting apoC3 for the treatment of
hypertriglyceridemia. ApoC3 is a component of lipoprotein particles
in the blood; it inhibits lipoprotein lipase and hepatic lipase,
reducing hepatic uptake of triglyceride-rich particles.
Polymorphisms in apoC3 have been associated with
hypertriglyceridemia; specifically, a gain-of function phenotype
leads to higher apoC3 and triglyceride levels, and reduced
triglyceride clearance. In contrast, loss-of-function mutations in
apoC3 result in greater triglyceride hydrolysis into free fatty
acids and increased triglyceride clearance; heterozygous
individuals have lower triglycerides and lower levels of very low
density lipoprotein (VLDL). Recent studies have identified rare
loss of function variants in apoC3 that appear to be
cardioprotective (Tachmazidou et al., Nat. Comm, 2013; Bochem
et.al. Clin Genet., 2014). The new data presented were from studies
conducted in mouse models that match human genetics. Specifically,
a single 3 mg/kg dose of a GalNAc-conjugated siRNA targeting apoC3
resulted in knockdown of apoC3 levels of up to 94%, with more than
60% knockdown sustained for at least 30 days. In a multi-dose
study, results showed that dosing of 3 mg/kg every other week
resulted in 96% knockdown of human apoC3 through day 35, the last
time point in the study. Alnylam plans to continue to conduct
additional pre-clinical work in this program to finalize its
Development Candidate.
In addition to ALN-PCSsc and ALN-AC3, Alnylam is also advancing
ALN-ANG, an investigational RNAi therapeutic targeting ANGPTL3 for
the treatment of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia. ANGPTL3 is an inhibitor of cellular lipases
involved in the metabolism of lipoproteins. Human genetic as well
as exome sequencing studies have identified a statistically
significant relationship of loss-of-function mutations in ANGPTL3
with decreased levels of triglycerides and LDL-C (Musunuru et al.,
N. Engl. J. Med (2010) 363:2220-2227). New data presented at AHA
demonstrated that a single dose of a GalNAc-siRNA targeting ANGPTL3
led to robust, dose-dependent knockdown of serum ANGPTL3 protein of
up to 99%, with a single dose ED90 of approximately 1 mg/kg. In
studies performed in an “ob/ob” mouse model of obesity and mixed
hyperlipidemia, ALN-ANG treatment as a single 3 mg/kg dose resulted
in a greater than 80% reduction in levels of triglycerides and
LDL-C. In addition, total cholesterol was reduced up to 68%. These
data with ALN-ANG support further advancement of this program for
the treatment of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia, which are associated with increased risk of
coronary artery disease and/or recurrent pancreatitis. Alnylam is
conducting additional pre-clinical research to finalize its
Development Candidate for the ALN-ANG program.
About Hypercholesterolemia
Hypercholesterolemia is a condition characterized by very high
levels of cholesterol in the blood which is known to increase the
risk of coronary artery disease, the leading cause of death in the
U.S. Some forms of hypercholesterolemia can be treated through
dietary restrictions, lifestyle modifications (e.g., exercise and
smoking cessation) and medicines such as statins. However, a large
proportion of patients with hypercholesterolemia are not achieving
adequate LDL-C levels with currently available therapies including
statins, including genetic familial hypercholesterolemia (FH)
patients, acute coronary syndrome patients, high-risk patient
populations (e.g., patients with coronary artery disease,
diabetics, symptomatic carotid artery disease, etc.) and other
patients that are statin intolerant. Severe forms of
hypercholesterolemia are estimated to affect more than 500,000
patients worldwide, and as a result, there is a significant need
for novel therapeutics to treat patients with hypercholesterolemia
whose disease is inadequately managed by existing therapies.
About Mixed Hyperlipidemia and Hypertriglyceridemia
Mixed hyperlipidemia is a genetically inherited condition
characterized by very high levels of cholesterol and triglycerides
in the blood, both of which are known to increase the risk of
coronary artery disease, the leading cause of death in the U.S. It
is estimated that as many as 1 out of every 100 individuals have
mixed hyperlipidemia and are at increased risk of developing
cardiovascular disease. Some forms of mixed hyperlipidemia can be
treated through dietary restrictions, lifestyle modifications
(e.g., exercise and smoking cessation), and medicines such as
statins or fibrates; however, a large portion of mixed
hyperlipidemia patients are unable to reach either their LDL-C
and/or triglyceride goals with the current standard of care.
Patients with severe, inherited forms of hypertriglyceridemia
(e.g., familial chylomicronemia syndrome, or “FCS”) are at
extremely high risk of developing recurrent pancreatitis. FCS is a
rare orphan genetic disease that affects 1 to 2 individuals per
million.
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 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) targeting transthyretin (TTR) for the
treatment of TTR-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc)
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 targeting
antithrombin (AT) for the treatment of hemophilia and rare bleeding
disorders (RBD); ALN-CC5 targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1 targeting
aminolevulinic acid synthase-1 (ALAS-1) for the treatment of
hepatic porphyrias including acute intermittent porphyria (AIP);
ALN-PCSsc targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT)
for the treatment of AAT deficiency-associated liver disease;
ALN-HBV targeting the hepatitis B virus (HBV) genome for the
treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the
treatment of beta-thalassemia and iron-overload disorders; ALN-ANG
targeting angiopoietin-like 3 (ANGPTL3) for the treatment of
genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3)
for the treatment of hypertriglyceridemia; ALN-AGT targeting
angiotensinogen (AGT) for the treatment of hypertensive disorders
of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting
glycolate oxidase (GO) for the treatment of primary hyperoxaluria
type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV)
genome for the treatment of HDV infection; ALN-PDL targeting
programmed death ligand 1 (PD-L1) for the treatment of chronic
liver infections; 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 revusiran 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-PCSsc for the treatment of
hypercholesterolemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3)
for the treatment of hypertriglyceridemia; and ALN-ANG for the
treatment of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia; including the timing of beginning clinical
studies and reporting data, the potential therapeutic opportunities
for ALN-PCSsc, ALN-AC3, and ALN-ANG, as well as its expectations
regarding its “Alnylam 5x15” product strategy, and its plans
regarding commercialization of RNAi therapeutics, including
ALN-PCSsc, ALN-AC3 and ALN-ANG, 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.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations and Corporate
CommunicationsorSpectrumLiz Bryan (Media), 202-955-6222 x2526
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